Immuno

STEM MODULE: IMMUNOLOGY / TRANSPLANTATION
TABLE OF CONTENTS
GOALS AND OBJECTIVES................................................................................................................. 3
SECTION 1: IMMUNOLOGY
TOPIC 1: NON-SPECIFIC DEFENCE MECHANISMS ...................................................................... 5
1.1. Non-Specific Defence Mechanisms ......................................................................... 5
1.2. Natural Immunity....................................................................................................... 6
1.2.1. Structural, chemical and microbiological features of body surfaces that
facilitate resistance to infection.................................................................... 6
1.2.2. Phagocytosis and the inflammatory reaction............................................... 6
1.2.3. The Complement System ............................................................................ 7
1.2.4. Acute Phase Proteins ................................................................................ 10
1.2.5. Natural Killer (NK) Cells ............................................................................. 10
1.3. The Major Histocompatibility Complex (MHC) ....................................................... 11
TOPIC 2: THE CELLS OF THE IMMUNE SYSTEM ........................................................................ 15

2.1. Lymphocyte Subsets .............................................................................................. 16
2.2. Functions of the Cells of the Immune System........................................................ 16
2.3. Cell Surface Markers .............................................................................................. 17
TOPIC 3: ANTIBODIES AND CYTOKINES..................................................................................... 19

3.1. Antibodies ............................................................................................................... 19
3.2. Cytokines ................................................................................................................ 22
TOPIC 4: ACTIVATION AND CONTROL OF THE NORMAL IMMUNE RESPONSE ................... 23

4.1. Superantigens......................................................................................................... 23
4.2. Polyclonal Activators............................................................................................... 24
4.3. First and Second Encounters with Antigen ............................................................ 25
4.4. Regulation of Immune Responses ......................................................................... 26
TOPIC 5: IMMUNITY TO INFECTION.............................................................................................. 27

5.1. Viruses .................................................................................................................... 27
5.2. Bacteria................................................................................................................... 28
5.3. Fungi ....................................................................................................................... 28
5.4. Protozoa and Worms.............................................................................................. 29
TOPIC 6: ABNORMAL IMMUNE RESPONSES.............................................................................. 30

6.1. Hypersensitivity....................................................................................................... 30
6.1.1. TYPE I (Anaphylactic) Hypersensitivity ..................................................... 30
6.1.2. TYPE II Hypersensitivity ............................................................................ 32
6.1.3. TYPE III Hypersensitivity Immune Complex Disease................................ 32
6.1.4. TYPE IV Hypersensitivity (Delayed Type Hypersensitivity - DTH) ............ 34
6.2. Auto-Immunity......................................................................................................... 35
6.3. The Immunodeficiencies......................................................................................... 35
ã Royal Australasian College of Surgeons – June 2000 Page 1 of 80

TOPIC 7: TRANSPLANTATION IMMUNOLOGY ............................................................................ 39

7.1. Large numbers of lymphocytes are reactive against alloantigens. Why? ............. 39
7.2. Graft versus Host Reactions (GvHR) ..................................................................... 40
7.3. Donor-Host Matching: Minor Histocompatibility Antigens ...................................... 40
7.4. Tissue Typing Terminology..................................................................................... 40
TOPIC 8: DIAGNOSTIC TESTING IN IMMUNOLOGY.................................................................... 41
SECTION 2: CLINICAL TRANSPLANTATION

TOPIC 9: ORGAN DONORS, ORGAN DONOR PROCUREMENT AND
ORGAN PRESERVATION ............................................................................................... 50
9.1. Living Donors.......................................................................................................... 52
9.2 Brain-Dead Organ Donors...................................................................................... 50
9.3. Ethical Issues.......................................................................................................... 53
9.4. Organ Preservation................................................................................................. 53
9.5. Donor Care and Organ Retrieval............................................................................ 54
TOPIC 10: THE RECIPIENT............................................................................................................... 66

10.1. Indications and Contraindications for Transplantation ........................................... 67
10.2. The Complications of Whole Organ Transplantation.............................................. 68
10.3. Ethics in Transplantation ........................................................................................ 70
10.4. Outcome For Transplant Patients........................................................................... 71
TOPIC SUB-HEADINGS INCLUDE:
SELF-TEST TASKS
KEY ISSUES
CASE SCENARIOS
MULTIPLE CHOICE QUESTIONS
REFERENCES
ETHICS
OUTCOMES

GOALS AND OBJECTIVES
SECTION 1 - BASIC IMMUNOLOGY

Authors: Barbara Heslop, Margaret Baird
Basic immunology in this module is presented in eight topics, which correspond to specific objectives
3.1 - 3.8 of the syllabus for Part 1 FRACS. Each of these topics identifies the salient points of the subject
matter under discussion, or refers the reader to the relevant pages of specified textbooks, editions as current
in 2000. The syllabus for Part 1 FRACS specifies selected topics from two textbooks: Chapters 1-5,
8-10,13,14,17,18 from Essential Immunology by Roitt (9th edition) and Chapter 7 (Diseases of Immunity)
from Robbins’ Pathological Basis of Disease (6th edition) by Cottran, Kumar and Collins). Some sections in
the following module make reference to the British multi-author textbook: Immunology, by Roitt, Brostoff and
Male, as an alternative to Essential Immunology. Those candidates who are pressed for time and who
prefer a less discursive (although less entertaining) presentation than is offered in Essential Immunology,
may prefer this alternative. Both immunology texts cover essentially the same material. Additional reading
over and above these textbooks relates to transplantation surgery, discussed in the second part of the
module.
The module content in this section comprises an abbreviated summary of the immunology content of the
Dunedin Basic Medical Sciences Course. The Royal Australasian College of Surgeons gratefully
acknowledges permission to reproduce the material, copyright of which is held conjointly by the Dunedin
Basic Medical Sciences Course Trust and by the College.
SECTION 2 - CLINICAL TRANSPLANTATION

Author: A K House
The overall goal in transplantation is to provide an individual with a failed tissue or organ with a replacement
tissue or organ that will save life or improve the individual’s quality of life. To be most optimally eligible for
transplantation, there should be no other comorbid factors influencing the health status of the individual.
To achieve this broad goal, understanding is required of:
· The principles relating to organ and tissue donation
· Tissues and organs that can be transplanted
· The factors that limit the outcome for graft and patient survival.

Organ and tissue transplantation has become one of the more successful clinically driven patient
management modalities. The success of this treatment is attributable to:
· Understanding the immunological process related to rejection.
· The development of agents to control rejection.
· Understanding the most effective ways to manage donor organs, including the mechanisms of ischaemic
injury and their control.
· On the recipient side there has been better appreciation of the individual disease processes, the nature
of their progression and the impact of these diseases on tissue and graft survival.
· Other factors that have impacted on transplantation have been the development of legislation to define
‘brain death’ and an appreciation of the ethical factors relating to organ donation and recipient
management.
After concluding this module it is expected that candidates will have acquired an understanding of the basic
science aspects of immunologic processes and their clinical applications, including principles of clinical
organ and tissue transplantation.

SECTION 1: IMMUNOLOGY
TOPIC 1: NON-SPECIFIC DEFENCE MECHANISMS

(NATURAL AND ACQUIRED IMMUNITY TO INFECTION,
THE COMPLEMENT SYSTEM,
THE MAJOR HISTOCOMPATIBILITY COMPLEX)
1.1. Non-Specific Defence Mechanisms
Over the course of vertebrate evolution the body has developed a range of defences against infection.
The general term immunity to infection encompasses all of these. It is conventional to distinguish two
separate categories:
A. Natural immunity refers to all those mechanisms by which the body resists infection, but which do
not involve specificity and memory.
KEY ISSUE
Natural immunity includes:
· The physical and chemical features of body surfaces which contribute to resisting infection
· Phagocytosis and the inflammatory reaction
· Complement
· The acute phase proteins
· Natural killer (NK) cells
B. Acquired immunity, or adaptive immunity, is concerned with those responses that are
characterised by:
· Specificity
· Memory
KEY ISSUE
The effector cells of adaptive immunity are lymphocytes, whose receptors - between them - are
capable of distinguishing an enormous range of different antigenic molecules. These cells also
manifest immunological memory following experience with antigen. This ensures that they
perform better on a second or subsequent encounter with the relevant organism or its antigenic
products.

KEY ISSUE
The relative importance of the different resistance systems is illustrated by the infections that
occur when one or other of these defence systems is impaired or absent.
1.2. Natural Immunity
1.2.1. Structural, chemical and microbiological features of body surfaces that facilitate
resistance to infection
The different ways in which organisms are prevented from gaining entry to the tissues are
clearly discussed in standard textbooks. Their importance is illustrated by a wide range of
examples, such as:
· The infections that complicate extensive skin loss in burns.
· The respiratory infections that follow damage to the bronchial epithelium in heavy smokers.
· Vulvovaginitis that occurs when vaginal acid production is impaired.
1.2.2. Phagocytosis and the inflammatory reaction
Phagocytosis is a central feature of both natural immunity (in relation to inflammation, in which
microorganisms are ingested and destroyed) and acquired immunity (in relation to antigen
presentation). The efficacy of phagocytosis is greatly enhanced by acquired immunity in the
following ways:
a) Macrophages are activated by cytokines.

b) Macrophages have receptors for the heavy chain of IgG antibodies, thereby facilitating the
adhesion of organisms (with IgG antibodies attached) to the cell.
c) Macrophages have receptors for complement. These facilitate the attachment to the cell of
IgM (early) and IgG (late) antibodies. IgM fixes complement efficiently, but unlike IgG finds
no Fc receptors (ie receptors for its heavy chain) on the phagocytic cell.
KEY ISSUE
An opsonin is any substance that facilitates the adherence of organisms to phagocytes. Thus,
opsonins are often antibodies; but they can also be other substances, such as complement, or
acute phase proteins (eg C reactive protein, mannose-binding protein) which adhere to
microorganisms and activate complement.

1.2.3. The Complement System
KEY ISSUE
Complement consists of a series of twenty proteins which are activated in sequence to
produce a cascade reaction: ie the product of one reaction catalyses the next one in the
sequence. The central component of the complement system is C3. Complement
activation by any means involves the production of a C3 convertase which cleaves C3
into fragments C3a and C3b.
Cleavage of C3 is triggered in three ways:

a) Spontaneous cleavage occurs at a low rate all the time. The resultant C3b fragment reacts
with other complement components Factors B and D to produce a C3 convertase (C3bBb).
Regulatory mechanisms usually inhibit this convertase, thus preventing large scale
spontaneous triggering of the complement cascade.
b) Some microorganisms can react directly with the C3bBb convertase, which is stabilised by
properdin. This pathway of complement activation is referred to as the alternative pathway
or the properdin system. Some of the circumstances in which this pathway can be
triggered are listed below.
c) Complexes of antigen plus IgG, or antigen plus IgM, trigger complement activation by the
classical pathway. The g and m immunoglobulin heavy chains of IgG and IgM respectively
have receptors for C1 (the first component of the classical complement cascade).
Combination of either of these immunoglobulins with antigen triggers the complement
cascade sequence in the order 1,4,2 to produce a C3 convertase C4b2b.
NOTE that in the examples listed above, b) indicates a proteolytic fragment produced from the
relevant precursor.
Activation of the classical pathway:
A. Mainly by the combination of IgG (all subclasses except IgG4) or IgM with antigen.
B. Occasionally by:
· Aggregated immunoglobulins
· C-reactive protein
· Polyanions and cations (eg heparin, protamine)

· Staphylococcal protein A
· Some proteolytic enzymes
· Some RNA viruses
Activation of the alternative pathway:

· Aggregated immunoglobulins
· Lipopolysaccharide (endotoxin) of Gram negative bacteria
· Plant and animal polysaccharides
· Some proteolytic enzymes
· Radiographic contrast media
· C3 nephritic factor (an antibody to an enzyme activating C3)
KEY ISSUE
Note that the classical pathway of complement activation is usually activated by
immunological means (antigen-antibody combination), whereas the alternative pathway
is usually activated by non-immunological means. The alternative pathway preceded the
appearance of the adaptive immune system in evolution, so its activation by non-
immunological means is only to be expected.
Complement component activation sequence

The component proteins of the classical pathway are activated in the sequence C1, C4, C2, C3,
C5, C6, C7, C8, C9 ie almost in numerical order. In this pathway, amplification occurs with each
reaction up to C3. Thus, one molecule of C1 activates several molecules of C4. Each molecule
of C4 activates several molecules of C2, and so on. Full amplification is reached at C3. The
alternative pathway uses a different C3 convertase (see above), without C1, C4 or C2.
Various regulatory mechanisms exist to prevent runaway activation of the complement

cascade. Details are beyond the requirements of this examination.
Results of complement fixation (activation)
The effects of complement activation are mediated by fragments produced during proteolytic
cleavage. Their most important effects include:
a) Enhancement of phagocytosis and inflammation: Immune adherence facilitates

phagocytosis. Thus, C3b (attached to antibody together with microorganisms) adheres to
complement receptors on phagocytes, thus delivering the organisms to the cells that can

destroy them. Polymorphs and macrophages have receptors for C3b. C3a and C5a are both
anaphylotoxins, provoking mediator release from mast cells and basophils. They also
stimulate the respiratory burst in phagocytes. C5a can stimulate vasodilatation and
increased vascular permeability directly, and is strongly chemotactic for neutrophils. It thus
plays a major part in acute inflammation.
b) Membrane damage in some situations: Full activation of the complement cascade up to C9

generates the membrane attack complex, which results in the formation of a
transmembrane channel in the cell wall. The ensuing water influx commonly leads to cell
lysis. Organisms susceptible to the membrane attack complex are usually Gram negative
bacilli. The effects of the membrane attack complex can also be seen in the red cell lysis of
ABO incompatible blood transfusions and acquired (antibody mediated) haemolytic anaemia.
c) Disposal of immune complexes: Complement plays an important part in the solubilisation

and normal disposal of these.
Complement Receptors
A number of fragments of C3 produced during activation of complement binds to receptors on a
variety of cells. There are four different complement receptors (CR1, CR2, CR3, CR4). Binding
of complement fragments to these receptors has several effects including:
a) uptake of particles opsonised by complement (eg IgM antibodies plus bacteria)

b) the cell expressing the receptor may be activated (eg B cells in some circumstances)
c) the receptor may pick up immune complexes and transport them to fixed macrophages in
the liver and spleen (eg red cells with surface CR1 transport immune complexes to the fixed
phagocytes in those organs).
Some of these receptors are referred to again in Topic 2 (see Cell Surface Markers).
Complement activation (via the alternative pathway) by endotoxin and anaesthetic agents
may account for endotoxic shock and for some anaphylaxis-like untoward reactions to
anaesthetics and other drugs.

