Immunosuppressants

Slide 2:
• Immunosuppressant drugs are a class of drugs that suppress or reduce the strength of
the body’s immune system.
• Many of the currently available immunosuppressant were developed for use in
oncology or transplantation.
• Immunosuppressants are used to control severe manifestations of allergic,
autoimmune and transplant-related diseases.
• Some drugs have a diffuse effect on the immune system while others have specific
targets.
• Some immunosuppressants act through immunodepletion of effector cells, while
others are predominantly immunomodulatory, affecting the activity of cells, usually
through cytokine inhibition.
 Immunosuppressant is a class of medicine that inhibit or decrease intensity of immune
response in body
 Most of these medications are used to allow the body to less likely to resist the
transplanted organ
 Other immunosuppressant drugs are often used to treat autoimmune disorders such as
lupus, psoriasis, and rheumatoid arthritis
Slide 4:
Immunosuppressive drugs can be classified into five groups:
• I. Glucocorticoids
• II. Cytostatics
• III. Antibodies
• IV. Drugs acting on Immunophilins
• V. Other drugs
 Immunosuppressive agents are drugs that suppress immune system and reduce risk of
rejection from foreign bodies such as transplant organs
 Different classes of immunosuppressive agents have different mechanism of action
 Immunosuppressive agents are used as cancer chemo in autoimmune diseases such as
rheumatoid arthritis and to treat severe allergy
Slide 5:
• Cortisone was the first immunosuppressant identified, but its wide range of side
effects limited its use.
• Corticosteroids are the mainstay of most immunosuppressive regimens in both the
induction and maintenance phases.
• Glucocorticoids suppress the humoral and cell-mediated immunity.
• It acts by inhibiting genes that code for the cytokines IL-1, IL-2, IL-3, IL-4, IL-5, IL6, IL-8
and TNF-γ.
• Second-line drugs, such as azathioprine, mycophenolate or methotrexate, may have a
steroid-sparing effect in the maintenance phase of treatment.

 Glucocorticoids are one of the most potent anti-inflammatory and immunosuppressive

agents
  They inhibit synthesis of almost all types of cytokines and of several cell surface
molecules required for immune functions
 Due to their strong immunosuppressive, anti-inflammatory, and anti-allergic effects on
immune cells, tissues, and organs, glucocorticoids significantly improve the quality of life
of patients suffering from diseases caused by dysregulation in the immune system
 However, their clinical efficacy is compromised by the metabolic effect of long term
treatment, which include osteoporosis, dyslipidemia, hypertension, and type 2 diabetes
Slide 6:
• Patients prescribed corticosteroids should be told to expect the common early adverse
effects, such as sweatiness, hoarse voice, loss of diurnal sleep patterns, and appetite
stimulation.
• Rarely, more serious acute psychiatric disturbances are seen such as agitation,
aggression or psychosis.
• Long-term, adverse effects include Cushingoid appearance, proximal myopathy,
hypertension, hyperlipidemia, diabetes, cataract formation, peptic ulceration,
osteopenia and aseptic necrosis of bone.
 Common problems with glucocorticoids include weight gain, water retention or
swelling, mood swings, blurred vision, feeling nervous or restless, trouble in sleeping,
muscle weakness, acne, and stomach irritation
 Glucocorticoids induce osteoporosis  well known and devastating adverse effect of
long term use of glucocorticoids. Up to 40% of patients of long-term glucocorticoids
develop bone loss leading to fractures
 Steroid induced myopathy, which is a reversible painless myopathy, is a direct result of
muscle breakdown. It can occur in both the upper and lower extremities, usually with
high dose long term use of glucocorticoids
 Osteonecrosis can be seen with long term use of Prednisone more than 20mg daily
 Systemic glucocorticoids cause the dose dependent increase in fasting glucose level, and
a more significant increase in post prandial values in patients without pre-existing
diabetes
Slide 7:
• Corticosteroids bind to the intracellular glucocorticoid receptor and modulate a
multitude of cellular functions by binding to glucocorticoid-responsive elements in the
nucleus.
• Effects on the immune system are also numerous but most clearly related to inhibition
of all cytokine transcription by blocking transcription factors, such as NF-kb and
activator protein-1 .
• Depletion of T cells because of inhibition of IL-2, inhibition of Th1 differentiation, and
induction of apoptosis, eosinophil apoptosis (either directly or by inhibition of IL-5),
and macrophage dysfunction because of inhibition of IL-1 and TNF-a.
• B cells are not significantly inhibited by corticosteroids, with only mild decreases in Ig
production.
  Glucocorticoids are proton inhibitors of nuclear factor kB (NFkB) activation. Because
NFKB activates many immunoregulatory genes in response to proinflammatory stimuli,
the inhibition of its activity can be a major component of the anti-inflammatory activity
of glucocorticoids
Slide 10:
• Cytostatics inhibit cell division.
• They affect the proliferation of both T cells and B cells.
• Purine analogs are most frequently administered.
• It includes the following:
a) Alkylating agents
b) Antimetabolites
c) Cytotoxic antibiotics.
 Alkylating agents are a family of anti-cancer drugs that interfere with cell’s DNA and
inhibit cancer cell growth
 There are called alkylating agents because of their ability to add alkyl groups o biological
molecules such as DNA and proteins
 Cyclophosphamide is a proton immuno suppressant that can decrease the immune
response by blocking production of DNA in cells.