1.2.4. Acute Phase Proteins
KEY ISSUE
The acute phase proteins comprise a group of plasma proteins which undergo a dramatic
increase in response to macrophage-derived interleukin-1 (IL-1) and other cytokines secreted
in response to tissue injury or infection. The group includes some highly conserved mediators
of the non-specific ‘alarm’ response to tissue damage.
The acute phase proteins are listed in Roitt, Essential Immunology; page 17, Table 1.1. It
should be noted that the most dramatic increases involve proteins such as C-reactive protein
and mannose binding protein, both of which can bind to some microorganisms, and can also
activate complement by the classical pathway, thereby acting as opsonins and facilitating
phagocytosis. The serum amyloid P component (SAP) is also noted, as indirectly it achieves a
similar end.
1.2.5. Natural Killer (NK) Cells
These cells account for about 5-15% of the circulating blood lymphocytes, where they are
morphologically identifiable as the large granular lymphocytes. NK cells originate from a stem
cell in the bone marrow, and do not depend on the thymus for their maturation. They are able to
kill virus-infected cells and some neoplastic cells by direct contact. This entails inserting perforin
into the target cell membrane, thereby creating a channel through which granules are
transferred into the cytoplasm. Apoptosis of the target cell supervenes, followed by release of
the cytoplasmic contents.
KEY ISSUE
NK cells show very limited specificity - they can distinguish between some MHC (major
histocompatibility complex) Class I molecules, but they lack the T cell receptor and do not
recognise antigen. Knowledge of their recognition processes is still rudimentary, but both
activating and inhibitory receptors have been identified. Interestingly, the absence of MHC
antigens on a target cell can be an activating stimulus for NK cells. Thus, viruses which down-
regulate Class I MHC antigens on the cells that they infect (and thereby subvert the host
defence by cytotoxic T cells) may fall victim to NK cells reacting to the ‘absent MHC’.
One of the NK cell surface markers (CD16) is an Fc receptor for the heavy chain of IgG. When
IgG antibody is directed against the cell surface antigens of a target cell, NK cells may attach to
this antibody via the Fc receptor. This results in enhanced killing activity by the NK cell, with

resultant death of the target cell. This process - antibody dependent cell-mediated cytotoxicity or
ADCC - is an impressive laboratory phenomenon whose significance in vivo is uncertain. NK
cells engaged in ADCC were once called K (killer) cells. They are now known to be NK cells.
1.3. The Major Histocompatibility Complex (MHC)
KEY ISSUE
The major histocompatibility complex (MHC) is a group of closely linked genetic loci (ie loci situated
close together on the same chromosome). In man the MHC is on the short arm of chromosome 6 and
is called HLA - which stands for human leucocyte antigen.
The genes of the MHC code for three separate groups of molecules:
a) The Class I molecules, sometimes called the Class I antigens, because they were first recognised in
the context of allograft rejection. They comprise a series of cell surface glycoproteins, each of which
is non-covalently associated with b-2 microglobulin. Several loci in the MHC code for Class I
antigens. The most important of these in man are HLA-A, -B, and -C.
b) The Class II molecules. The main loci for Class II antigens are HLA-DP, -DQ and - DR. Class II
antigens are also glycoproteins each made up of two chains. In contradistinction to Class I
molecules they are not associated with b-2 microglobulin.
c) Products of Class III genes are a heterogeneous group:

(i) several molecules which are important in the immune response (eg some complement
components, tumour necrosis factor); and
(ii) some enzymes.
Donor-host differences with respect to MHC Class l and Class II molecules were first recognised in the
context of experimental transplantation where they were responsible for the brisk rejection of skin
allografts in mice. Hence the term histocompatibility or transplantation antigens for the relevant
molecules. For many years this remained their only known function. Since transplantation is a biological
artefact (it has been said that ‘transplantation antigens were never meant to be transplanted’) it was
difficult to explain the emerging evidence that:
· the MHC had been extensively conserved in evolution, and

· enormous MHC variability between individuals existed in several species, including man.

KEY ISSUE
Clearly the biological importance of the MHC must be less trivial than merely thwarting transplant
surgeons - late arrivals on the evolutionary scene! Since then it has became apparent that the MHC
genes and their products are critically important in a wide variety of immunological and other
phenomena, and that their main function lies in the recognition processes that underpin the response
to antigen.
The distribution of MHC antigens on cells
Class I antigens are expressed on the surface of all nucleated cells, although the quantity varies, and
they may be up-regulated or down-regulated in different circumstances. Class I antigens are also found
on platelets and red cells in some species.
Class II antigens are normally expressed only on:

· Dendritic cells and related variants (Langerhans cells, interdigitating cells etc)
· Macrophages
· B lymphocytes
They may be expressed on other cells in pathological circumstances.
KEY ISSUE
In general, Class II antigens have a much more restricted distribution than Class I antigens, and
are found only on the cells that present antigen to T helper/inducer cells (a group commonly
referred to as the antigen-presenting cells or APCs).
MHC variability in man is such that apart from identical twins, it is extremely uncommon to find two
people with identical MHCs. This variability is due to:
a) The many genetic loci making up the MHC.
b) The large number of alleles at many of the loci. In addition to the serologically identified loci (about
80 for HLA-A, -B and -C combined, and about 35 for HLA-DP, -DQ and -DR), many more loci have
been identified by DNA typing. The total number of HLA alleles now runs to hundreds.
c) The fact that there are heritable differences in each of the two chains making up the Class II
molecules (but remember that the beta-2 microglobulin chain that makes up one of the two chains in
Class l molecules is invariant).

KEY ISSUE
MHC Class l and Class II molecules belong to the immunoglobulin superfamily (see Topic 3), a
basic structure that provides the potential for enormous variability between individual molecules. This
variability is largely confined to a cleft of the molecule in which antigen (usually a peptide) is
accommodated (for the structure of these molecules see diagrams in the standard reference texts).
Peptides presented with MHC Class I molecules: These are derived from proteins that spend all or
some of their time in the cytosol: ie cellular products such as heat shock proteins, enzymes and
histones, and also viruses that have infected the cell. Proteins are broken down into peptides in
proteasomes. The complex of ‘antigen (ie peptide) plus MHC Class I’ is assembled in the endoplasmic
reticulum and is transported through the cytosol to the cell surface. The peptide in the Class I groove
contains about eight or nine amino acids. The cell surface complex can be recognised only by cytotoxic
T lymphocytes (TC) which are CD8 positive (CD markers are discussed in Topic 2). Presentation by this
route allows the immune system to ‘police’ body cells. The killing of virus-infected cells exemplifies this
‘policing’ function in action.
Peptides presented with MHC Class II molecules: These represent processed extraneous antigens
(eg bacterial antigens, foreign proteins, allergens). The whole antigen is taken into antigen-presenting
cells and broken down in endosomes. The resultant peptides are transported through the cell within
organelles, without entering the cytosol. They become associated with Class II molecule very shortly
before the antigen-MHC complex is expressed on the cell surface. This represents a different
processing route from that utilised for presentation of antigen with Class l molecules - the extraneous
antigen is kept out of the cytosol. The peptides associated with the Class II groove are longer than
those associated with Class l. The complex of ‘antigen plus MHC Class II’ on the cell surface is
recognised by T helper cells (TH) which are CD4 positive. This recognition represents the initiation of
the immune response.
Immunological memory to antigens and the activation of cytotoxic T cells both depend on the Class II
presentation pathway and TH cells. Thus, although viral antigen is normally presented to TC cells in the
cleft of the Class I molecule, immunological memory to the virus will depend on help from TH cells.
Exactly how this happens is currently uncertain.
The biological significance of MHC variability: The wide range of cleft structures in the different
MHC molecules of a species allows it to accommodate - among all of its members - a correspondingly
large assortment of antigenic peptides. In other words, the immune systems of individual members of

the species can between them cope with a wide range of infections, including new infections. This
contributes to the survival of the species.
Other MHC functions: Excretion of soluble Class l products in the urine may underlie the ability of
animals to recognise one another by scent. Mating preference in mice has been associated with the
MHC. Some MHC molecules form part of hormone receptors. The Class III genes code for a number
of molecules that are important in the immune response - some complement components, tumour
necrosis factor, and some heat shock proteins.
KEY ISSUE
Disease associations with the MHC: Associations have been found between MHC antigens and
disease, both in man and in animals. A list of established human disease associations is found in Roitt
page 372. Note that these should not be thought of as ‘a gene for a disease’ - they are merely
associations. Different ethnic groups vary in the extent to which HLA antigens are associated with
disease, so any table of data should ideally specify the ethnic group(s) to which it refers.

TOPIC 2: THE CELLS OF THE IMMUNE SYSTEM

( FUNCTION, INTERACTIONS, CELL SUBSETS,
CELL SURFACE MARKERS AND RECEPTORS)
All the cells of the immune system originate from bone marrow precursors. The main effector cells of the
immune system are lymphocytes which make up about 20% of the circulating blood leucocytes. Mature
lymphocytes constantly circulate between blood, lymph and the lymphoid organs (excluding the thymus).
Candidates are referred to the reference textbooks for an account of lymphocyte traffic.
KEY ISSUES
T lymphocytes (thymus dependent - requiring the thymus for their maturation) make up about
60%-70% of all blood lymphocytes and comprise:
· T helper/inducer/delayed hypersensitivity cells (TH)
· T cytotoxic T cells (TC)
· The ratio of TH to TC is normally about 2:1
B lymphocytes (maturing in bone marrow and making up 10-20% of all blood lymphocytes) have
two main subsets:
· T independent B cells
· T dependent B cells (See Topic 3)
NK cells (large granular lymphocytes - 5-15% of all blood lymphocytes) - see Topic 1.2 Natural
Immunity.
Antigen presenting cells (APCs):
· Dendritic cells and variants (eg Langerhans cells, interdigitating cells)
· Macrophages
· B lymphocytes
Polymorphonuclear leucocytes, which are important in natural immunity, are considered under
Inflammation (1.2.2).
Eosinophils, mast cells, and basophils: see also under Inflammation and in the appropriate
reference texts.

2.1. Lymphocyte Subsets
The above summary of lymphocyte subsets represents an oversimplification since it takes no account of
exceptions and apparent inconsistencies. These are not elaborated upon here. There is considerable
sharing of cell surface structures, and also of functional attributes, not only between different cell
lineages, but also between cell subsets within a lineage. This is clearly illustrated in the table of CD
markers in Immunology, Roitt, Brostoff and Male; page 398 (for brief perusal only!). The significance of
much of this overlap is currently uncertain.
Receptors for antigen: The T cell receptor is a two chain molecule belonging to the immunoglobulin
superfamily. Like the constituent chains in antibody molecules these have variable and constant
regions. The development of a huge array of T cell receptors entails a process roughly comparable to
the generation of diversity among antibodies (see Genetics of Antibody Variability in Topic 3). The great
majority of T cell receptors have a and b chains. A small proportion of T cells uses g and d chains for
the receptor. The T cell receptor b chain is referred to in connection with superantigens in Topic 4.
2.2. Functions of the Cells of the Immune System
T Lymphocytes
(1) T helper cells (TH) comprise multiple different clones, each clone having receptors for only one
antigen. They recognise the appropriate antigen when it is presented as a peptide in the cleft of MHC
Class II molecules on antigen-presenting cells, usually dendritic cells. T helper cells comprise two
subsets, which differ in the cytokines that they produce, and thereby in the sort of immune response that
they orchestrate. These subsets with two of the major cytokines that each produces (there are several
others) are:
· TH1 cells, which produce IL-2 and IFNg and are responsible for cell mediated responses.
· TH2 cells, which produce IL-4 and IL-5 and provide help for antibody responses.
· A number of lymphocytes in man (sometimes called TO) have the cytokine profile of both TH1 and
TH2.
What decides whether TH1 or TH2 cells predominate? This is not yet certain, but cytokines
generated by phagocytic and other cells (perhaps NK cells) in the infective lesion, and possibly
determined by the nature of the antigen, may skew the direction of the response.

T Lymphocytes
(2) Cytotoxic T cells (TC) respond to viral antigen displayed in the cleft of MHC Class l antigen on
virtually any infected cell. They also kill some neoplastic cells (see Topic 3.1 MHC).
Suppressor T cells: While there is functional evidence for the existence of suppressor T cells, they do
not exist as the clearly identifiable subset which was once presumed.
NK cells: large granular lymphocytes - considered under Topic 1.2 Natural Immunity.
B lymphocytes
B lymphocytes differ from other lymphocytes in being able to recognise native (unprocessed) antigen
by virtue of their surface immunoglobulin. They can internalise this antigen and re-present it to T cells in
the cleft of MHC Class II molecules on the cell surface. B cells are the precursors of plasma cells that
export antibodies. The immunoglobulin expressed on the surface of B lymphocytes is predominantly
IgD or monomeric IgM. By the time the B cell has developed into a plasma cell, neither surface Ig nor
MHC Class II antigen is present. The cell is now exporting antibody, and copious RNA and
immunoglobulin are both demonstrable in the cytoplasm. Note that immunoglobulin receptors on B cells
recognise different antigenic epitopes (see below) from T cells. Thus, in the hapten plus carrier
situation (see below), the T cell may recognise the carrier and the B cell the hapten.
Terminology: An epitope is that part of an antigenic molecule that reacts directly with the combining
site or paratope of an antibody. A hapten is a molecule too small to be antigenic on its own, but which
can function as an antigen by associating with a larger molecule (a carrier) or by attaching to a cell.
Thus, nickel (in underwear fastenings and jewellery) is a common allergen that behaves as a hapten.
Some immunogenic drugs also behave as haptens.
2.3. Cell Surface Markers
KEY ISSUE
The cells of the immune system are commonly identified by molecules expressed on the cell surface.
This has been possible on a large scale only since the development of monoclonal antibodies (see
Topic 8). Many of these markers relate to a known function of the cell. For others a function still has to
be assigned.
CD markers: Most of the cell markers have CD (cluster designation, or sometimes cluster of
differentiation) numbers. The CD terminology stems from international workshops, when a given cell
surface antigen was recorded as reacting with a cluster of similar monoclonal antibodies provided by the
workshop participants. CD nomenclature has now been extended to most cell surface markers.

Receptors for antigen: Individual T cell receptors for antigen, and the individual antigen-combining
sites on the surface immunoglobulin molecules of B cells, will distinguish one cell from another. But
obviously they do not lend themselves to CD notation - there are simply too many individual structures
(estimates run into the millions). The immunoglobulin class of the surface immunoglobulin on B cells
can, of course, be fairly easily identified using suitable typing reagents (eg anti-IgD, anti-IgM).
MHC surface molecules: MHC Class l and Class II molecules have their own terminology and do not
use CD notation.
Complement receptors: To make things confusing, the complement receptors are described using
both CR and CD notation. Thus, B cells express the complement receptor CR2, also known as CD21,
and previously known only as the receptor for EB virus (which infects B cells via this portal of entry).
Likewise CR1 on phagocytic cells has the alias CD35 (it is possible to be a very competent surgeon
without remembering these numbers!).
NOTE: The absence of a given marker on a cell under investigation may be just as informative as the
presence of other markers. Thus, while NK lymphocytes express CD16 and CD56, the absence of
CD3 will also provide useful evidence that this lymphocyte is not a T cell.
Commonly Used Cell Markers
The following list of cell surface markers and cellular attributes represents a small selection from some
very large lists. The most important - those which are used diagnostically and those that highlight an
important function of the cell - are in bold type. MHC Class l antigen has not been mentioned because
all the cells in the list express it.
Refer to Resource Unit Immunology & Clinical Transplantation Table Commonly Used Cell
Markers
http://www.bst.racs.edu.au/racs/servlet/disp/25004
Scroll down to thumbnails and select the appropriate image

TOPIC 3: ANTIBODIES AND CYTOKINES

(STRUCTURE, FUNCTION, GENETICS OF
SECRETORY PRODUCTS OF CELLS INVOLVED IN
THE IMMUNE RESPONSE INCLUDING IMMUNOGLOBULINS,
INTERLEUKINS, VARIOUS OTHER FACTORS)
3.1. Antibodies
Immunoglobulin structure has been extensively conserved in evolution and is found not only in
antibodies, but also, in modified form, making up the T cell receptor, major histocompatibility complex
Class l and Class II antigens, adhesion molecules, CD4 and CD8 and so on. The basic structure of
antibodies is well described in standard immunology texts, and the main features of the different
immunoglobulin classes is briefly summarised in Tables such as those in Roitt, Essential Immunology,
9th edition, page 55 and Roitt, Brostoff and Male, Immunology; 5th edition page 73. The following
account briefly indicates the salient points.
Chains making up the different antibody classes: The basic immunoglobulin molecule (see Roitt,
Brostoff and Male, pp 72,73) is a four chain structure comprising two identical heavy chains (which can
be either g, a, m, d or e) and two identical light chains (which can be either k or l). Dimers (IgA) and
polymers (IgM) are made up of two or more identical basic units held together by J chain(s).
Terminology
Isotype (=class) is defined by the heavy chain. Thus, the g heavy chain defines the IgG isotype (or
class). Similarly, by virtue of their different heavy chains, IgG and IgM represent different isotypes. The
subclasses (eg IgG1, IgG2) are also referred to as isotypes.
Allotypes: These are genetically determined differences in the constant region of an antibody chain.
(Think of them as being akin to blood group differences). Thus, the human gamma heavy chain of IgG
shows Gm variants - allelic differences involving a few amino acids.
Idiotype: This is the combining site of an antibody molecule viewed (by virtue of its unique chemical
configuration) as a potential antigen. (Idiotypes can in theory act as auto-antigens. This is the basis of
network theory, in which anti-idiotypic antibodies regulate and modify immune responses).
Specificity = combining site. The relevant jargon - ‘a specificity’ - can sound a little odd.
What antibody classes subserve what functions? See tables referred to above.