 It is used for severe complication of systemic lupus, systemic sclerosis, and some form of
vasculitis, myopathies such as polymyositis and dermatomyositis, and sometimes
rheumatoid arthritis
 The alkylating agents used in immunotherapy are cyclophosphamide, nitrosoureas,
platinum compounds and others.
 Cyclophosphamide is probably the most potent immunosuppressive compound.
 In small doses, it is very efficient in the therapy of systemic lupus erythematosus,
autoimmune hemolytic anemias, Wegener's granulomatosis and other immune
diseases.
 High doses cause pancytopenia and hemorrhagic cystitis
Slide 11:
• Antimetabolites interfere with the synthesis of nucleic acids.
• It includes:
a. folic acid analogues, such as methotrexate
b. purine analogues, such as azathioprine and mercaptopurine
c. pyrimidine analogues, such as fluorouracil
d. protein synthesis inhibitors.
• By preventing the clonal expansion of lymphocytes in the induction phase of the
immune response, it affects both the cell and the humoral immunity.
 Anti-metabolite drugs disrupt nucleic acid synthesis by interfering with production of a
major nucleotide metabolite or by substituting for the natural metabolite. Like most
cytotoxic agents, anti-metabolites are toxic to normal cells especially those in the bone
marrow and GI tract
Slide 12:
AZATHIOPRINE
CHEMISTRY:
• Derivative of mercaptopurine.
• Inhibits de novo synthesis of purines required for lymphocytes proliferation.
• Prevents clonal expansion of both B and T lymphocytes.
 Azathioprine is an immunosuppressive agent that acts through its effect as an
antagonist of purine metabolism resulting in the inhibition of DNA, RNA, and protein
synthesis
 It has been used as an immunosuppressive agent for the treatment of a variety of
disorders including rheumatoid arthritis, dermatomyositis, polymyositis, systemic
sclerosis and systemic vasculitis, inflammatory bowel disease, and prevention of organ
transplant rejection
Slide 13:
Pharmacokinetics
• orally or intravenously.
• Metabolized in the liver to thiouric acid (inactive metabolite) by xanthine
oxidase.
• excreted primarily in urine.
USES
• Acute glomerulonephritis
• Systemic lupus erythematosus
• Rheumatoid arthritis
• Crohn’ s disease.
• Autoimmune hemolytic anemia.
 Azathioprine is metabolized in the liver before becoming active
 One metabolic pathway is through its conversion to 6-mercaptopurine
 Azathioprine is also metabolized by other pathways independently of 6-mercaptopurine
 Azathioprine inhibits DNA and RNA synthesis by preventing interconversion among the
precursors of purine synthesis and suppression of de novo synthesis
 Azathioprine and 6-mercaptopurine block lymphocyte proliferation in vitro and the
production of IL-2 which is probably an important aspect of anti-proliferative activity
 Xanthine oxidase has an important role in the catabolism of 6-mercaptopurine
 If allopurinol is used with azathioprine, it is mandatory to reduce the dosage of
azathioprine significantly because the allopurinol inhibits the xanthine oxidase pathway
 Although the metabolites are excreted in the urine, these are inactive and no reduction
in dosage is required in the presence of a non-functioning kidney
Slide 14:
Adverse Effects

• Bone marrow depression: leukopenia, thrombocytopenia.

• Gastrointestinal toxicity.
• Hepatic dysfunction.
• Increased risk of infections.
  Azathioprine may cause bone marrow depression, and leukopenia is a main toxic effect
that may occur after therapeutic doses and overdoses of the drug
Slide 15:
MYCOPHENOLATE MOFETIL
Mechanism of action:
• Inhibits de novo synthesis of purines.
• mycophenolic acid is a potent inhibitor of inosine monophosphate
dehydrogenase (IMP), crucial for purine synthesis deprivation of
proliferating T and B cells of nucleic acids.
 Mycophenolate mofetil is a prodrug of mycophenolic acid and is classified as a
reversible inhibitor of inosine monophosphate dehydrogenase (IMP)
 Prodrug: medications that turn into active form once in the body
 Mycophenolate mofetil stops B cell and T cell proliferation through the lack of inhibition
of de novo pathway of purine biosynthesis
Slide 16:
CLINICAL USES:
In solid organ transplantation
In autoimmune disorders:
• Rheumatoid arthritis, & dermatologic disorders.
ADVERSE EFFECTS:
• GIT toxicity: Nausea, Vomiting, diarrhea, abdominal pain.
• Leukopenia, neutropenia.
• Lymphoma
Contraindicated during pregnancy

 It is widely used to prevent tissue rejection following organ transplant as well as for
treatment of certain autoimmune diseases
 Serious side effects include leukopenia and neutropenia, thrombocytopenia, stomach
problems such as bleeding ulcers or perforations, swollen veins or blood clots, serious
inflammatory response with fever, muscle pain, joint pain, and joint stiffness, allergic
reaction, anemia, risk of serious infarction, and risk of certain types of cancer such as
lymphoma and skin cancer
Slide 17:
Methotrexate
• folic acid antagonist
• Orally, parenterally (I.V., I.M).
• Excreted in urine.
• Inhibits dihydrofolate reductase required for folic acid activation
(tetrahydrofolate)
• Inhibition of DNA, RNA &protein synthesis
• Interferes with T cell replication.