What antibody classes fix complement? (see Tables previously referred to) The importance of
complement fixation (activation) in phagocytosis has been referred to elsewhere. IgM and IgG (most of
its subclasses) fix complement by the classical pathway, and the resultant anaphylotoxins C3a and C5a
promote histamine release from mast cells and basophils. Note that IgE does not fix complement, but
as the mediator of Type 1 hypersensitivity (see Topic 6) is responsible for the release of granules from
mast cells and basophils. Thus, both IgE-mediated (Type 1) hypersensitivity and complement-mediated
reactions entail the release of histamine.
Quantities of the different antibody classes in plasma: G>A>M>D>E

NOTE that while the IgG is the major immunoglobulin in the plasma (up to 1.6g/l, and making up about
80% of the circulating immunoglobulins), IgA is the major immunoglobulin in the whole body. Far more
IgA than IgG is produced daily. NOTE also that plasma levels of IgE are normally very low (17-450
ug/l).
Difference between circulating and secretory IgA: See Tables previously referred to.
Functions of the F ab and Fc portions of antibody molecules:

F ab: Combining with antigen
Expressing the idiotype
F(ab)2: The same as F ab except that there are two conjoined F ab fragments
Fc: Every other function of antibodies:

· crossing the placenta
· fixing complement
· adhering to structures bearing Fc receptors
KEY ISSUE
The genetics of antibody variability: The body produces hundreds of thousands of different
immunoglobulin molecules. This observation originally raised the question of how it managed to do this
without committing most of the genome to the project. The solution was to use a limited number of
genetic loci, each with a number of alleles (alternatives), thus allowing for a huge number of different
molecular combinations. This method of generating diversity is roughly comparable to that employed
by telecommunications engineers who use a set of about a dozen digits, each with ten alternatives
(0-9 inclusive), to provide millions of different telephone numbers world wide. As has been noted
above, immunoglobulin-like molecules form the basis of two other systems characterised by enormous
variability - the T cell receptor and the MHC antigens.

A minimum of 7 genes codes for an antibody molecule: A few more genes are committed to isotype
subclasses and allotypes.
For each heavy chain four genes are necessary:

· V (variable)
· D (diversity)
· J (joining)
· C (constant)
For each light chain 3 genes are necessary:

· V (variable)
· J (joining)
· C (constant)
The V, D, and J genes of the two immunoglobulin chains between them code for the combining site, and
can be thought of as equivalent to five packs of cards. Each antibody-combining site corresponds to a
‘hand’ - one card dealt randomly from each of the five packs. The ‘packs of cards’ (=sets of genes) vary
in size. The V genes represent the largest set, with about 100 genes. Enormous variability between
individual ‘hands of cards’ (=antibody combining sites) can be generated in this way. Additional
variability is provided by a variety of other genetic manipulations and modifications, including mutation.
The C genes code for the constant region of the relevant chain (see diagrams of these regions in the
standard reference texts).
NOTE: Do not confuse J genes (above) with the J chains which join two or more immunoglobulin
molecules to form dimers (IgA) or pentamers (IgM).
T independent antibodies: The production of most antibodies requires T cell help. A few antigens can
stimulate B lymphocytes directly - these are usually large polymers with repeating unit structures. The T
independent antibodies are IgM. T cell help is always necessary for the class switch that characterises
the secondary immune response (see Topic 5).
ABO red cell antibodies: These are usually IgM. Only after incompatible transfusions are they likely to
be IgG.
Complement receptors on immunoglobulin chains: The immunoglobulin classes that fix complement
via the classical pathway have receptors for C1 (the first component of the classical sequence).

3.2. Cytokines
KEY ISSUE
Cytokines are protein cell regulators and are responsible for communication between a wide variety of
cells. They comprise interleukins, colony stimulating factors, tumour necrosis factors, interferons,
chemokines and others. Most of them have been described only in the last 25 years, and information
on their complex inter- relationships is still very incomplete. The following account represents a
general overview. The attributes of a selected small group of cytokines is briefly summarised.
General attributes of cytokines:

· Low molecular weight secreted proteins (<80kDa).
· Produced by a wide variety of cells.
· Usually produced transiently and locally.
· Paracrine (interact with cells near by) and autocrine (interact with the same cell that secreted the
cyotokine) rather than endocrine.
· Very potent, acting in picomolar concentrations.
· Able to interact with high affinity receptors on the cell surface.
· Able to alter protein synthesis as a result of cell binding.
· Potentially (or actually) useful in therapy (eg colony stimulating factors, interferons, IL-2).
Individual cytokines have multiple overlapping regulatory functions.
The response of a given cell to a cytokine depends on:

· The local concentration of the cytokine.
· The nature of the target cell.
· The presence or absence of other cell regulators to which the cell may be exposed.
Tables listing the major cytokines are found in Roitt, Essential Immunology; page 181 and Roitt, Brostoff
and Male, Immunology; page 402.
Refer to Resource Unit Immunology & Clinical Transplantation Table - Some highlights from the
cytokine tables:
http://www.bst.racs.edu.au/racs/servlet/disp/25009
Scroll down to thumbnails and select the appropriate image

TOPIC 4: ACTIVATION AND CONTROL OF

THE NORMAL IMMUNE RESPONSE
The effector cells of the immune system are activated following recognition of antigen. The processing of
extraneous antigen by dendritic cells has been referred to previously, and is illustrated in the video cartoon
Antigen Presentation (access to this may be obtained, if desired, by separate purchase from the Dunedin
Basic Medical Sciences Course Trust).
The salient points are:
For TH lymphocytes: (see also Topic 2)

a) T cell recognises processed antigenic peptide plus MHC Class II on APCs (mainly dendritic cells)
b) CD4 (which characterises T helper cells) reacts with MHC Class II
c) CD3 (the marker for all T lymphocytes) has a transducing function for the T cell receptor
d) a second signal is necessary for activation (CD28-B7)
e) absence of the second signal may induce anergy (a ‘switch off’)
For TC lymphocytes: (see also Topic 2)

Antigen is recognised in a pattern similar to that illustrated for TH cells, except that:
a) Antigen lies in the groove of MHC Class I molecules.
b) CD8 performs the function undertaken by CD4 with CLASS II MHC.
Activation of TC depends on help from TH lymphocytes, as does immunological memory. It is not clear how
this happens.
For B lymphocytes: (see also Topic 2)

a) Surface immunoglobulin can react with native (unprocessed) antigen.
b) Antigen is internalised and re-processed in CLASS II antigens on surface.
c) B cells recognise different antigenic epitopes from T cells.
4.1. Superantigens
Some exogenous antigens can activate the immune system in a non-antigen specific manner. Instead
of the usual pattern of activation of processed antigens (see Figure 1), superantigens activate a large
number of lymphocytes by crosslinking the T cell receptor b chain and MHC Class II molecules outside
the usual site for processed antigen (see Figure 2). By binding to certain sequences in the b chain of
the T cell receptor (which may be shared by many - perhaps most - of the T cells), superantigens
manage to activate many more T cells than would be activated in a normal immune response. This

causes a large scale and excessive production of cytokines. Overproduction of IL-2 has been held to
account for most of the adverse effects of the superantigen staphylococcal enterotoxin (fever, malaise,
nausea, diarrhoea, and shock). A similar immunological phenomenon was responsible for the tampon-
toxic-shock syndrome first reported a few years ago.
Refer to Figure 1 – Conventional Antigens

http://www.bst.racs.edu.au/racs/imserv/333.jpg
Refer to Figure 2 – Super Antigens

REFERENCE
See also the video cartoon Antigen Presentation, obtainable from the Dunedin Basic Medical
Sciences Course Trust, C/- Pathology Department, Otago Medical School, Dunedin, NZ.
Ph: +64 (3) 479 7286; Fax: +64 (3) 477 2042; Email: jenny.hurley@stonebow.otago.ac.nz. For
further information on how to access the Antigen Presentation video refer to
http://healthsci.otago.ac.nz/PART1FRACS.
4.2. Polyclonal Activators
These activate T or B cells in the absence of any contact with antigen. They include:
For T cells: phytohaemagglutinin (PHA)
pokeweed mitogen (PWM)
concanavalin A (con A)
anti-CD3
For B cells: anti-Ig (which reacts with all surface immunoglobulin molecules)
EB virus
Pokeweed mitogen (PWM)
S.aureus (Cowan strain 1)
PHA, PWM and Con A are lectins - proteins of plant origin that bind to carbohydrates.
Polyclonal activators are sometimes referred to as mitogens because they stimulate mitosis. Their
importance relates to:
a) The possibility that they underlie the hypergammaglobulinaemia of AIDS, and also the B cell
neoplasia that sometimes follows EB virus infection in immunosuppressed patients.
b) Their use in assessing T and B cell function (see Topic 6.3 Immunodeficiencies).

4.3. First and Second Encounters with Antigen
KEY ISSUES
The host response depends on whether it is a first encounter with the relevant antigen, or a second (or
subsequent) encounter. The essential feature of a first encounter (the primary response) is that it
provokes the development of specific memory cells. This has the following features:
a) The reactive T and B cell clones undergo expansion. This takes 7-10 days, so the response is
relatively slow.
b) The magnitude of the response is small. Thus, little if any antibody is produced.
c) Such antibody as is present is likely to be IgM and to have low affinity.
The characteristics of a second or subsequent encounter with antigen (the secondary response)
include:
a) The response is relatively quick (hours rather than days) - an attribute of memory cells.
b) The magnitude of the response (T cell or B cell) is greater than is seen in the primary
response.
c) Antibody is IgG rather than IgM and includes relatively more high affinity antibody.

Memory is thought to depend on:

a) Increased size of the relevant clones.
b) Increased expression of certain adhesion molecules: eg the leucocyte-common antigen CD45 exists
in different form in naive (CD45RA) and memory (CD45RO) cells.
c) (Probably) persistence of antigen on dendritic cells in the lymph node cortex. This is thought to
keep the relevant lymphocytes in a state of chronic activation.
Immunisation against disease aims to induce specific memory, so that the host mounts a
secondary response, rather than a primary response, to the relevant infection.
4.4. Regulation of Immune Responses
All biological systems are subject to regulation. The nature and magnitude of the immune response
depends on a variety of factors:
a) The form of the antigen: eg polysaccharide bacterial capsules generally induce IgM; intracellular
bacteria induce TH1 responses, soluble protein antigens TH2 response, and so on.
b) The route of administration: Experimentally the route of administration can determine whether an
immune response occurs at all, and whether tolerance or immunity results. The magnitude and
characteristics of the response are also determined by the route of administration of antigen.
c) The state of activation of the antigen-presenting cell influences the extent to which it expresses
MHC Class II molecules, and also its ability to express costimulatory molecules (see Cartoon
video).
d) The genetic background of the individual. For a period before their function was clearly delineated,
MHC Class II genes were referred to as ‘immune response genes’ because the reaction to
specified antigens was governed by the MHC. Numerous examples have been reported in mice
and other laboratory animals. A human counterpart is the protection from Plasmodium falciparum
conferred by one of the HLA haplotypes common among West Africans.
e) Previous experience with the antigen: See above.
Regulation of established immune responses can be effected by several subsets of T lymphocytes, a

variety of antibodies, immune complexes, a range of cytokines, and neuroendocrine networks. This is a
complicated topic in which the information comes mainly from animal experiments. Candidates who are
interested should consult Roitt, Brostoff and Male, Immunology; Chapter 13, page 171, although this sort
of experimental detail lies outside the syllabus requirements for Part 1 FRACS.

TOPIC 5: IMMUNITY TO INFECTION
(INCLUDING VIRUSES, BACTERIA, FUNGI AND PROTOZOA)
All microorganisms use a variety of methods to subvert the host immune defences. Indeed, almost every
conceivable way of escaping host recognition and action has been utilised by one or other organism.
The following list supplies a few examples:

· Antigenic variation
· Mutation to produce new toxins
· Escaping for the cell’s lysosomes
· Preventing complement activation
· Producing carbohydrate capsules
· Repelling phagocytes
· Down-regulating MHC Class I antigen
· Impairing interferon production
· Interfering with antibody and complement production
5.1. Viruses
· NK cells kill some virus-infected cells - they probably represent the earliest response to viral
infection.
· Cytotoxic T cells operate slightly later.
· All three interferons limit the extent to which neighbouring cells can be infected by the relevant virus.
· g interferon (from lymphocytes) increases NK cell activity and activates macrophages.
· Help from T cells is necessary for antibody production and immunological memory. Exactly how this
happens is still not certain.
Virus infections accompanying the immunodeficiencies

Virus infections are a feature of T cell immunodeficiencies, and some NK cell deficiencies. Neither
complement deficiency nor B cell immunodeficiencies show very striking increases in the number of virus
infections.

5.2. Bacteria
The main defence against bacteria is ultimately provided by phagocytes. The adaptive immune system
enhances phagocytosis largely by the production of opsonising antibodies. These facilitate
phagocytosis by delivering organisms to macrophages and polymorphs, both of which have Fc
receptors for IgG, and complement receptors (both IgG and IgM fix complement). In situations where
bacteria are not destroyed by the phagocytes that ingest them (eg tuberculosis, leprosy), TH cell-
mediated immunity enhances the immune response. Antitoxic antibodies to bacterial exotoxins are
very effective in situations where the toxin rather than the invasive organism is responsible for
pathogenicity (eg diphtheria, tetanus).
Bacterial infections accompanying the immunodeficiencies: Repeated infections by pyogenic

organisms are characteristic of the B cell immunodeficiencies. Tuberculosis is a feature of the T cell
immunodeficiencies, and of AIDS in particular.
KEY ISSUE
Overwhelming post-splenectomy infection (OPSI): is of particular interest to surgeons. This is a
recognised complication of splenectomy and the asplenic state; and is more likely to occur in children
than in adults. The most likely infectious agents are the encapsulated bacteria Streptococcus
pneumoniae, Neisseria meningitidis and Haemophilus influenzae. Patients undergoing elective
splenectomy should be immunised against these organisms, preferably at least two weeks pre-
operatively, but after splenectomy if there is no other option. The recognition of OPSI underlies the
preference for splenic conservation rather than removal.
Vaccines made from the above organisms use subcellular microbial capsular fragments.
Polysaccharide vaccines are always conjugated to a protein carrier.
5.3. Fungi
Relatively little is known about the immune reaction to fungi, although this appears to be largely cell-
mediated. There are no effective fungal vaccines.
Fungal infections accompanying the immunodeficiencies: Fungal and viral infections are a feature
of the T cell immunodeficiencies. Candida infection is prominent in AIDS and other T cell
immunodeficiencies.

5.4. Protozoa and Worms
NOTE: The main heading of Topic 5 lists protozoa but not worms. Nevertheless, among the significant
organisms listed in the microbiology section of the syllabus (see 5. Infection: Specific Objective 1.4) is
the worm Echinococcus granulosus. Candidates’ attention is drawn to this parasite on account of its
surgical importance in Australasia.
The large number of parasites, and the variable strategies that they adopt to avoid the immune system
of their hosts has prompted Roitt to comment ‘ … each type of parasite is virtually a world unto itself in
the complexity of the mechanisms by which (its survival in the host) is achieved’. Thus, it is difficult to
generalise, except on a very limited scale:
a) Most parasites are immunosuppressive in one way or another. Their own survival depends on
relatively ineffectual host immune response.
b) The immunological response to many parasite infections is associated with extensive damage to the
host. Some of these are briefly considered in Roitt, Brostoff and Male, Immunology; page 259.
c) Eosinophilia is common in worm infestation.
d) High IgE also characterises infestation by some worms and may result in anaphylaxis when large
quantities of antigen are released (eg when a hydatid cyst ruptures).
e) No vaccines are yet available for routine use against parasites.
Vaccination against Infectious Diseases
Chapter 19 in Roitt, Brostoff and Male, Immunology, page 263, provides an excellent summary of the
various vaccines that are available and their attributes.
KEY ISSUE
Candidates’ attention is drawn to the use of live vaccines. It is worth reiterating that live vaccines
should not be given to immunocompromised hosts because of the risk of opportunistic infection. The
live attenuated vaccines in current use are poliomyelitis (Sabin), measles, mumps, rubella, yellow fever
17D, varicella-zoster (human herpes virus 3) and BCG.

TOPIC 6: ABNORMAL IMMUNE RESPONSES

(INCLUDING HYPERSENSITIVITY, AUTO-IMMUNE DISORDERS
AND IMMUNODEFICIENCY DISORDERS)
6.1. Hypersensitivity
Hypersensitivity reactions comprise a group of immunological responses that are associated

with damage to the host. All are either exaggerations of normal immunological reactivity, or
inappropriate responses.
KEY ISSUE
It is important to remember that the typical manifestations of hypersensitivity occur only in hosts who
have encountered the relevant antigen before and who have been primed to it. These reactions are
not seen on first encounter with antigen.
6.1.1. TYPE I (Anaphylactic) Hypersensitivity
A very rapid (within minutes) reaction follows exposure of the sensitised host to antigen. The
systemic manifestation - anaphylactic shock - may be life-threatening. Fortunately anaphylactic
shock is much less common than the local manifestations, which include asthma, hay fever,
hives, and gastro-intestinal allergy. The clinical effects are mediated by IgE. This
immunoglobulin adheres to mast cells and basophils (both of which have Fc receptors for IgE).
The antigen (often called an allergen in this context) adheres to the cell-bound IgE, cross-
linking two antibody molecules and thereby triggering release of granules from the cytoplasm.
Salient Features
A. Atopy is an inherited tendency to manifest Type 1 reactions. The manner of inheritance is

not certain. It is HLA-associated within some atopic families, but no single HLA haplotype
within the general population is particularly associated with atopy.
B. The pathophysiological processes include:

(i) contraction of smooth muscle
(ii) vasodilatation and exudation of fluid
(iii) excessive mucus secretion
(iv) inflammatory cell infiltration, particularly with eosinophils. Note that eosinophil
infiltration characterises Type 1 hypersensitivity (Parasite infestation is also often
associated with eosinophil infiltration)

C. The mediators of Type I hypersensitivity. The more important of these are in bold type:
(i) Derivatives of mast cell granules (primary mediators):
· Histamine (increasing vascular permeability, smooth muscle contraction,
glandular secretion)
· Eosinophil chemotactic factor
· Various enzymes
· Heparin
(ii) Lipid mediators and cytokines (secondary mediators):

· Leukotrienes C4, D4 (increasing vascular permeability, smooth muscle
contraction)
· Leukotriene B4 (chemotactic for eosinophils and other cells)
· Platelet-activating factor
· Various cytokines
After the initial Type I response (due to mast cell/basophil degranulation), a later
response (due to cytokine production) sometimes occurs several hours later. Hence
the designation primary mediators/secondary mediators (above).
D. The dose of antigen required to trigger a Type I reaction may be extremely small.
E. Timing of the reactions: A first encounter with antigen will not cause a Type I response. A
first encounter, as might be expected, triggers a primary response which takes several
days.
Reactions resembling anaphylaxis but not mediated by IgE: IgE brings about the release of
mast cell granules without any assistance from complement (it cannot activate complement).
But complement activation (for any reason) can achieve the same clinical result via the
complement components C3a and C5a (the so-called anaphylotoxins), which likewise cause
mast cell degranulation. Thus, a sufficiently large-scale degranulation following complement
fixation can cause symptoms resembling anaphylaxis in the absence of Type I hypersensitivity.
Some drug reactions belong in this category, as does any substance that can fix complement
via the alternative pathway, including endotoxin from Gram negative organisms.

6.1.2. TYPE II Hypersensitivity
This is mediated by antibody (usually IgG or IgM) directed against an antigenic component of
the cell wall, or occasionally against a non-cellular structure such as the glomerular basement
membrane. The cellular antigen may be:
a) A normal cell structure (eg ABO or Rh blood group antigens).
b) A hapten (eg a drug that is not itself antigenic), that becomes intimately associated with the
cell; and thereby achieves full antigen status.
Cell destruction occurs by either:

a) complement-mediated cell lysis (as in ABO incompatibility); or by
b) opsonisation and ingestion by phagocytes (as in Rh incompatible transfusions); or by
c) possibly the action of NK cells which are able to destroy target cells to which small quantities
of antibody are attached (ADCC - see Topic 1.2.5 Natural Immunity).
Clinical examples of Type II hypersensitivity:

· Incompatible blood transfusions.
· Some drug hypersensitivities. When drugs adhere to platelets, an immune response can
lead to purpura. Other lesions include agranulocytosis and haemolytic anaemia.
· Acquired haemolytic anaemia.
· Hyperacute graft rejection (antibody-mediated).
· Goodpasture’s syndrome caused by anti- glomerular basement membrane antibodies is
usually included under this heading, albeit a little reluctantly (because the antigen is not
cellular).
· Anti-receptor antibodies, as in thyrotoxicosis.
6.1.3. TYPE III Hypersensitivity Immune Complex Disease
Immune complexes are produced whenever antigen and antibody combine, and are normally
removed by the liver and spleen, where phagocytic cells of the mononuclear phagocyte system
line the sinusoids. Most of the complexes are transported to these organs attached to red cells
which have receptors for C3b (CR1 receptors - about 700 receptors per red cell). Immune
complex diseases are apt to occur when there is complement deficiency, since the normal
clearing of immune complexes is impaired.
Antibody molecules have a valency of at least two (ie they have two antigen-combining sites),
while antigenic molecules may have valencies that are much higher (a given antigenic molecule

or microorganism may have repeated epitopes, all of which are capable of combining with
antibody). Not all of the available combining sites will necessarily be occupied, so the
proportion of antigen to antibody in immune complexes can be very variable. In connection with
the diseases that they produce:
a) Soluble complexes are able to circulate around the body, and are arrested in various organs,
where they produce lesions. Serum sickness (originally named because it followed the
administration of horse serum) is an example of this. NOTE that mouse immunoglobulin in
monoclonal antibodies is the modern counterpart of the horse serum one used for passive
immunity (see Topic 8).
b) Insoluble complexes remain near the site where antigen enters the body. The host usually
has high levels of circulating antibody, and the complexes form in situ. (Remember that the
smallest antibody molecule has a molecular weight of about 150 000, so the complexes that
form in antibody excess tend to be large and to precipitate near the site of formation).
Immune complex disease with insoluble complexes is seen in farmers’ lung and other similar
respiratory diseases. They are covered by the general term Arthus type reactions. Acute
inflammation is a prominent feature.
Type III hypersensitivity occurs in circumstances when immune complexes not normally
removed. The reasons are not entirely clear, but increased vascular permeability and local
vascular turbulence probably play an important part. The role of complement in the normal
disposal of immune complexes has been referred to above.
KEY ISSUE
The deleterious effects of immune complexes are largely due to the inflammatory
consequences of complement fixation (see Topic 1). Complement-mediated inflammatory
damage may be exacerbated by the release of polymorph granules in sites where the
polymorphs are unsuccessful at ingesting complexes: eg in the kidney where larger soluble
complexes may be stuck to the basement membrane of the glomeruli (smaller soluble
complexes get through the basement membrane). This is sometimes called frustrated
phagocytosis. The fluid component of the inflammatory exudate may predominate in some
Type III lesions (eg serum sickness) and the cellular component in others (eg the polymorph
infiltration in Arthus type reactivity).

6.1.4. TYPE IV Hypersensitivity (Delayed Type Hypersensitivity - DTH)
This differs from Types l, II and III hypersensitivity in being mediated by T cells,
predominantly TH.
Salient Features
(a) The reaction takes 24-72 hours to reach its maximum in sensitised hosts - hence the term
‘delayed’.
(b) T helper cells are the main effector cells.
(c) The infiltrating cells are TH1 in the first instance, followed by macrophages activated in
response to cytokines produced by the T cells. The T cells are initially perivascular, and later
more diffuse.
(d) The major cytokines involved are:

· IFN g which activates macrophages.
· IL-2 which causes proliferation of T cells (autocrine and paracrine).
(e) DTH occurs in response to several infections, especially those in which the infecting
organisms are intracellular (mycobacteria, fungi, viruses and some parasites: eg
toxoplasmosis, cryptosporidiosis).
(f) DTH is the basis of several skin tests, of which the prototype is the tuberculin test
(exemplified by Mantoux, Heaf tests).
(g) DTH is a common cause of contact dermatitis in response to a variety of chemicals (eg
nickel in underwear fastenings).
(h) Skin allograft rejection is mediated by both DTH and cytotoxic T cells. The relative
importance of each has still not been finally settled, although experimentally TC are
ineffectual without some input from TH.
(i) DTH underlies many granulomatous lesions (eg tuberculosis). These are
characterised by lymphocyte and macrophage infiltration, with modification of macrophages
to produce epithelioid cells and giant cells. Fibrosis supervenes later. Granulomas
represent unsuccessful (or only partially successful) attempts to deal with the infection.
(j) TC activity may be upregulated during the course of Type IV hypersensitivity, but basically
the effector cells are TH lymphocytes.

6.2. Auto-Immunity
Auto-immunity entails a reaction against ‘self’ body components and is thus a disorder of normal self
tolerance. Autoreactive T cells and autoantibodies against ‘self’ body components can be found in
normal persons, especially in old age. Thus, before ascribing a disease to autoimmunity, it is necessary
to ask whether the immune reaction has caused the disease, or whether the immunological reaction
represents a response to a preceding lesion. Because the question cannot be answered with absolute
certainty, there is a long list of probable autoimmune diseases, which includes acquired haemolytic
anaemia, systemic lupus erythematosus (SLE), Hashimoto’s disease, thyrotoxicosis, myasthenia gravis,
pernicious anaemia, insulin-dependent diabetes mellitus, rheumatoid arthritis and several other
conditions.
KEY ISSUE
The general features of autoimmune diseases include:
a) Autoantibodies are demonstrable (eg pernicious anaemia, acquired haemolytic anaemia).
b) Histological lesions may suggest involvement of the immune system - lymphocytes, plasma cells
and macrophages are plentiful and there may be evidence of immune complexes (see histology of
Hashimoto’s disease, SLE).
c) More than one autoimmune disease may be present (eg patients with thyroid autoimmunity have a
higher than normal incidence of gastric autoimmunity, and vice versa).
d) Autoimmune diseases tend to occur in families.
e) Certain HLA haplotypes are associated with autoimmune disease.
f) Autoimmunity shows a female preponderance.
g) Autoimmune reactions damage the host. The lesions characterising autoimmune disease are thus
classifiable as hypersensitivity - Types II, III and IV.
For the features of individual autoimmune diseases candidates are referred to the relevant sections of
the reference textbooks. The thyroid autoimmune diseases will be of particular interest to surgeons.
6.3. The Immunodeficiencies
Some general points on the immunodeficiency diseases should be noted:

· Immunodeficiencies are seldom complete. Partial immunodeficiencies occur more frequently than
complete T cell or B cell immunodeficiency.
· The commonest immunodeficiency after AIDS is common variable immunodeficiency.
· The role of T cells and B cells is most clearly illustrated by diGeorge syndrome (T cells) and Bruton’s
agammaglobulinaemia (B cells), although neither is common.

· Immunodeficiencies are often accompanied (perhaps unexpectedly) by auto-immune disease and by

an increased tendency to lymphoid neoplasms. Both are possibly explained as disorders of immune
regulation.
· Immunodeficiency may be iatrogenic, as in transplantation.
· Temporary immunodeficiency can result from:
§ burns
§ severe trauma
§ uraemia
§ severe exertion
§ measles, chicken pox
Some of the above situations will be encountered in clinical surgery.
Attributes of T Cell Immunodeficiency

· Resistance is poor to infections depending on T cells (eg fungal and viral infections, and bacterial
infections by intracellular organisms such as those which cause tuberculosis and leprosy).
· Initiation of new immune responses (which depends on TH cells) is poor.
· Prolonged survival of allografts (and sometimes xenografts) occurs.
· Type IV hypersensitivity reactions are impaired (eg negative tuberculin test).
· Examples: di George’s syndrome (defective thymic development), AIDS. Much of the information
on T cell immunodeficiencies comes from mice, rats and guinea pigs homozygous for the nude
gene. These animals are hairless and have a poorly developed thymus.
KEY ISSUE
AIDS is the commonest T cell immunodeficiency - indeed, it is the commonest of all
immunodeficiencies. It is considered in detail elsewhere.
Attributes of B Cell Deficiency

· The reaction to bacterial antigens and toxins is impaired. Mortality from pyogenic infections is
therefore high. Graft rejection and delayed type hypersensitivity reactions are both normal.
· Examples: Agammaglobulinaemia (more correctly hypogammaglobulinaemia), post splenectomy
syndrome (characterised by particular susceptibility to St. pneumoniae), selective IgA deficiency,
common variable immunodeficiency.

Attributes of Stem Cell Deficiency

· This combines the features of all the immunodeficiencies in varying proportions.
· Example: Severe combined immunodeficiency (SCID). This is a collection of disorders that result
from several different genetic anomalies. Some forms result from deficiency of one or other of the
recombinase enzymes necessary for assembling receptors for antigen. Some of the first gene
therapy experiments have been directed towards correcting the enzyme deficiencies in these
patients.
Some Other Immunodeficiencies:

· NK cell deficiency: Very rare, but patients lacking NK cells have had life threatening virus infections
with EBV, varicella and CMV.
· Complement deficiencies: A variety of bacterial infections (often involving Neisseria) and immune
complex diseases have been described.
· Defective phagocytosis: Several disorders have been described (see under Inflammation). Basically
they involve:
§ Defective production of polymorphs
§ Defective leucocyte adhesion
§ Defective chemotaxis
§ Failure of cellular oxidative reactions
KEY ISSUE
In order to Test T Cell Competence:
· Count the T cells in blood (using anti-CD3 which identifies all T cells).
· Determine the ratio of CD4 (TH) to CD8 (TC) cells - normally about 2:1 (ratio is low in AIDS).
· Test the ability of T cells to multiply in response to polyclonal activators such as the lectins
phytohaemagglutinin (PHA) and concanavalin A (con A).
· Test the ability of T cells to proliferate in the presence of MHC incompatible cells (the mixed
lymphocyte reaction - MLR).
· Examine the cellularity of T cell areas in lymph nodes and elsewhere.
· Test delayed hypersensitivity responses (which depend on TH cells) using tuberculin, mumps
antigen, dinitrochlorobenzene (DNCB) etc.