 Methotrexate is a folate derivative that inhibit several enzymes responsible for

nucleotide synthesis
  Since inhibition leads to suppression of inflammation, as well as prevention of cell
division, methotrexate is often used to treat inflammation caused by arthritis, or to
control cell division in neoplastic diseases such as breast cancer and Non-Hodgkin’s
lymphoma
Slide 19:
Indication:
• Autoimmune disorders as rheumatoid arthritis & psoriasis and Crohn disease
Adverse effects
• Pulmonary fibrosis
• Nausea-vomiting-diarrhea
• Alopecia
• Bone marrow depression
• Teratogenicity
• Among these, dactinomycin is the most important.
• Binds to double stranded DNA through intercalation between adjacent guanine-
cytosine base pairs.
• Inhibits all forms of DNA dependant RNA synthesis.
• It is used in kidney transplantations.
• Other cytotoxic antibiotics are anthracyclines, mitomycin C, bleomycin, mithramycin
 Cytotoxic drugs prevent cell division or cause cell death
 They act predominantly on rapidly dividing cells such as T lymphocytes and are
therefore immunosuppressive and anti-inflammatory
 They are used for treatment of cancer and autoimmune disease
Slide 20:
• Antibodies are used as a quick and potent immunosuppression method to prevent the
acute rejection reaction as well as a targeted treatment of lymphoproliferative or
autoimmune disorders.
• They are of two types: Polyclonal antibodies & Monoclonal antibodies
• Polyclonal antibodies: Antilymphocyte globulins (ALG)/ Antithymocyte globulins
(ATG).
• Monoclonal antibody: Basiliximab/Daclizumab
 Monoclonal antibodies are effective treatment for autoimmune diseases, hematological
malignancy, solid organ malignancy, and viral illnesses
 Their successful use in cancer and autoimmune diseases in human have made them one
of the fastest growing classes of new drugs approved for these indications in the last
few decades
Slide 21:
• Polyclonal antibodies inhibit T lymphocytes and cause their lysis.
• In this way, polyclonal antibodies inhibit cell-mediated immune reactions, including
graft rejection, delayed hypersensitivity, and the graft-versus-host disease (GVHD).
• Polyclonal antibodies affect all lymphocytes and cause general immunosuppression
possibly leading to post-transplant lymphoproliferative disorders
  Polyclonal immunoglobulin have been in use since the 19 th century to protect against
infectious agents, toxins, and autoimmune diseases
 These immunoglobulin preparations are made from pools of selective human donors
with high titers of antibodies against viruses and toxins
 This antibody treatment provides passive transfer of high titer antibodies that either
reduce risk, or reduce severity of infection
 With the advent of human organ and tissue transplantation as treatment options, these
polyclonal antibody therapies in combination with other treatment are being used to
lower ability of body’s immune system to reject these transplants
 However, their use is not without risk as complication includes development of immune
complexes and severe allergic reactions
Slide 22:
• A group of antibodies produced by identical clones of B lymphocytes against a
particular antigen.
• A novel way of targeting antigens in a wide variety of diseases and conditions.
• mAbs are the important group of therapeutic molecules in clinical trials for treating
different disorders such as inflammatory and autoimmune diseases (e.g. rheumatoids
arthritis, systemic lupus erythematosus, psoriasis, inflammatory bowel diseases),
malignancies (e.g. leukemia, melanoma, breast cancer, and multiple myeloma),
cardiovascular, and infectious diseases.
 Monoclonal antibodies are laboratory made proteins designed to act like human
antibodies by binding to specific proteins in the body called antigens
 These antigens may include proteins from cancers, bacteria, viruses, or inflammatory
cells
 Monoclonal antibodies are a group of antibodies produced by identical clones of B
lymphocytes against a particular antigen
 Monoclonal antibodies are identical in several properties such as protein sequence,
antigen binding site region, binding affinity for their targets, and identical downstream
functioning effects
Slide 23:
• Murine mAbs was the first generation of monoclonal antibodies.
• They have no human components in their structure and could result in producing
human anti-mouse antibodies (HAMAs).
• HAMA response caused hypersensitivity reactions (e.g. anaphylaxis and serum
sickness)
• Genetic engineering approaches and using transgenic animals were developed to
overcome these troubles; and produce an antibody structurally closer to human
antibodies.
• These modified antibodies are known as chimeric mAbs because their constant region
is human while their variable region is murine
• Humanized and fully human mAbs were developed to reduce mAb immunogenicity
and their side effects.
  Murine monoclonal antibodies are the first generation of monoclonal antibodies
developed
 However, because of their murine origin they can trigger the anti-mouse antibody
response in the host, which can accelerate monoclonal antibody clearance and
undesirable allergic reactions upon repeated administration
 This issue was resolved by developing engineering methods towards producing less
immunologic chimeric or humanized antibodies
 Monoclonal antibodies application has become a novel way of targeting antigen in a
wide variety of diseases such as autoimmunity, malignancy, asthma, and transplantation
Slide 24:
• Therapy
– Infectious diseases
– Transplantation
– Auto immune diseases
– Cancer
• Diagnostics
– In vitro
– In vivo
 In addition, high specificity and high affinity binding properties of monoclonal antibodies
make them effective biological reagents in immune diagnosing assays
 They can be used in diagnosing infectious diseases and detection of certain antigen or in
serological assessment for detection of antibodies against a certain antigen
Slide 25:
• Monoclonal antibodies could be designed specifically against a target antigen found
on cancer cells.

• Rituximab, an antiCD20 chimeric antibody, was approved in 1997 for treating non-
Hodgkin B cell lymphoma.