KEY ISSUE
In order to Test B Cell Competence:
· Measure total serum immunoglobulins (below 2 g/l =immunodeficiency).
· Determine the proportions of the different antibody classes (approximate normal % = IgG 80%,
IgA 13%, IgM 6%, IgD 0-1%, IgE <0.002%).
· Count circulating B cells (identified by surface immunoglobulin).
· Determine whether B cells proliferate on exposure to polyclonal activators such as pokeweed
mitogen (PWM).
· Examine B cell areas of lymph nodes and look for plasma cells.
· Measure levels of natural antibodies (eg to ABO antigens, to sheep red cells).
· Test whether antibody is produced on suitable immunisation - but NEVER use live vaccines in
immunodeficient hosts (because of the risk of opportunistic infection).

TOPIC 7: TRANSPLANTATION IMMUNOLOGY

(MECHANISMS OF TRANSPLANT REJECTION
AND HOW THESE MAY BE AVOIDED OR
MODIFIED BY THERAPEUTIC INTERVENTION)
The major histocompatibility complex was outlined in Topic 1. Clinical transplantation is covered in detail in
the second part of this module. The basic sciences section of the module briefly comments on four points
relevant to transplantation.
7.1. Large numbers of lymphocytes are reactive against alloantigens. Why?
Very few T lymphocytes - perhaps as few as 1 in 10 000 - are capable of recognising most extraneous
antigens. By contrast, over 10% of all lymphocytes react against alloantigens. Why? The most likely
explanation runs along these lines:
a) The large population of alloreactive cells is responding to the large number of different peptides
occupying the grooves of the MHC molecules of the graft cells. The structure of the MHC governs
what peptides can be accommodated, so the allogeneic donor (whose MHC is - by definition -
different from that of the host) will present peptides that differ from those that the host MHC can
present. The peptides in the donor MHC molecules may comprise molecules that the host has
never learned to recognise as ‘self’ (including allelic variants of normal body proteins - the graft
carries one allele, the host another).
b) After the graft has been in residence for a few days, host dendritic cells are known to infiltrate the
graft. These dendritic cells are able to present graft antigen (minor histocompatibility antigen and
other cell products) released from graft cells.
c) Do the host lymphocytes react directly against the graft MHC alloantigens rather than against the
peptides occupying the MHC groove? It has been known for many years that the initiation of graft
rejection depends not on the specialised cells making up most of the graft, but on the graft
dendritic cells (once referred to as ‘passenger leucocytes’). It seems likely that the alloreactivity
directed against dendritic cells represents a reaction to MHC Class II alloantigens.
KEY ISSUE
In summary, alloreactive cells are numerous because they are responding to an assortment of non-self
antigens. Their large numbers are probably accounted for mainly by the large assortment of peptides
that they offer the host immune system, as in a) above.

7.2. Graft versus Host Reactions (GvHR)
Graft versus host reactions are possible whenever large numbers of lymphocytes are transferred to
recipients whose ability to reject them is impaired. Impaired capacity to reject allografts accompanies:
· immaturity (mainly in the experimental situation)
· immunodeficiency
· immunosuppression
KEY ISSUE
Graft versus host reactions are mediated by T cells (TH and perhaps TC), probably with a large
contribution from cytokines. They are a major problem in bone marrow transplantation, where T cell
depletion of the graft is usually undertaken to reduce the chances of GvHRs. They are most severe
when donor and host are MHC incompatible, and D region incompatibility is particularly important.
They can, however, also occur as a result of minor histoincompatibility. Most organ grafts are unlikely
to contain sufficient lymphocytes for GvHRs to be a problem.
7.3. Donor-Host Matching: Minor Histocompatibility Antigens
KEY ISSUES
At present only HLA and ABO transplantation antigens can be identified in man. There are,
however, multiple minor histocompatibility loci, whose gene products are probably allelic forms of
normal cell constituents. Tissue typing laboratories are currently unable to identify the minor antigens
in man. In the experimental situation, alleles at all of these minor loci can provoke graft rejection,
although its tempo is usually slower than that associated with MHC incompatibility.
In clinical transplantation, even when donor and host are identical at ABO and HLA (as in some full
sibling combinations), incompatibility at an assortment of minor histocompatibility loci will be inevitable.
7.4. Tissue Typing Terminology
Genotype = the distribution of HLA genes on both chromosomes on the pair.
Haplotype = the HLA genes on one chromosome of the pair (= half the genotype). Haplotypes and
genotypes are deducible from family studies.
Phenotype = the HLA genes carried by an individual without any indication of the chromosomal
arrangement. (It may help to recall that ‘the phenotype is what you look like and the genotype is what
you are’).

TOPIC 8: DIAGNOSTIC TESTING IN IMMUNOLOGY

(WITHOUT DETAIL OF METHODOLOGY,
BUT WITH EMPHASIS ON THE APPLICATION OF
SUCH TESTS AND THEIR LIMITATIONS)
Many of the diagnostic methods in current use, and especially the tests that identify cell markers, entail the
use of monoclonal antibodies, the development of which has been referred to as the ‘monoclonal antibody
revolution’.
Polyclonal and Monoclonal Responses to Antigen
Even the simplest antigenic molecule administered to an intact recipient will be recognised by many different
clones of T and B cells. Among the total population of receptors that will recognise the antigen, some will be
a good fit for the relevant epitope (for which they are said to have high affinity), while others will exhibit low
affinity and will dissociate readily. (Remember that the epitope is the part of the antigenic molecule with
which the receptor combines). Thus, the reaction of the intact host to any antigen will be polyclonal.
Polyclonal antisera will inevitably contain an assortment of antibodies of different affinities. A given
antiserum is a ‘one off’ event, that depends on the circumstances which prevailed when it was raised. With
such reagents standardisation between different laboratories, and even within the same laboratory, obviously
presents difficulties. With any antiserum, most of the immunoglobulins (over 90%) will not react with the
relevant antigen at all. Those that do react will consist of an assortment of antibodies of different affinities. In
these circumstances non-specific binding to antigen can be high with the result that the ‘signal:noise’ ratio is
low (this means that specific binding to antigen is obscured by non-specific binding). The availability of
monoclonal antibodies instead of conventional antisera has greatly improved the results obtainable using
serological tests.
KEY ISSUE
With monoclonal antibodies every immunoglobulin molecule in the reagent has the same binding site,
class, allotype and affinity. The same reagent can be used in laboratories all over the world.
The ‘monoclonal antibody revolution’ resulted from the development of hybridomas; cells produced
by fusing myeloma cells with normal B cells. Normal cells die in cell culture after a limited number
of divisions, whereas cancer cells are immortal. The hybridoma combines the immortality of the
myeloma cell with the antibody-producing capacity of the B cell.

The myelomas suitable for use in hybridoma production call for special growth characteristics, and only a
minority fulfil the requirements. Most have come from selected strains of laboratory mice and rats that have
a high incidence of myelomas. Human myelomas have been less satisfactory. Most of the monoclonal
antibodies currently on the market result from hybridoma technology. Other methods of obtaining
monoclonal antibodies are available, but they are not discussed here. The varied uses of monoclonal
antibodies are summarised in Table 6.1, p.123 in Roitt. In relation to their clinical use, it should be noted that
these are animal proteins and therefore very immunogenic. Mouse immunoglobulin carries similar risks to
those associated with the use of horse serum many years ago (see Type III hypersensitivity - serum
sickness).
Individual Immunodiagnostic Tests
Neither the methodology nor the pitfalls of individual tests are considered here. The interpretation of tests
used in clinical surgery (eg for oncofetal antigens, prostate specific antigen) will usually be concerned with
the biological significance of positive/negative results rather than with methodological considerations. Each
test should be considered against the background of the surgical situation in which it is used.

TYPE A (ONE OF FIVE)

Q1 A 45-year-old male smoker presents with recurrent respiratory infections. His tuberculin test is negative.
His blood shows greatly reduced levels of CD3 and CD4 lymphocytes, with no other abnormality. It is
most likely that he has
A. AIDS
B. agammaglobulinaemia
C. cancer of the lung
D. immune complex disease
E. a complement deficiency
TYPE B (MULTIPLE TRUE-FALSE)

Q2 Regarding HLA typing
1. HLA-A,-B,-C and-DR are routinely identified using T lymphocytes
2. complement-dependent lymphocytotoxicity is the most commonly used laboratory technique for
HLA typing
3. the mixed lymphocyte reaction (MLR) identifies donor-host incompatibility with respect to MHC
Class II antigens
4. DNA typing reveals approximately the same number of HLA alleles as are identifiable by serological
methods
Q3 A three-year-old boy undergoes splenectomy. Because of this he needs to be vaccinated against

1. St.pneumoniae
2. Haemophilus influenzae
3. Neisseria meningitidis
4. Measles
Q4 Which of the following long-term effects can be expected in a community following immunisation of
85% of its members with tetanus toxoid?
1. Protection on the unvaccinated members of the community as a result of herd immunity.
2. A relative reduction in the frequency with which prophylactic tetanus antitoxin is administered after
injury.
3. A relative increase in the frequency with which tetanus toxoid is administered after injury.
4. Persistence of the changes effected by immunisation for several years.

Q5 A 25-year-old man receives a renal allograft from his mother. Which of the following is/are true
1. the donor and recipient are almost certainly HLA haplo-identical
2. a kidney donated by the patient’s father would probably be HLA haplo-identical
3. donor-host ABO compatibility is not important in parent/offspring allografts
4. HLA identity between mother and son occurs with a frequency of about 1:200
Q6 Which of the following events are absolute requirements for the manifestation of Type I (anaphylactic)
hypersensitivity?
1. mast cells and basophils express receptors for immunoglobulin E (IgE)
2. IgE molecules are cross linked by antigen
3. complement is fixed when IgE and antigen combine
4. gamma interferon activates macrophages
Q7 Regarding immunoglobulin G (IgG)

1. it is the only antibody that can cross the placenta
2. more IgG is made in the body each day than any other immunoglobulin
3. IgG is the characteristic ‘early antibody’ of the immune response
4. the ABO antibodies are mainly IgG
Q8 Regarding the antibodies produced by one B cell and the plasma cells that are its mitotic progeny
1. all have the same specificity (combining site)
2. all belong to the same class
3. the B cell but not the plasma cells have receptors for antigen
4. the B cell cytoplasm contains copious quantities of RNA
Q9 The secondary immune response differs from the primary response in having
1. higher titres of antibody
2. higher affinity antibodies
3. IgG antibodies rather than IgM antibodies
4. expanded T and B cell clones reactive with the antigen(s)
Q10 A positive tuberculin test in a 30-year-old woman indicates that she

1. is capable of mounting a delayed hypersensitivity reaction
2. is unlikely to be suffering from a T cell immunodeficiency
3. is manifesting a secondary response to tuberculoprotein
4. has almost certainly encountered live mycobacteria previously

Q11 A renal allograft recipient is given anti-CD3 (a monoclonal antibody) to treat a rejection episode.
Possible outcomes include
1. Type III hypersensitivity
2. the production of anti-mouse antibodies
3. suppression of the rejection episode
4. rejection of the allograft
Q12 Phagocytosis by macrophages is enhanced as a result of

1. activation by IFNg (interferon gamma)
2. adherence of IgG antibodies
3. adherence of IgM antibodies
4. fixation of complement by IgM antibodies

Answers and Commentary
A1 A
The patient’s history raises the possibility of cancer or immunodeficiency. Agammaglobulinaemia is
unlikely at his age. Recurrent infections complicate some complement deficiencies, but no evidence is
provided that would support this diagnosis. His blood picture shows a low T cell (CD3) count
particularly involving T helper (CD4) cells. The negative tuberculin test is consistent with a T cell
immunodeficiency (although not diagnostic of it). All the evidence given points to AIDS as the most
likely diagnosis (which is what was asked in the stem).
KEY ISSUE
NOTE: The more searching Type A MCQs usually ask for the best answer out of a list of alternatives,
rather than calling for true/false statements.
A2 1. False Normal T cells do not express Class II (HLA- DR) antigens. B lymphocytes are necessary
for this.
2. True
3. True The MLR identifies HLA-D region (Class II) incompatibilities.
4. False DNA typing reveals many more alleles than are currently identifiable serologically.
It remains uncertain how important some of them are in graft rejection.
A3 1. True
2. True
3. True Patients undergoing splenectomy, and especially children, should be vaccinated against all
three of the above encapsulated organisms. They are each well documented as causing
overwhelming post-splenectomy infection.
4. False Splenectomised patients are not unduly prone to get measles. But apart from this, live
vaccines such as measles are contra-indicated when there is any possibility that the immune
system is compromised.

A4 1. False Immunisation against tetanus does not lead to herd immunity, because Cl tetani normally
lives outside the human body. Herd immunity operates only in the case of infective organisms
whose survival depends on human hosts.
2. True Prophylactic antitoxin after injury will be confined to the unimmunised, now a minority of the
population.
3. True Toxoid rather than antitoxin will be given after injury to the immunised, who now make up
the majority of the population.
4. True Memory after toxoid administration should last for several years.
A5 1. True
2. True Each parent will contribute one HLA haplotype (=the HLA antigens on one chromosome) to
each of their children. Thus, both parents will almost certainly be HLA haplo-identical with their
son. The slight uncertainty (which verges on the pedantic) relates to the remote possibility that
crossing over at meiosis has given the son a haplotype that differs from the original parent
haplotype.
3. False ABO compatibility is mandatory in renal transplantation
4. False HLA identity between mother and son is extremely rare in the absence of significant
inbreeding. Complete HLA identity, however, occurs with a frequency of 1 in 4 among full siblings
(children of the same parents).
A6 1. True
2. True
3. False IgE does not fix (activate) complement.
4. False Gamma interferon does activate macrophages, but anaphylaxis can occur without this
taking place.
A7 1. True Note that this option can come another way - asking the significance of IgG and IgM rubella
antibodies in cord blood. IgG antibodies are maternal (the fetus cannot make IgG), whereas IgM
antibodies are fetal (= intrauterine infection) because IgM cannot cross the placenta.
2. False More IgA than IgG is made each day (notwithstanding the level of plasma IgG).
3. False Early antibody is IgM.
4. False Except after incompatible transfusion they are IgM, a point that has fascinated physiology
and pathology examiners for years.
General comment: Both the structure and function of antibodies lend themselves very readily to
MCQs.

A8 1. True
2. False One specificity is shared among all the antibody classes made by a single clone of B cells
(ie descendants from a common ancestor). Thus, surface immunoglobulin on a B given cell may
be IgD or IgM or both, and the antibodies exported by its plasma cell descendants are likely to be
IgG or IgA. The combining site remains the same while the constant region is ‘switched’.
3. True Surface Ig (the antigen receptor of B cells) is not expressed on plasma cells.
4. True At first glance a hard option? Remember that any cell that is exporting protein on a large
scale will contain plenty of RNA. (Cells that are making protein prior to dividing will likewise have
plentiful cytoplasmic RNA. Hence the basophilia (affinity for basic dyes) of plasma cells and bone
marrow stem cells).
A9 1. True
2. True
3. True
4. True This is a straightforward question, except possibly for Option 4, which might raise some
uncertainty in relation to ‘both T cells and B cells?’ T cells will always be involved - they are
necessary to initiate the immune response and to induce memory. Maybe not every antigen will
necessarily provoke antibody production (some TH1 reactions for instance). But in this question
antibodies feature in three of the options, so clearly B cell clones are not out of place.
A10 1. True The tuberculin test (eg Mantoux or Heaf test) is a manifestation of delayed hypersensitivity.
2. True The tuberculin reaction is used as a test of T cell function.
3. True Hypersensitivity reactions all represent manifestations of the secondary immune response -
they do not occur on first exposure to antigen.
4. True Tuberculin-positive young adults have either been immunised or have been infected with
M. tuberculosis. If she has been immunised she will have been given a live attenuated vaccine -
probably BCG. Thus, the antigen that provoked her tuberculin hypersensitivity almost certainly
came with live mycobacteria (Tuberculoprotein given in skin tests is not an effective immunogen).
A11 1. True
2. True
3. True
4. True Most monoclonal antibodies are mouse immunoglobulins. Animal proteins are very
immunogenic, so the host is likely to produce anti-mouse antibodies (Option 2), Immune complex
disease (serum sickness) is a recognised complication of administering animal protein (Option 1).
Anti-mouse antibodies may divert the anti-CD3 (=anti-T cell) monoclonal antibody so that it does
not interfere with the graft rejection reaction (Option 4). If the host does not produce antibodies to
the mouse immunoglobulin, or is slow to do so, graft rejection may be averted (Option 3).