• Rituximab interacts with CD20 antigen expressed on B cell tumors and then eliminates
malignant cells through an effective immune response.
• Rituximab is also effective in different autoimmune Diseases: Systemic lupus
erythematosus, rheumatoid arthritis, dermatomyositis, antineutrophil cytoplasmic
antibody (ANCA)-positive vasculitis and in renal transplantation of highly sensitized
recipients.
 Monoclonal antibodies could be designed specifically against a target antigen found on
cancer cells
 Several therapeutic monoclonal antibodies have been approved against different cancer
types after the discovery of proto-oncogenes and specific tumor antigens
 CD20 antigen is a phosphoprotein expressed on B lymphocyte involved in B cell
proliferation and activation by initiating an intracellular signaling pathway
 Targeting CD20 by monoclonal antibodies induces B cell apoptosis and could inhibit B
cell function through antibody dependent cell mediated cytotoxicity (ADCC) and
complement dependent cytotoxicity
  Successful therapeutic applications of mAbs have been shown in several inflammatory
conditions such as psoriasis, rheumatoid arthritis (RA), juvenile arthritis, Crohn’s
disease, and multiple sclerosis
Slide 27:
• IL-6 is an inflammatory cytokine involved in the initiation or progression of immune
responses in several autoimmune diseases such as RA.
• Tocilizumab or atlizumab (Actemra® or RoActemra®), is a humanized anti-IL-6 receptor
mAb and binds to both soluble and membrane-bound IL-6 receptor.
• Its efficacy is currently being explored in the treatment of RA, systemic juvenile
idiopathic arthritis in children, systemic lupus erythematosus (SLE), juvenile
dermatomyositis (DM), vasculitis, and juvenile scleroderma
 Treatment of rheumatic diseases such as rheumatoid arthritis or systemic onset juvenile
idiopathic arthritis and new therapies targeting pro inflammatory cytokines, have been
developed
 IL-6 is a cytokine with a wide range of biological activity including a pro inflammatory
mediator activity
 Overproduction of IL-6 has been reported to be involved in rheumatoid arthritis and
therefore blockade of IL-6 actions may improve the disease
 Since IL-6 plays a pathological role in rheumatoid arthritis, Tocilizumab therapy, which is
a humanized monoclonal antibody against human IL-6 receptor has been introduced to
the patient with refractory disease and has shown a strong therapeutic effect
Slide 28:
• IL-1 is a proinflammatory cytokine and a primary effector of many inflammatory
conditions, including RA and adult-onset Still’s disease.
 The role of IL-1 family and their receptors are well known in inducing and regulating
inflammatory and autoimmune disorders
 Promising results have been shown in patients with autoimmune diseases after using
anti IL-1 monoclonal antibodies or targeting IL-1 receptors such as with Anikinra
Slide 29:
• TNF-a is an acute-phase cytokine released by macrophages, T cells, B cells,
neutrophils, natural killer cells, mast cells, and some nonimmune cell types (smooth
muscle and epithelial cells) in response to tissue injury
• Either monoclonal antibody or a circulating receptor such as infliximab
(Remicade®),etanercept (Enbrel®), or adalimumab (Humira®) that binds to TNF-α and
prevent it from inducing the synthesis of IL-1 and IL-6 and the adhesion of lymphocyte
activating molecules.
• They are used in the treatment of rheumatoid arthritis, ankylosing spondylitis, Crohn's
disease and psoriasis.
• These drugs may raise the risk of contracting tuberculosis or inducing a latent
infection to become active.
 Because of their crucial role in inflammatory responses, TNF-alpha is considered as an
important cytokine involved in the pathogenesis of several disorders such as
rheumatoid arthritis, Crohn’s disease, and spondylitis
  Anti-TNF agents have become an efficient approach in the treatment for these diseases
 Inhibiting TNF-alpha could prevent the production of proinflammatory cytokines such as
IL-1, IL-6, and IL-8
Slide 30:
• Cyclosporin/ Tacrolimus: calcineurin inhibitor.
• One of the most widely used immunosuppressive drugs.
• It binds to the cytosolic protein cyclophilin (an immunophilin) of immunocompetent
lymphocytes, especially T lymphocytes.
• Cyclosporin is used in the treatment of acute rejection reactions
• Tacrolimus is more potent than cyclosporin and has less pronounced side effects.
• Side effects
• Tacrolimus and cyclosporine: increase in BP as well as diminished renal perfusion.
• It can result in renal ischemia and acute tubular necrosis in the acute setting, and with
prolonged ischemia, it can result in chronic kidney injury.
• Calcineurin inhibitors have been linked with post-transplant malignancies and skin
cancers in organ transplant recipients.
 Immunophilins are a large family of broadly expressed proteins that bind to certain
immunosuppressive agents such as cyclosporin A, tacrolimus, and rapamycin
 Due to their potent immunosuppressive effects that predominantly targets T
lymphocytes, these agents are fundamental components of immunosuppressive
regiments in both solid organ and bone marrow transplantation
 Sirolimus, tacrolimus, and cyclosporin A act by interacting with the intracellular protein
an immunophilin, thus forming an oval complex which selectively disrupts the signal
transduction event of lymphocyte activation
Slide 31:
• After initial TCR binding, a calcineurin-dependent signaling pathway is induced that
leads to initial T cell gene transcription necessary for additional activation.
• Calcineurin inhibitors inhibit the ability of calcineurin to dephosphorylate nuclear
factor (NF) of activated T cells, required for translocation from cytoplasm to nucleus,
and prevent calcineurin-dependent gene transcription transplantation with dramatic
reductions in acute rejection rates.
 Cyclosporin has a potent immunosuppressive property reflecting its ability to block the
transcription of cytokine genes in activated T cells
 It is well established that cyclosporin A, through formation of a complex with cyclophilin
inhibits the phosphatase activity of calcineurin, which regulates nuclear translocation
and subsequent activation of NFAT transcription factors
 Interferons are a family of pleiotropic cytokines with antiviral, anti-proliferative and
immuno-modulatory properties.
 The interferon family is subdivided into two subfamilies: types I and II.
 Type I interferons are a family of monomeric cytokines with an aminoacid similarity of
30– 80%, very similar three-dimensional structure helix-bundle), that use the same
receptor (interferon a/b receptor, IFNAR) to initiate a signaling response.
Slide 33:
  Interferons
 Families:
 Type I IFNs ( IFN-α, β )
 IFN- α:
 Hepatitis B & C infections
 Treatment of cancer (malignant melanoma)
 IFN-β : IFN-β suppresses the production of Th1 cytokines and the activation of
monocytes.
 It is used to slow down the progression of multiple sclerosis.
 Type II IFN (IFN-γ)
 IFN- γ :
 treatment of chronic granulomatous diseases
 Recombinant IFN-alpha forms are widely employed with some success in the treatment
of hepatitis B, hepatitis C virus infection, and some forms of cancer
 IFN-beta, treatment for multiple sclerosis, is regularly used to limit exacerbation of
multiple sclerosis
 There are 2 forms of cancer for which IFN are commonly employed as therapy
 About 15% of metastatic renal cell carcinoma responds to treatment with IFN-alpha
alone
 The other major cancer for which IFN treatment is employed as therapy is for cutaneous
melanoma that has metastasized to local lymph nodes
 IFN-gamma has been approved for clinical use only in a rare congenital disorder: Chronic
Granulomatous Disease
Slide 34:
 Monitoring patients under immunosuppressive drugs is required because
immunosuppressive drugs increase the risk of infarctions, malignancies, cardiovascular
disease, and bone marrow suppression
 Some drugs have additional risk which require specific monitoring
 Vigilance is needed as adverse effects may have atypical clinical appearance
Slide 35:
• Patients need to be under constant surveillance.
• Therapeutic drug monitoring is available now for a number of drugs, for example
cyclosporin, tacrolimus, sirolimus and mycophenolate.

 Immunosuppressants require therapeutic drug monitoring because of their narrow

therapeutic index and significant inter-individual variability blood concentration
 This variability can be due to factors such as drug nutrient interaction, drug disease
interaction, renal insufficiency, inflammation and infarction, gender, age, polymorphism
and liver mass
 Drug monitoring is widely practiced especially for cyclosporin, tacrolimus, sirolimus, and
mycophenolic acid
Slide 36:
• Immunosuppression increases susceptibility to infections .
 • At first, common bacterial Infections, but after 1–2 months of therapy opportunistic
infections emerge, particularly herpes viruses, pneumocystis pneumonia, fungi and
atypical mycobacteria.
• Vaccinations against influenza (injected) and pneumococcus are recommended in
chronically immunosuppressed patients.
• Live attenuated virus vaccines, such as varicella or measles, should not be given to
immunosuppressed patients
 Patient under immunosuppressive treatment may be infected by common community
acquire or by opportunistic organisms
 The risk of infection increases with the degree of immunosuppression
 Infections with Pneumocystis, nocardia, aspergillus, cryptococcus and reactivation of
varicella zoster, herpes simplex, cytomegalovirus (CMV), hepatitis B and C, as well as
tuberculosis are not uncommon in patients who are deeply immunosuppressed
 Patients often present with atypical symptoms and disseminated disease
 All patients taking immunosuppressants should have a thermometer at home and
should seek urgent medical assessment if they develop a temperature over 38°C
 Annual influenza vaccination, and pneumococcal vaccination at baseline and one-time
revaccination after five years, is recommended by the American College of
Rheumatology
 Patients with significant immunosuppression should not receive live vaccines
 In those exposed to chickenpox, administration of herpes zoster immunoglobulin is an
option
Slide 37:
• In patients taking immunosuppressants, early cancers are often lymphoproliferative
disorders and cervical cancer.
• In the long term, nearly all common cancers are increased, but particularly skin
cancers.
 The risk of cancer, especially cutaneous and haematological malignancies, is increased
 Patients taking immunosuppressive drugs should have at least yearly skin checks by
their general practitioners, and be up to date with the normal recommended cancer
screening programs such as fecal occult blood for those over 50, cervical smears and
mammography
 Many autoimmune diseases are associated with an increased risk of malignancy.
 Dermatomyositis and polymyositis are associated with adenocarcinomas, while
rheumatoid arthritis, systemic lupus erythematosus and Sjogren's syndrome are
associated with lymphoid malignancy
Slide 38:
• Bone marrow suppression is a common dose-limiting toxicity for most
immunosuppressive drugs, apart from hydroxychloroquine and the glucocorticoids.
• Immunosuppressive drugs should be suspended if there is significant neutropenia (less
than 1.5 x 106/L) and the specialist should be contacted immediately.