A12 1. True This is an important part of TH1 responses.

2. True Macrophages have receptors for IgG.
3. False Macrophages do not have receptors for IgM.
4. True Macrophages have complement receptors, and phagocytose IgM antibodies that have fixed
complement by virtue of these.
REFERENCE
Candidates wishing additional audiovisual reference material can obtain the video cartoon Antigen
Presentation from the Dunedin Basic Medical Sciences Course Trust C/- Pathology Department,
Otago Medical School, Dunedin, NZ. Ph: +64 (3) 479 7286; Fax: +64 (3) 477 2042
Email: jenny.hurley@stonebow.otago.ac.nz.
For further information on how to access the Antigen Presentation video refer to
http://healthsci.otago.ac.nz/PART1FRACS.

SECTION 2: CLINICAL TRANSPLANTATION
TOPIC 9: ORGAN DONORS, ORGAN DONOR PROCUREMENT

AND ORGAN PRESERVATION
Factors related to organ donors, organ procurement and preservation are integral to the process of
transplantation. It is presupposed that the organ that is implanted in the patient should have perfect function
from the onset. This is the primary ethical consideration relating to organ implantation in the recipient.
9.1. Living Donors
Organ donation has been made from two principal sources, living and cadaver donors. Ethical aspects
of allografts from living donors are complex; a landmark was the first successful graft from a living donor
by kidney transplantation in Boston between identical twins (isogeneic allograft or isograft). Since then
allografts from living donors other than identical twins have played an important role in organ and tissue
transplantation. Live donors have been used for grafts of both regenerative (bone marrow, skin, liver)
and non-regenerative (kidney, heart, lung, pancreas, bowel) tissues and organs.
Live donors have been most extensively used for bone marrow and renal allografts. Experienced
special centres have successfully used live donors for segmental liver, pancreatic and small bowel
allografts.
In renal transplantation, allografts from living donors (particularly those from related donors) show
overall better graft survival than cadaver allografts, despite advances in immunosuppression, tissue
matching and organ preservation.
The genetics of HLA specificities and their inheritance is relevant here (Figure 3).

Refer to Figure 3
9.2. Brain-Dead Organ Donors
Until recently, live donors have constituted the minor component of donor organ supply, the majority
having been derived from cadaver sources. There is no doubt that the most suitable major source of
donor organs continues to be from the certified brain-dead individual. The brain-dead cadaver,
maintained on a ventilator, can sustain organ function for a period, and cardio-pulmonary supports
adjusted to maintain and preserve a homeostatic media with near-normal haematological and
biochemical parameters. To achieve this goal it has been essential to establish brain death criteria.
These criteria’s should be revised in the reference texts relating to the subject; and the management
system of organ donation within the health care services of each of the international communities
should be reviewed.

The most successful of the organ donation agencies are to be found in Spain and in South Australia
(which is modelled on the Spanish example). Working arrangements for these models should be
investigated. Each encompasses a specific post filled by a medically qualified transplant co-ordinator,
whose principal task is to identify potential organ donors, and who is an individual with well honed
interpersonal skills to enable discussion of organ donation in an empathetic and conclusive manner with
the next of kin. The same individual should have the skills to direct the management of the donor, to
maintain cardio-respiratory function in the optimal range for continuing normal function of the intended
donor organs. Donor management is a difficult task as the death of the brain initiates vasomotor
instability that requires pharmacological manipulation and ventilatory control to optimise lung function.
These interventions should not result in ischaemia of the intended organs for donation.
REFERENCE
Toouli J et al, Integrated Basic Surgical Sciences, Arnold, London, 2000; Chapter 27: House, Kierath,
Bell.
nd
Morris PJ, Malt RA (Eds), Oxford Textbook of Surgery, 2 Edition, Oxford University Press, Oxford, in
press 2000; Marshall V et al, ‘Organ and Tissue Preservation for Transplantation’.
SELF-TEST TASK
· List the requirements for brain death.

· Create a figure showing the managerial structure of a successful organ donation agency.
· Formulate a table depicting the key requirements for organ donation.
· Create a second table noting the organ specific requirements of organ donation.
Refer to learning materials listed above.

9.3. Ethical Issues
There is a broad range of ethical considerations pertaining to organ donation. Broadly these relate to
the competence of the caring staff, the requirements for the certification of brain death, that the person
seeking consent for organ donation shall not be involved in the process of transplantation, that the
wishes of the donor and the donor family shall be respected and initiated. If the organs or tissues are
not suitable for donation an appropriate explanation should be given to the individual consenting to
organ donation. The donated organs should be distributed on grounds of medical priority, to those most
suitable and in most urgent need of transplantation. The ethical issues relating to the community
revolve around the allocation of funds in support of organ transplantation and are governed by the
outcome and quality of life conferred on the recipient.
SELF-TEST TASK
· Create a table defining the ethical issues of organ donation and for those receiving an
organ transplant.
9.4. Organ Preservation
Effective organ preservation facilitates the transplant process and is achieved by strict adherence to
limiting the ischaemic injury. This is greatest at body temperature and is diminished with organ cooling
to 4ºC. Below this temperature cell damage may again occur by freezing. The preservation process
aims to limit the movement of sodium and potassium ions across the cell membrane, and to prevent
disruption of the cell by swelling promoted by extracellular water entering the cell by osmosis.
Preservation fluids have been designed to neutralise these pathological changes that occur with
hypoxia.
SELF-TEST TASK
· List the currently used preservation fluids and their principal components, with their physiological
function.
· Create a figure outlining the mode of organ injury in ischaemia and preservation. Indicate the site
of action of the components of the preservation fluids.

9.5. Donor Care and Organ Retrieval
The aim is to maintain blood pressure and oxygen saturation from the time of donor identification to
organ retrieval. Organs are to be cooled and stored at 4ºC as rapidly as possible from the cessation of
circulation.
SELF-TEST TASK
· List the steps taken in multiple organ retrieval.
· List sources of organ donors other than cadavers, and note the limitations for their use.
REFERENCES
Learning Material
Toouli J, Russell RCG, Devitt P, Ingham Clark C (Eds), Integrated Basic Surgical Sciences,
Arnold, London, 2000; Chapter 27: House, Kierath, Bell.
Diagnosis of Brain Death, British Medical Journal, 1976; 2: 1187-1188.
Other Reading
nd
Morris PJ, Malt RA (Eds), Oxford Textbook of Surgery, 2 Edition, Oxford University Press,
Oxford, in press 2000; Marshall V et al , ‘Organ and Tissue Preservation for Transplantation’.
Matesanz R, Miranda B (Eds), Organ Donation for Transplantation, The Spanish Model; Aula
Medica Madrid, Barcelona, 1996; Chapter 11, page 133. Meeting the organ shortage, current
states and strategies for improvement of cadaveric organ donation.
Chapman J, Deilerhoi M, Wight C (Eds), Organ and Tissue Donation for Transplantation, 1996;
Chapter 5: page 62, Sir Roy Calne. Ethics in Organ Donation and Transplantation. The Position
of the Transplantation Society (1996);
Chapter 6: page 62. Ian Pearson. Brain Death.
Chapter 11: page 200. Vernon C Marshall. Organ and Tissue Preservation.
Chapter 18: page 361, Rapael Matesanz, Blanca Miranda. The Spanish Experience in Organ
Donation.

(TYPE X – MULTIPLE TRUE - FALSE)
Q1 Modern organ transplantation owes its success to the contribution of which of the following individuals?
1. Gibson, Medawar and Billingham
2. Murray and Merrill.
3. Starzl
4. Calne
Q2 Brain death
1. is best diagnosed by a single medical practitioner
2. requires the heart to stop contracting
3. can only be diagnosed by angiography
4. is established by confirmation of absent brain-stem function
Q3 Organ donation rates in many countries in the world are low in terms of donors per million of population.
As a consequence
1. patients waiting on organ transplant lists are dying on waiting lists
2. health care dollars are consumed by the requirement for an increasing number of patients
remaining on renal dialysis programmes who would be better served by a kidney transplant
3. can be improved by more focused National Organ Donor Agencies similar to that in Spain
4. can be improved by better identification of potential donors
Q4 Brain stem death requires management of specific problems as outlined below
1. hypotension by high doses of catecholamines

2. poor urine output by volume expansion
3. maintenance of systolic blood pressure at 90-100mmHg
4. maintenance of arterial oxygen saturation of 95-100%
5. maintenance of body temperature

Q5 Any individual can be an organ donor after death except
1. those with malignancy

2. those with severe sepsis
3. those who have drowned
4. those over 50 years of age
Q6 The principles governing organ preservation include
1. minimising ischaemic time

2. preserving the intracellular osmotic pressure
3. minimising oxygen consumption and metabolism of the cell
4. adding glutathione to the perfusion fluid
Q7 Xenotransplantation is limited by
1. hyperacute rejection
2. the potential for animal virus transmission to man
3. development of breeding programmes for donor animals
4. the uncertain physiological function of animal organs in man
Q8 Organ transplantation from a live donor can occur for which of the following organs?
1. The Kidney
2. The Liver
3. The Pancreas
4. The Lung

Answers and Commentaries
A1 1. True A number of individuals have made observations concerning the presence of

lymphocytes in implanted tumours but it was the observations in burned patients of Gibson,
Medawar and Billingham that established the basis of the current understanding of the
immune process in transplantation. They treated the severely burned with allograft skin
grafts and observed that the first of these grafts were rejected in 10-14 days. On regrafting
from the same donor there was an accelerated rejection process. They established that the
predominant cell involved in this rejection was the lymphocyte. These observations
stimulated extensive work in this field to define the role of lymphocytes in the immune
response. The work extending their observations was performed in many institutions
throughout the world; but of particular note was that performed in the Walter and Eliza Hall
Institute in Melbourne. Medawar and Burnet subsequently received Nobel Prizes in
Medicine.
2. True Murray, surgeon, and Merrill, nephrologist, performed the first successful kidney
transplant between identical twins in Boston; and in so doing established the surgical
technique and the basis for developing immune suppression that subsequently enabled renal
transplantation between nonidentical individuals. Other kidney transplants had been
performed unsuccessfully around the world, in France and Russia; and prior to this vascular
suturing had been pioneered by Alexis Carrel in the early 1900s as a method of joining blood
vessels. Joseph Murray subsequently received the Nobel Prize for his contribution.
3. True Thomas Starzl initiated a great deal of scientific work relating to transplantation in
Boston, and then in Denver Colorado U.S.A, where he transplanted a number of livers in
animal models and subsequently in humans. A number of these first human liver transplant
recipients are alive and well today. Subsequently in Pittsburgh he established a highly
successful liver transplant unit that is now supported by a multi-million dollar transplantation
research institute. The Pittsburgh Unit under the direction of Professor Starzl pioneered the
clinical trials in the use of FK506 (tacrolimus) now one of the major immunosuppressive
agents available to treat organ rejection seen in all branches of transplantation.
4. True Sir Roy Calne was intimately involved with the development of immunosuppression,
particularly the use of azathioprine and corticosteroids. At first this was with the Boston
group but subsequently in Cambridge, where he was responsible for the establishment of
one of the major European Centres for liver transplantation and pioneered also experimental
and clinical studies in the use of cyclosporin. The Cambridge Unit in the United Kingdom, like
the Pittsburgh Unit in the United States, was responsible for training a large number of
surgeons in the field of transplantation. These individuals have successfully initiated liver
transplantation services throughout the world.

A2 1. False The requirements for the diagnosis of brain death are stringently defined by
legislation. Diagnosis must be undertaken by two appropriately qualified medical
practitioners performing the tests for brain death independently of one another. The testing
being undertaken is separated by a time interval. Prior to testing it must have been
established that there is no pharmacological reason for brain function to be suppressed (for
example by the presence of sedative medications, or of metabolic or endocrine
derangement).
2. False Brain death does not require the heart to have stopped contracting. In fact if asystole
had occurred the use of brain death criteria would become redundant. However brain death
may generate cardiac irregularity, which if unmanaged may lead to cardiac arrest. Hence the
management of the brain-dead subject requires careful supervision and expert care.
3. False The establishment of brain death is a clinical diagnosis that follows strict guidelines to
establish that brain stem function has ceased. The brain stem functions are listed in the text
Integrated Basis Surgical Sciences; Toouli J et al, Chapter 27: House, Bell, Kierath; and they
are the subject of a seminal article in the British Medical Journal. Occasionally if there are
severe injuries or disruption of the face making clinical testing impossible, a four vessel
cerebral angiogram will be used to establish that there is no cerebral blood circulation.
4. True Confirmation of brain death is a clinically based diagnosis. The testing is performed by
two medically qualified individuals, proficient in performing the task and undertaken on two
separate occasions. The functions of the brain-stem are tested and found to be irreversibly
absent before the diagnosis can be made.

A3 1. True The requirement for organ transplantation is expanding due to an increasing

expectation for survival and improved quality of life for organ transplant recipients. Those
more likely to benefit from this treatment are being more precisely identified. Organ donor
rates of 20–25 per million are a realistic expectation and can be achieved; as has been the
case in Spain and South Australia. This number of donors would substantially reduce
waiting lists and reverse the trend of the steadily increasing number of patients on renal
dialysis waiting for transplantation. The number of patients dying on the current liver and
heart transplantation waiting lists is of the order of 15–20%.
2. True The cost of maintaining a patient on renal dialysis is considerably greater than the
costs associated with renal transplantation. Hence there is an escalating cost of the
increasing number of patients requiring renal dialysis who, although eligible for renal
transplantation, cannot be transplanted on account of organs not being available. If this
finance were used to support a better process of organ donation there could be substantially
improved numbers of organ donors with the potential for a greater number of renal
transplants and a decline in renal dialysis patient numbers.
3. True The Spanish and South Australian Donor Agency have conclusively demonstrated that
a greater number of organs for donation per million of population can be achieved through
more focused programmes administered through single donor agencies that are supported
by a national one line budget, administered by a medical director, employ medically qualified
donor co-ordinators, have a specific and dedicated programme of donor co-ordinator
education and specifically identify potential organ donors.
4. True Currently there are many more potential donors available for organ donation than are
identified. This has been demonstrated in a number of national surveys and relates
specifically to patients who may not reach treatment in Intensive Care Departments.

A4 1. False Hypotension in the brain-stem dead organ donor should not be preferentially
managed with high doses of catecholamines. These stimulate vaso-constriction in the renal
and mesenteric blood flow and hence potentiate organ ischaemia and organ damage.
Hypotension is best managed by fluid volume replacement; and if need be, the use of small
doses of dopamine, which potentiate renal and mesenteric blood flow.
2. True Brain-stem death often is associated with destruction of the hypothalamic-pituitary axis
and diabetes insipidus. This state requires vigilant fluid replacement. If the reverse occurs
and urine output falls intra-vascular volume expansion may be required by fluid replacement
to maintain a high central venous pressure. On occasion poor urine output may be
stimulated by treatment with mannitol or frusemide to initiate a diuresis. Renal function in
the recipient after transplantation is often better where the urine output in the donor has been
maintained at a high level.
3. True Systolic blood pressure in the donor should be maintained above the minimal values of
90-100mm Hg to ensure that there is adequate perfusion of the transplantable organs.
Hypovolaemia is often the reason for a low blood pressure; and as a consequence
increasing the rate of fluid infusion to maintain a central venous pressure will assist with
maintenance of a systolic blood pressure.
4. True Failure to maintain arterial oxygen saturation at a high level in the donor compounds
the ischaemic injury in transplantable organs. Positive pressure ventilation should be
maintained to optimise and maintain lung function.
5. True Brain stem death is associated with body cooling due to loss of temperature control.
Hypothermia to temperatures below 33ºC can increase the risk of cardio-vascular instability.
Hence body warming devices may be needed to maintain donor body temperature prior to
and during organ retrieval. However once organ perfusion with preservation fluid begins
rapid cooling of donor organs is essential.