 Bone marrow suppression is a common dose-limiting toxicity for most
immunosuppressive drugs, apart from hydroxychloroquine and the glucocorticoids
  The recommendations for monitoring are largely based on expert consensus and often
differ slightly
Slide 39:
• The most common cause of long-term morbidity and mortality in patients with
autoimmune disease is cardiovascular disease.
• This increase in risk is attributed to the chronic inflammatory state as well as the
hyperglycemic and hyperlipidemia adverse effects of immunosuppressive drugs such
as glucocorticoids, cyclosporin and tacrolimus.
• Patients should be encouraged to cease smoking and have regular monitoring of
weight, blood pressure, fasting lipids and glucose.
• The threshold for further cardiac investigation should be low in the presence of
symptoms, even if they are atypical.
 The most common cause of long-term morbidity and mortality in patients with
autoimmune disease is the cardiovascular risk
 Women less than 45 years old with systemic lupus are 50 times more likely to have a
myocardial infarct in the next 8-10 years when compared with healthy age-and sex-
matched controls
 Patients under immunosuppressive treatment should be encouraged to cease smoking
and have regular monitoring of weight, blood pressure, fasting lipids and glucose
 Although there are no evidence-based cardiovascular guidelines specifically for patients
on immunosuppressive drugs, efforts to achieve risk factor reduction should be more
rigorous than those for the general population
 The threshold for further cardiac investigation should be low in the presence of
symptoms, even if they are atypical
Slide 41:
 Active immunity and passive immunity are 2 types of acquired immunity
 A prominent difference is that active immunity is developed due to production of
antibodies in one’s own body while passive immunity is developed by antibodies that
are produced outside then introduced into the body
 Active immunity:
 It is usually long-lasting, sometimes life-long
 It is produced by the antibodies of the host in response to direct contact with an antigen
 It produces an immunological memory
 Passive immunity:
 It lasts only for a few weeks or months
 It is produced by the introduction of antibodies from outside into the host
 It does not produce immunological memory
Slide 42:
• Administer a killed or an infectious agent, or a component of a microbe, that does not
cause disease but elicits an immune response that provides protection against
infection by the live, pathogenic microbe.
• Vaccines are most effective if the infectious agent does not establish latency, does not
undergo antigenic variation, and does not interfere with the host immune response.
 • A vaccine is Antigenic but not Pathogenic.
• Best vaccines: stimulate the development of long-lived plasma cells that produce high
affinity antibodies and memory B cells.
 Vaccination constitutes a major advance in the prevention of infectious diseases
 The principle of vaccination is to induce protection against a pathogen by mimicking its
natural interaction with the human immune system
 The vaccine reduces the risk of complications and mortality following subsequent
exposure to an infectious agent
Slide 44:
• Live vaccines
• Attenuated live vaccines
• Inactivated (killed vaccines)
• Polysaccharide and polypeptide (cellular fraction) vaccines
• Surface antigen (recombinant) vaccines
 Live attenuated vaccines contain whole bacteria or viruses which have been weakened
or attenuated so that they create a protective immune response but do not cause
disease in healthy people
 Live vaccines tend to create a strong and lasting immune response, however they are
not suitable for people with immunodeficiency either due to drug treatment or
underlying disease
 This is because the weakness of virus or bacteria could in some cases multiply too much
and might cause disease in these people
 Virulent pathogenic organisms are treated to become attenuated and avirulent but
antigenic.
 They have lost their capacity to induce disease but retain their immunogenicity.
 The live-attenuated oral polio vaccine has nearly eradicated the disease, but in rare
cases the virus in the vaccine is reactivated and itself causes paralytic polio.
 It should not administrated to persons with immunodeficiencies (eg. leukemia-
lymphoma- malignancies- radiation- immunosuppressive drugs- pregnancy) or pregnant
women, or immunocompetent people living with immunocompromised people
Slide 45:
• Composed of antigens purified from microbes or inactivated toxins and are usually
administered with an adjuvant.
• Adjuvant (e g. alum precipitation) is used to increase the potency of vaccine.
• One effective use of purified antigens as vaccines is for the prevention of diseases
caused by bacterial toxins.
• Toxins can be rendered harmless without loss of immunogenicity, and such toxoids
induce strong antibody responses.
• Diphtheria and tetanus are two infections whose life-threatening consequences have
been largely controlled because of immunization of children with toxoid preparations
 Some bacteria release toxins when they attack the body
 It is these toxins rather than the bacteria itself that we want to be protected against
  The immune system recognizes these toxins in the same way it recognizes the antigens
on the surface of bacteria, and is able to produce an immune system to them
 Some vaccines are made with inactivated versions of these toxins
 They are called “toxoids” because they look like toxins but are not poisonous
Slide 46:
• Organisms are killed or inactivated by heat or chemicals but remain antigenic.
• The attenuated or killed bacterial vaccines currently in use generally induce limited
protection and are effective for only short periods.
• Examples: inactivated polio vaccine, some inactivated flu vaccines, hepatitis A vaccine.
 Inactivated vaccines contain whole bacteria or viruses which have been killed or have
been altered, so that they cannot replicate
 Because inactivated vaccines do not contain any live bacteria or viruses, they cannot
cause the diseases against which they protect, even in people with severely weakened
immune systems
 However, inactivated vaccines do not always create such a strong or long-lasting
immune response as live attenuated vaccines
Slide 47:
• Vaccines composed of bacterial polysaccharide antigens are used against
pneumococcus and Haemophilus influenzae.
• Because polysaccharides are T-independent antigens, they tend to elicit low-affinity
antibody responses and are poorly immunogenic in infants .
• High-affinity antibody responses may be generated against polysaccharide antigens by
coupling the polysaccharides to proteins to form conjugate vaccines.
• The currently used H. influenzae, pneumococcal, and meningococcal vaccines are
conjugate vaccines.
 Conjugate vaccines have been developed to induce a robust immune response against
bacterial capsular polysaccharides
 Unfortunately, those vaccines, while partially immunogenic in adults, were completely
unable to induce an antibody response in infants and children, the population for whom
the vaccines were mostly needed
 The problem was solved in the 1980s when it was reported that bacterial capsular
polysaccharides become very immunogenic when covalently linked to a carrier protein
and thus started working on a conjugate vaccine against Hemophilus Influenza, which
worked greatly in infants and children
Slide 49:
• A goal of vaccine research has been to identify the most immunogenic microbial
antigens or epitopes, to synthesize these in the laboratory, and to use the synthetic
antigens as vaccines.
• HPV vaccine: recombinant viral proteins from four strains (HPV 6, 11, 16, and 18)are
made in yeast and combined with an adjuvant.
 A goal of vaccine research has been to identify the most immunogenic antigens or
epitopes and to synthesize these and to use the synthetic antigens as vaccines
  It is possible to deduce the protein sequences of microbial antigens from nucleotide
sequences data and to prepare large quantity of protein by recombinant DNA
technology
 Vaccines made of recombinant DNA derived antigens are now in use for hepatitis B virus
and HPV
Slide 50:
• Another approach for vaccine development is to introduce genes encoding microbial
antigens into a noncytopathic virus and to infect individuals with this virus.
• Virus serves as a source of the antigen in an inoculated individual.
• An adenovirus 26 vector (humans generally lack antibodies to this adenovirus) and a
chimpanzee adenovirus vector have been used to generate vaccines to a number of
viruses, including Ebola virus, Zika virus, and SARS-CoV-2.
• Non-replicating adenoviruses infect numerous host cells and thus produce a significant
amount of the viral antigen.
 Recombinant vector vaccines are live replicated viruses that are engineered to carry
extra genes derived from a pathogen
 These extra genes produce proteins against which we want to generate immunity
Slide 51:
• Inoculation of a plasmid containing complementary DNA (cDNA) encoding a protein
antigen leads to humoral and cell-mediated immune responses to the antigen.
• cDNA is transcribed and translated into immunogenic protein that elicits specific
responses.
 DNA vaccines involve the direct introduction into appropriate tissues of a plasmid
containing the DNA sequence encoding the antigens against which an immune response
is sought, and relies on the in-situ production of the target antigen
 This approach offers a number of potential advantages over the traditional approach
including the stimulation of both B and T cell responses, improve vaccine stability, and
the absence of any infectious agent
Slide 52:
• The main advantages of mRNA vaccines are the ease with which they can be rapidly
developed, and the ability to combine mRNAs encoding many different protein
antigens from a pathogen into a single vaccine.
• The mRNA is encapsulated in lipid nanoparticles that facilitate uptake by cells,
including dendritic cells, and also function as an adjuvant.
 mRNA vaccines work by introducing a piece of mRNA that corresponds to a viral protein:
usually a small piece of a protein found on the virus outer membrane
 Using this technique, cell produce the viral protein, and as a part of the normal immune
response, the immune system recognizes that this protein is foreign and produces
specific antibodies
Slide 55:
Currently available SARS-CoV-2 vaccines:
• Conventional methods include administration of attenuated inactivated (killed) virus
or recombinant viral protein vaccines to develop immunity.
 • Novel approaches include replication-deficient, adenovirus vector-based vaccines that
contains the SARS-CoV-2 spike protein and mRNA-based vaccines that encode for a
SARS-CoV-2 spike protein.
• Available mRNA COVID-19 vaccines require three separate inoculations separated by
three to four weeks.
 This type of COVID-19 vaccine typically uses the RNA segment of the viral genome that
codes for the virus spike proteins prepared in a suspension of lipid nanoparticles
 mRNA vaccines are antigen-coding strands of
messenger RNA (mRNA) delivered inside a lipid coat
 Once inside cells, the mRNA is translated into the protein antigen
 The antigen is recognized, inducing an immune reaction
 T helper, cytotoxic T cells and antibodies are induced
 mRNA is recognized by cells as a pathogen stimulating a strong immune response.
Slide 56:
• Viral vector vaccines use a non coronavirus vector (eg, adenovirus) modified to include
a gene that encodes a target antigen
• Can be replicating or non replicating
• Replicating: upon infection produces SARS-CoV-2 antigen in that cell and new virus,
which infects other cells
Non-replicating: infects a cell and produces SARS- CoV-2 antigen in that cell but does
not produce new virus
• The SARS-CoV2 antigen inside the cells is seen by the body as if this is a SARS-CoV-2
infection and induces T helper cells and cytotoxic I cells
 Several COVID-19 vaccines are based on this technology, including the Johnson &
Johnson, Oxford/AstraZeneca, and Sputnik V vaccine
 In fact, in this method, non-replicating viral vector vaccines are used and they infect
cells resulting in the production of the vaccine antigen, but the viral vector cannot be
reproduced
Slide 57:
• Deep subcutaneous (MMRV)
• Intramuscular route (DTaP- HepA- HepB- IPV)
• Oral route (oral BCG vaccine)
• Intradermal route (BCG vaccine)
• Intranasal route (live attenuated influenza vaccine)
 Each vaccine has a recommended administration route and site
 This information is included in the manufacturer’s package inserted for each vaccine
 Deviation from the recommended route may reduce vaccine efficacy or increase local
adverse reaction
Slide 58:
• Primary vaccination
- One dose vaccines (BCG, variola, measles, mumps, rubella, yellow fever)
- Multiple dose vaccines (polio, PT, hepatitis B)
 • Booster vaccination
To maintain immunity level after it declines after some time has elapsed (DT. MMR)
 Some vaccines are best able to protect the greatest number of people if they are given
more than once
 The chickenpox vaccine is one example of this. After one dose, 78% will be protected.