A5 1. True Any patient with systemic malignancy is not suitable as an organ donor. There is a
serious potential for transmission of malignant cells with the transplanted organ. This
general concept of not using organs of those with malignancy is becoming more difficult; as
there are now patients with relatively occult malignancy (such as in situ-carcinoma of the
breast and thin melanomas) where the potential for metastatic spread is extremely small.
However these patients are presently excluded from donation. Primary malignancies of the
brain do not metastasise, so patients with primary brain malignancy are eligible for organ
donation unless a shunting procedure has been performed from CSF to the systemic
circulation or to the peritoneum. After such procedures brain malignancies can spread
systemically and can be transmitted by organ transplantation to a recipient.
2. True Patients with severe sepsis (including bacterial sepsis, HIV, hepatitis B & C and other
viral infections) are generally not suitable as donors, but the circumstances surrounding each
case must be considered on merit. For example Cytomegalovirus (CMV) positive donors are
suitable when the organs are transplanted into CMV-positive patients. Circumstances
surrounding the Hepatitis’s are now less clear; as there are means whereby those without
Hepatitis B can be immunised against the virus and under these conditions or in urgent
circumstances transplantation may be considered. Again organ donation in the presence of
sepsis requires ongoing and constant re-evaluation.
3. False Patients who have suffered premature death on account of drowning may be eligible
donors; provided the ischaemic interval between cardiac arrest and resuscitation with the
establishment of cardio-pulmonary function is short. If this is the case and brain death has
been certified, these patients may be suitable for organ donation. Generally such patients
are not suitable for lung donation. The governing factor in this situation, as in all donors
suffering untimely death, is the ischaemic interval between cardiac arrest and cardio-
pulmonary resuscitation.
4. False Patients over the age of 50 may be suitable for organ donation. Usually patients in
this age group are carefully scrutinised if they are to be considered for heart donation but for
the other organs, kidney, liver and lungs, provided the organs are functioning normally age is
not a criteria for exclusion. At the moment patients to the age of 70 can be considered for
organ donation.

A6 1. True The ischaemic time, both warm and cold, should be minimised in organ preservation to
optimise organ function after vascular re-anastomosis. This is achieved first by attempting to
manage the donor in a haemodynamically stable state, then cooling the organs by perfusion
with a cold solution to obtain rapid organ core cooling. The organ is maintained in a cooled
state at 0º - 4ºC either by immersion in ice or by machine perfusion. There is a limit to the
tolerated period of cold ischaemia. This is organ specific and hence each of the whole
organs, heart, lung, pancreas, liver and kidney must be implanted within a prescribed period
of time.
2. True With ischaemia, the cell membrane high energy phosphates (HEPs) cannot drive the
sodium/potassium pump. An influx of sodium into the cell follows and the resultant osmotic
attraction of water into the cell causes cell swelling and lysis. Preservation fluids are all
constructed to contain impermeable solutes to counter the potential movement of water from
the extracellular space into the cell. Many also have high potassium levels, but the
electrolyte content can be variable.
3. True The oxygen consumption and metabolism of the cell is greatest at normothermia and
very reduced at 4ºC. Hence rapid cooling diminishes the cell oxygen consumption and its
metabolism; and accordingly preserves cell viability for a longer period. Indeed oxygen
consumption falls by a factor of 12 from normothermia to 0ºC; so tissues that are able to
withstand one hour of ischaemia at normothermia, can be stored for up to 12 hours by
simple hypothermia (0º - 4ºC).
4. True Glutathione is a component of many perfusion fluids. It is a free radical scavenger

which helps to block the cell enzymes responsible for the production of superoxide radicals.
In this way the re-perfusion injury that occurs on re-oxygenation of the ischaemic tissue is
minimised.

A7 1. True Hyperacute rejection occurs in Xenograft transplants. Animal breeding programmes

and genetic engineering is under investigation in an attempt to modify this response, which
resides in the carbohydrate component of the cell membrane. Some success has been
achieved in mice and pig breeding programmes.
2. True There is potential for the transmission of animal viruses to man; but the true extent of
this is unknown. It is thought that the major influenza epidemic of Europe might have arisen
as a variant of swine fever. It is anticipated that with careful breeding programmes and
appropriate animal housing this potential side effect of xenotransplantation might be avoided.
3. True At the moment there are no defined breeding programmes for donor animals.
Presently the process is experimental; but if the biologically defined obstacles can be
overcome specific breeding programmes will be required to carefully monitor and control the
animals’ breeding environment.
4. True Although mammalian organs have similar basic functions there are species
differences, which at this stage have not been defined for animal organs transplanted into
man. A baboon to man liver transplant in Pittsburgh was associated with very low levels of
uric acid in the recipient. This indicated one aspect in which the metabolism of the baboon
liver was different from that of a human.

A8 1. True Living kidney transplantation occurs regularly between close relatives (siblings,
parents to siblings, siblings to parents), and also between unrelated individuals (spouses and
partners). Concern remains about widening this process to unrelated and unassociated
individuals. There are perceived ethical and social problems which potentially could create
disharmony between donor and recipient after the event.
2. True Liver transplantation between relatives is becoming more popular and more universal.
This has occurred on account of the shortage of donor organs, the diminished and now
minimal morbidity and mortality associated with hepatic resection. The outcome for split liver
or liver lobe grafts is as good in terms of organ survival and function as whole organ
transplants.
3. True Partial pancreatectomy from a live related donor, with transplantation of the pancreatic
segment by vascular anastomoses to the recipient, has been performed. There has been a
high prevalence of pancreatitis and diabetes reported in the donors of pancreatic transplants,
and hence nowadays this form of living related transplantation is infrequently considered.
4. True Living related lung transplantation has been successfully undertaken. This has been
possible where the donor is of larger size than the recipient; the lower lobe of the lung is
usually used. This procedure is infrequently performed. Lung and pancreas transplantation
from living donors illustrate the difficulties of informed consent for procedures on live donors,
and the often complex and controversial ethical issues involved.

Study the scenarios and review and revise the appropriate section in the prescribed texts.
CASE SCENARIO 1
A 49-year-old male was admitted collapsed and unconscious requiring intubation and ventilation.
An intra-cerebral bleed secondary to an aneurysm is diagnosed.
SELF-TEST TASK 1
1. Is this patient a potential organ donor at this stage? List the positive and negative factors
concerning this patient acting in this role.
2. What steps should be taken in the care of the patient?
3. When can the patient be considered an organ donor?
4. List the steps taken to establish the individual as an organ donor.
CASE SCENARIO 2
The individual becomes an organ donor from whom the kidneys and liver are removed for donation.
Preservation is by cold storage after cooling with a preservation fluid.
SELF-TEST TASK 2
1. List the principal components of an organ perfusion fluid. (for example University of Wisconsin
(UW) fluid)
2. List the actions of four of these components.
3. In removing the liver what anatomical structures are isolated and where?
4. In removing the kidneys which anatomical structures are mobilised?

TOPIC 10: THE RECIPIENT
Potential transplant recipients are individuals whose bone marrow, corneas, bones, skin, solid organs, heart,
lungs, liver, kidney, small bowel and pancreas have failed; and as a consequence the life or quality of life is
threatened. Under these circumstances transplantation can be considered as a modality of therapy.
Recently the loss of a hand or digit has been included in a group of organs or tissues transplanted.
Transplantation is only considered for whole organs when there is end stage disease and the patient will
shortly die without a new organ. For the kidney, and in some circumstances the heart, pancreas and small
bowel, patients may be maintained on a machine or by other organ support mechanisms such as insulin or
intravenous nutrition. The indications for transplantation may be broadened if the supply of donatable
organs became greater, this would allow recipients with less favourable prognosis to be considered as
recipients (for example in the case of the liver, those with a hepatoma).
All allografts are associated with rejection. The severity of this rejection varies with the organ or tissue. Skin
and bone marrow tend to be associated with a vigorous rejection process, whilst with bone transplants this
response is of less significance. In the latter circumstance the bone allograft acts as scaffolding for new
bone formation while the osteocytes are rejected. Small bowel transplantation is also associated with
vigorous rejection on account of the extensive quality of lymphoid tissue implanted with the graft. When
rejection is vigorous and requires extensive immunosuppression, there is an increased probability of
opportunist infection (particularly from viruses) and of the development of neoplasia (lymphomas in
particular) occurring in the host. When there is excessive lymphoid tissue implanted with the graft there is
also the risk of graft versus host disease or the development of lymphoproliferative disease.
SELF-TEST TASK
1. Construct a table demonstrating the probable difficulties that might occur in an allograft hand
transplant. How will this differ from a hand replantation as an autograft?
2. Construct a table of the general contraindications that will preclude a patient from transplantation
of a whole organ allograft.

10.1. Indications and Contraindications for Transplantation
There are specific indications for transplantation: these are end stage organ failure that severely limits
life expectancy or impairs the quality of life. Generally the recipient should be well, except for failure of
the organ in question. This implies that none of the general contraindications listed in Toouli J et al,
Integrated basic Surgical Sciences, Arnold, London, 2000; Chapter 27: House, Kierath, Bell prevail. It
is also imperative that recipients have stable social support; and are free from psychiatric illness in
order that they comply with ongoing treatment and do not succumb to alcohol or drug abuse. There are
age limits below or beyond which a patient will not be accepted for transplantation, as the benefit from
transplantation is likely to be eclipsed by the age factor.
SELF-TEST TASK
Construct a list of the organ-specific aetiologies that lead to end organ failure and that are compatible
with allotransplantation.
Each organ requiring transplantation has specific indications and contraindications determined by the
projected graft survival and patient survival after transplantation. The primary disease inducing end-
stage organ failure has the capacity to recur in the graft in a variable manner, depending on the
precipitating illness causing end-stage organ failure. The specific organ determined indications for
transplantation are listed in Toouli J et al, Integrated Basic Surgical Sciences, Arnold, London, 2000;
Chapter 27: House, Bell, Kierath. As a general rule those disease processes with an immune
vasculopathy or with a systemic viral illness contributing to the aetiology are more likely to recur in the
recipient. Those diseases with mechanical or toxic causes for end-stage disease are less likely to recur
in the recipient, provided these aetiologies have been corrected.
SELF-TEST TASK
Construct a table of the organ-specific diseases that are likely to recur in the grafted organ.
In general terms, the fitter the patient at the time of transplantation, the greater the expectation in
terms of graft and patient survival. Tissue typing has a variable impact, and is organ-specific. It is
most relevant for kidney transplantation and appears to be least relevant for liver transplantation.
Organ size in relation to the recipient has an impact on outcome. If the organ is too small it will fail to
have sufficient output to maintain life-sustaining functions. If it is too large there will be the mechanical
difficulty of implanting it in the available space. In this regard the development of the technical expertise
to reduce donor organs to match the size of the recipient, has enabled a more efficient use of available
donor organs. This is particularly important in liver transplantation where a child and an adult, or two

small adults, can be transplanted from a single liver. This practice has considerably reduced the
waiting list for paediatric transplantation with a consequence of reducing waiting list recipient mortality in
paediatric liver transplants.
10.2. The Complications of Whole Organ Transplantation
In general the first twelve months after transplantation is associated with the greatest number of
complications leading to graft loss. Beyond this period, graft attrition occurs at a much slower rate,
more frequently related to chronic rejection, sepsis and the loss of the recipient secondary to the
development of neoplastic or vascular disease.
The complications resulting in early graft loss include primary non-function of the graft, technical
problems, rejection and infection.
Primary Non-function
Primary non-function has a variable impact; in the kidney it can be treated by placing the patient back
on dialysis, but in the heart and liver is far more likely to result in the patient’s death.
Technical Problems
Technical problems may occur in up to 10% of grafts, but they vary with the organ being transplanted.
Rejection
Rejection may rarely be a hyperacute phenomenon in which the graft becomes cyanotic, swollen and
non-functional within hours or minutes of implantation. This form of rejection is secondary to preformed
antibodies which induce platelet activation and coagulation of the blood, particularly in the
microvasculature.
Acute Rejection
Acute rejection is a cellular response in which T lymphocytes are activated to induce inflammatory
changes usually seen in and around the functional part of the graft such as glomerulus, portal tracts,
microvasculature of the heart, the bronchi, and islet cells of the pancreas.

The Management of Rejection

Rejection is prevented or suppressed with immunosuppressive therapy that includes glucocorticoids,
azathioprine, cyclosporin or tacrolimus. Other drugs used include mycophenolate, serolimus and
the anti-lymphocyte antibodies. Acute rejection episodes are initially treated with bolus injections of
glucocorticoids, but may also require the use of anti-lymphocyte antibodies. Rejection therapy has to be
maintained to control rejection on the one hand, but not too vigorously on the other, so as to minimise
the risk of opportunistic viral, fungal or bacterial sepsis. Excessive immunosuppression over a long
period is likely to be associated with the development of malignancy.
Infection
Infection is a common cause of graft loss, both in the initial early period after transplantation and in the
long term follow up of the transplant recipient. Early infections more frequently are associated with
bacteria that gain entrance to the body via wounds, drains, airways, urethra and the biliary tree. The
later infections tend to be viral, fungal, cryptococcal or Pneumocystis and are opportunist, secondary to
immunosuppression.
Malignancy and Vascular Disease in Transplantation

Malignancy is an increasing cause of recipient death after transplantation. The development of these
malignancies are incrementally time-based and the tumours include the entire spectrum of malignant
disease. Skin malignancies tend to be the most common, and lymphomas the most specific; but
malignancy of any organ can and does occur.
Vascular disease is a common manifestation after transplantation. It occurs as progressive atheroma

and may result in coronary artery or cerebral vascular disease, but also is associated with hypertension
and renal failure. Renal failure is more common with cyclosporin or tacrolimus immunosuppression,
which have nephrotoxicity problems.
Re-transplantation
Transplant graft failure progressing to death can be treated by re-transplantation, but in this
circumstance the probability of graft failure and recipient mortality is considerably higher than with first
grafts.

Recurrent Primary Disease

Recurrent primary disease is a common feature with all organs for particular disease processes. For
example hepatitis B and C in liver transplantation are associated with a probability of recurrence
between 5-10%. Similarly other disease processes can and do occur in the recipient. The section on
‘Complications of Whole Organ Transplantation’ should be reviewed in Toouli J et al, Integrated Basic
Surgical Sciences, Arnold, London, 2000; in Chapter 27: House, Bell, Kierath.
SELF-TEST TASK
Construct a Table denoting the organ-specific complications after transplantation – Early and Late.
10.3. Ethics in Transplantation
General considerations relate to cadaver organ donors, living organ donors and the recipient. There
are also considerations relating to the quality of organs transplanted, the distribution of these organs,
and ethical issues involving the community and the provision of health services. These should be
reviewed in the section relating to the subject in Toouli J et al, Integrated Basic Surgical Sciences,
Arnold, London, 2000; Chapter 27: House, Bell Kierath.
SELF-TEST TASK
1. Construct a table of the headings under which the ethics of organ transplantation should be
considered.
2. What are the guiding ethical principles in organ transplantation?

10.4. Outcome For Transplant Patients
A number of factors have been cited that determine the outcome after transplantation. These include:
· The era of transplantation
· Donor factors
· Donor/recipient matching
· The presence of infection (particularly cytomegalovirus infection)
· The health status of the recipient at the time of transplantation
· The need for re-grafting
· The availability of effective immunosuppression
The progressively improved survival outcome after transplantation has been remarkable; and
enhanced considerably by development of better disease understanding and effective
immunosuppression management. The outcome now is superior to many commonly treated illnesses
such as colorectal cancer, peripheral vascular disease and other forms of cancer. Outcome is
expressed in terms of graft survival and patient survival; it is also expressed in quality of life terms.
Most whole organ allograft recipients can now expect to be alive and be well in 70-90% of patients at
five years. These results are governed by the organ transplanted, the matching between donor and
recipient and the disease process which made transplantation necessary. The social outcome for
transplantation is such that the recipient can return to a normal life style, participate in the work place,
and bear and raise children.
SELF-TEST TASK
1. Construct a five-year figure of organ survival after transplantation indicating the transplant era
effect and annotate the historical advances contributing to the change.
2. Construct a five-year figure of organ survival after transplantation indicating the primary disease
influence on organ survival. Annotate the factors influencing survival in the first year and
subsequent four-year periods.

(TYPE X – MULTIPLE TRUE - FALSE)
Q1 Organs or tissues commonly allografted include

1. bone marrow
2. the hand
3. small bowel
4. liver
5. bone
Q2 A whole organ transplant recipient (heart, liver, kidney) must be

1. in end organ failure
2. stable in social support and compliant
3. older than 65 years
4. in advanced disease with more than one organ failing
Q3 Organ transplantation is usually complicated by

1. Primary non-function of the graft
2. Technical problems of arterial or venous occlusion
3. Acute rejection
4. Early cardiopulmonary failure
Q4 Failing transplanted organs lost to rejection usually do so on account of

1. hyperacute rejection
2. acute rejection
3. chronic rejection
4. recurrent primary disease
Q5 The commonly used anti-rejection medications include

1. Glucocorticoids
2. Mycophenolate mofetil
3. Cyclosporin
4. Tacrolimus

Commentaries
A1 This is a type X question in which the statements 1, 2, 3 or 4 are true or false.
1. True Allografts of bone marrow are commonly transplanted for a number of haematological
disorders, including the lymphomas. The best results are obtained from living donors where
there is close HLA matching but the outcome is influenced by the development of graft-
versus-host, lymphoproliferative or primary disease.
2. False There have been few allografted hands. This procedure was undertaken recently in
France but is associated (to an even greater degree than are autografts), with long term
difficulties associated with nerve regeneration (and as a consequence the re-establishment
of sensation to the part) and of muscle movement. The procedure requires extensive
rehabilitation and constant surveillance with physiotherapy to maintain joint mobility,
protection of the part to avoid trauma associated with the neuropathy, and vigilance to
prevent rejection account of the high allogeneity of skin. Long term consequences are those
of prolonged high dose immunosuppression required to control the rejection process. Hence
the cost benefits and risks to the patient require careful evaluation and long term outcome is
unknown.
3. True Small bowel is now an established modality of treatment for short gut syndrome. On
account of the associated lymphoid tissue that is transplanted with the bowel the
complications include those of the development of lymphoma and lymphoproliferative
disease.
4. True Liver is now a frequently transplanted organ in most parts of the world. Transplants
are associated with a good long-term outcome with patient and graft survival in excess of
75% at five years. A variety of aetiologies are associated with end-stage liver disease and
these impact on long-term graft survival. Previous alcoholic liver disease has had a good
long-term outlook; but where transplantation has been for hepatoma the five-year prognosis
is reduced to less than 50%.
5. True Both autografts and allografts are used to increase bone mass and to support repair.
Bone allografts, although less effective than autografts (because they function as inert
scaffolding rather than providing viable osteoblasts), can be helpful as bone banks.

A2 1. True For patients to be considered suitable for organ transplantation they must be in end
organ failure but otherwise free of co-morbid illness. They cannot have severe infection,
malignancy, life threatening viral illness or other significant pathology that will influence graft
and patient survival.
2. True The organ transplant recipient must have stable socio-economic support, not suffer
from psychiatric disturbance and be compliant. Unless patients have these criteria it is
unlikely that they will regularly take their immunosuppressive medication, and as a
consequence are very likely to shortly loose their graft to rejection. Organs for
transplantation are a scarce resource and can only be provided to those likely to have a
reasonable prognosis.
3. False Organ transplantation is not usually undertaken in those above the age of 65-70
years or in the very young (under 12 months). In these extremes of age the patient outcome
is likely to be compromised by the age factor including the development of cardio-vascular
and neoplastic disease. However age as a single factor is not an absolute contra-indication
to transplantation.
4. False Organ transplant recipients should be fit and should not have co-morbid disease if
they are to have an optimal prognosis after transplantation. The presence of associated
illness, even if it is reversible as an acute entity, such as cardio-respiratory disease requiring
ventilation, or renal failure requiring dialysis, influence the outcome for the patient and the
graft. Liver transplant patients transplanted in these circumstances have a much poorer
prognosis than those who are active in an outpatient setting.

A3 1. False Primary graft non-function does occur; but this is an uncommon event that is seen in
approximately 1-5% of transplanted organs. If this occurs in kidney transplantation, the
patient can readily be returned to dialysis, but for the other whole organs (heart, liver and
lung) the patient’s life is threatened and immediate regrafting is required. Depending on the
availability of graftable organs this is usually a severely life-threatening situation. In the
Australasian community where the population density is low, grafts in these acute
circumstances are not usually available and as a consequence these patients usually die for
want of a functioning organ.
2. False Technical problems occur infrequently; but may be present in any of the joined
structures of artery, vein or the draining ducts. They account for 1-2% of problems in organ
transplantation. They present difficult management scenarios, particularly if the arterial
supply is compromised. In the kidney and liver this can mean the loss of the graft. If
draining ducts have a technical problem, leakage of bile, urine, blood or air can occur with
the potential for superadded infection. These problems often necessitate surgical re-
intervention.
3. True Acute rejection accounts for most of the complications encountered in the early post-
transplantation period for all organs. This process is largely responsible for the major loss of
organs in the first twelve months post transplant. In each instance up to 15% of organs can
be lost during this period. Management requires constant surveillance; because rejection
can only be assessed by careful monitoring of organ function aided by fine needle graft
biopsy and cytology.
4. False Early cardio-pulmonary failure after whole organ transplantation seldom occurs. Most
transplants require assisted ventilation for the first twelve to twenty four hours after the
procedure; but in many instances this is not required at all. Kidney transplantation patients
seldom are managed in the Intensive Care Unit. Liver transplantation patients may be
staged through the Intensive Care Unit but often reach the stage of extubation by the end of
the procedure. So long as the transplanted organ is functioning efficiently there is little need
for cardiopulmonary support.

A4 1. False Hyperacute rejection rarely accounts for graft organ loss. For heart and kidney
transplantation, antibodies in the recipient that might give rise to hyperacute rejection are
screened for by lymphocytotoxicity testing of donor lymphocytes against recipient serum. If
this testing is positive the transplantation does not proceed. In liver transplantation
hyperacute rejection is an extremely unusual phenomenon, matching is undertaken by ABO
blood group compatibility rather than by HLA typing. Lymphocyte toxicity testing also is
usually not undertaken for liver transplantation.
2. True Acute rejection accounts for the majority of organs lost. Acute rejection is very
prevalent in all forms of whole organ grafting, occurring in approximately 60-70% of kidney,
liver and heart grafts. The majority of the rejection episodes can be reversed by bolus
steroid injection or the use of anti-lymphocyte globulin treatment, particularly OKT3. In spite
of this there is a significant early graft loss on account of acute rejection. Cumulative losses
from rejection in the first twelve to eighteen months after transplantation account for 10-15%
of losses; and in this way influence significantly the long term graft survival of transplanted
organs.
3. True Chronic rejection manifests in a number of ways; in the kidney by progressive

destruction of the glomerulus, in the heart by the development of atheroma and
microvascular occlusion, in the liver by obliteration of the bile ducts. This form of rejection
accounts of approximately 2-3% of graft losses per year after the first twelve to eighteen
months from transplantation.
4. True Recurrent primary disease is specific in its activity to those illness that have an
immune background, or are of viral or neoplastic origin. In the kidney the illness most likely
to recur is focal and segmental glomerulosclerosis, and mesangial proliferative
glomerulopathy – where the risk ranges from 10-80% of patients transplanted for these
conditions. In the liver the most common illness to recur is hepatitis B and C, followed by
autoimmune hepatitis, sclerosing cholangitis and primary biliary cirrhosis. In the heart the
predominant recurrent disease is atherosclerosis.

A5 1. True Glucocorticoids have been standard immunosuppression virtually since the inception
of whole organ transplantation. They do have unwanted side effects, such as the
development of diabetes, skin fragility, avascular necrosis of bone, the development of
Cushingoid appearance and the risk of infective complications. In some disease processes,
steroids may be intimately related with the recurrence of the original disease process.
Accordingly in all transplant programmes attempts are made to reduce the amount of
glucocorticoids used; and where possible to avoid them totally.
2. True Mycophenolate mofetil is a new immunosuppression agent similar to azathioprine. It

has now been trialed extensively in kidney and liver transplantation and shown to be an
effective substitute for azathioprine. It augments the use of cyclosporin and tacrolimus,
particularly in the management of chronic rejection. Its major side effects are depression of
the bone marrow and gastro-intestinal upsets with diarrhoea.
3. True Cyclosporin has been used very effectively since the 1980s, and has considerably
improved the ability to control rejection in all fields of organ transplantation. Its use has
made liver transplantation an acceptable modality of treatment; and cyclosporin has been
responsible for substantial improvement in graft survival at five years in all organs.
4. True Tacrolimus is one of the newer immunosuppression agents with actions similar to
cyclosporin, but with an efficacy that is comparable or slightly better than cyclosporin in the
control of chronic rejection. The unwanted side effects include the development of diabetes,
neurotoxicity and nephrotoxicity.

TRANSPLANT RECIPIENT CASE SCENARIOS
Study the scenarios and review the appropriate section in the prescribed texts.
CASE SCENARIO 1
A 55-year-old male presents with features of end-stage liver disease, muscle wasting, gross
ascites, bilirubin of 350 umol/L, a history of alcohol abuse and raised liver enzymes.
SELF-TEST TASK 1
1. Should this patient be considered for liver transplantation?
2. If yes or no, what are the ethical factors that should be considered in arriving at the conclusion?
3. If yes or no, what clinical steps should be taken to establish his condition for listing for
transplantation?
CASE SCENARIO 1 CONTINUED
He is subsequently listed for transplantation and a liver becomes available.
SELF-TEST TASK 1 CONTINUED
4. On what criteria will the liver be considered suitable for this patient?
5. What information should the patient be given on listing for transplantation and prior to surgery?
6. What anatomical structures will be mobilised in the recipient hepatectomy?
7. What will be the physiological impact to the recipient during transplantation of the liver of
occluding the common bile duct, portal vein, and inferior vena cava?

CASE SCENARIO 2
A 45-year-old diabetic female presents with end stage renal failure secondary to nephrosclerosis.
SELF-TEST TASK 2
1. What factors should be considered before listing this patient for dialysis and/or renal/pancreatic
transplantation?
2. When should a transplant occur and who should be the donor?
3. What factors will influence the outcome for the graft?
4. How might the influence of these factors be modified?
She is listed for transplantation of a combined kidney / pancreas allograft.
5. What structures and where will be mobilised in the recipient?
6. What physiological changes are likely to occur in the recipient and how will they be monitored?
Twenty-four hours after transplantation of the kidney and pancreas there is no urine production.
7. What are the likely reasons?
8. How might they be investigated?
9. The patient becomes acidotic, what are the likely explanations?

CASE SCENARIO 3
Two years after a heart, liver, kidney transplant to three different patients (a) to (c); in
(a) the left ventricular function begins to fail; in
(b) the bilirubin rises; and in
(c) the creatinine rises.
SELF-TEST TASK 3
(a) List the potential reasons.
(b) What tests and why, will clarify the situation?
(c) What remedial steps might be taken and why?
(d) Should re-transplantation or return to dialysis be considered?

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STEM MODULE: IMMUNOLOGY / TRANSPLANTATION

TOPIC 2: THE CELLS OF THE IMMUNE SYSTEM ........................................................................ 15

TOPIC 3: ANTIBODIES AND CYTOKINES..................................................................................... 19

TOPIC 4: ACTIVATION AND CONTROL OF THE NORMAL IMMUNE RESPONSE ................... 23

TOPIC 5: IMMUNITY TO INFECTION.............................................................................................. 27

TOPIC 6: ABNORMAL IMMUNE RESPONSES.............................................................................. 30

ã Royal Australasian College of Surgeons – June 2000 Page 1 of 80

TOPIC 7: TRANSPLANTATION IMMUNOLOGY ............................................................................ 39

TOPIC 8: DIAGNOSTIC TESTING IN IMMUNOLOGY.................................................................... 41

SECTION 2: CLINICAL TRANSPLANTATION

TOPIC 10: THE RECIPIENT............................................................................................................... 66

TOPIC SUB-HEADINGS INCLUDE:

MULTIPLE CHOICE QUESTIONS

ã Royal Australasian College of Surgeons – June 2000 Page 2 of 80

GOALS AND OBJECTIVES

SECTION 1 - BASIC IMMUNOLOGY

SECTION 2 - CLINICAL TRANSPLANTATION

To achieve this broad goal, understanding is required of:

· The principles relating to organ and tissue donation

· Tissues and organs that can be transplanted

ã Royal Australasian College of Surgeons – June 2000 Page 3 of 80

· Understanding the immunological process related to rejection.

· The development of agents to control rejection.

ã Royal Australasian College of Surgeons – June 2000 Page 4 of 80

TOPIC 1: NON-SPECIFIC DEFENCE MECHANISMS

1.1. Non-Specific Defence Mechanisms

ã Royal Australasian College of Surgeons – June 2000 Page 5 of 80

1.2. Natural Immunity

1.2.2. Phagocytosis and the inflammatory reaction

a) Macrophages are activated by cytokines.

ã Royal Australasian College of Surgeons – June 2000 Page 6 of 80

1.2.3. The Complement System

Cleavage of C3 is triggered in three ways:

Activation of the classical pathway:

ã Royal Australasian College of Surgeons – June 2000 Page 7 of 80

Activation of the alternative pathway:

Complement component activation sequence

Various regulatory mechanisms exist to prevent runaway activation of the complement

Results of complement fixation (activation)

a) Enhancement of phagocytosis and inflammation: Immune adherence facilitates

ã Royal Australasian College of Surgeons – June 2000 Page 8 of 80

b) Membrane damage in some situations: Full activation of the complement cascade up to C9

c) Disposal of immune complexes: Complement plays an important part in the solubilisation

a) uptake of particles opsonised by complement (eg IgM antibodies plus bacteria)

ã Royal Australasian College of Surgeons – June 2000 Page 9 of 80

1.2.4. Acute Phase Proteins

1.2.5. Natural Killer (NK) Cells

ã Royal Australasian College of Surgeons – June 2000 Page 10 of 80

1.3. The Major Histocompatibility Complex (MHC)

c) Products of Class III genes are a heterogeneous group:

· the MHC had been extensively conserved in evolution, and

ã Royal Australasian College of Surgeons – June 2000 Page 11 of 80

The distribution of MHC antigens on cells

Class II antigens are normally expressed only on:

They may be expressed on other cells in pathological circumstances.

a) The many genetic loci making up the MHC.

ã Royal Australasian College of Surgeons – June 2000 Page 12 of 80

ã Royal Australasian College of Surgeons – June 2000 Page 13 of 80

ã Royal Australasian College of Surgeons – June 2000 Page 14 of 80

TOPIC 2: THE CELLS OF THE IMMUNE SYSTEM