But after the second dose, 99% of the adults will be protected
 Its recommended that everyone get a second dose, since it’s safe to receive and extend
protection to more people
Slide 61:
 Some vaccines provide a greater response and higher level of protection after a
second dose. Haemophilus influenzae type b or Hib is an example of this.
 Some need several doses to produce the strongest immune response. DTaP vaccines
are an example of this.
• Unlike active immunity, which can take days or weeks to develop, passively
administered antibodies have the ability to provide rapid and immediate protection.
• Passive antibody is independent of the recipient’s immune status.
• Passive immunization may thus represent the therapy of choice in highly endemic
areas where vaccine responses may be poor, or in selected groups of patients such as
hospitalized individuals or those suffering from malnutrition and immunodeficiency,
or in individuals in whom vaccination is contraindicated.
• Protection conferred by passive immunization is of short duration and might need
repeated administration.
 Whereas active immunity refers to the process of exposing an individual to an antigen to
generate an adaptive immune response, passive immunity refers to the transfer of
antibodies from one individual to another
 Passive immunity provides immediate but short life protection, lasting several weeks up
to 3 or 4 months
Slide 62:
• Maternal passive immunity is a type of naturally acquired passive immunity and refers
to antibody-mediated immunity.
• Transfer of maternal antibodies from mother to fetus or the newborn is essential for
the development of the immune system and the protection of young animals from
various pathogens in their early lives.
• This generally occurs by transfer of maternal serum IgG from the mother to the
newborn either in utero or after birth, by ingestion of immunoglobulin-rich colostrum
by the neonate.
• The main role of colostrum consumption is to provide protection for the
gastrointestinal tract because the IgG required to provide systemic immunity is
transferred across the placenta before birth. This probably explains the high
proportion of SIgA (90%) and low proportion of IgG (2%) in human colostrum and milk.
 Passive immunity can occur naturally when maternal antibodies are transferred to the
fetus through the placenta or from breast milk to the gut of the infant
Slide 63:
 • Passive immunization is most commonly used for rapid treatment of potentially fatal
diseases caused by toxins such as tetanus, and for protection from rabies and
hepatitis.
• Antibodies against snake venom can be lifesaving when administered after poisonous
snakebites.
 Passive immunity also be produced artificially, when antibody preparations derived from
sera of immunized donors or, more recently, different antibody producing platforms are
transferred via systemic route to nonimmune individuals
Slide 64:
• Immunoglobulin, often referred to as gammaglobulin, is produced by combining the
IgG antibody fraction from thousands of adult donors.
• It is based on the assumption that a large pool will contain protective levels of
antibodies of different specificities including antibodies against many common
diseases such as hepatitis A, measles, and rubella.
• The Ig product is sterile and contains more than 95% purified IgG with small amounts
of IgA and IgM.
• It is used primarily for post-exposure prophylaxis for hepatitis A, rubella, and measles
and treatment of certain primary immunodeficiency disorders (X-linked α-
gammaglobulinemia and hypogammaglobulinemia), secondary immunodeficiency
(such as B-cell chronic lymphocytic leukemia), or autoimmune diseases.
 Intravenous immunoglobulin (IVIG) contains the pooled immunoglobulin G (IgG) from
the plasma of approximately a thousand or more blood donors
 IVIGs are sterile, purified IgG products manufactured from pooled human plasma and
typically contain more than 95% unmodified IgG and only trace amounts of IgA or IgM
Slide 65:
• Protection generated from passive immunity is immediate, but wanes over the course
of weeks to months, so any contribution to herd immunity is temporary.
• Passive immunization does not induce memory, so an immunized individual is not
protected against subsequent exposure to the toxin or microbe.
 Unlike active immunity which can take days or weeks to develop, passively administered
antibodies have the ability to provide rapid and immediate protection
 Unlike vaccination, with which protective immunity depends on the host’s ability to
mount an immune response, passive antibody is independent of the recipient’s immune
status
 Passive immunization may thus represent the therapy of choice in highly endemic areas
where vaccine responses may be poor, or in selected groups of patients such as
hospitalized individuals or those suffering from malnutrition and immunodeficiency, or in
individuals in whom vaccination is contraindicated
 However, protection conferred by passive immunization is of short duration and might
need repeated administration
Slide 66:
• 'Herd immunity', also known as 'population immunity', is the indirect protection from
an infectious disease that happens when a population is immune either through
vaccination or immunity developed through previous infection.
• Once the herd immunity has been reached, disease gradually disappears from a
population and may result in eradication or permanent reduction of infections to zero
if achieved worldwide.
• Herd immunity created via vaccination has contributed to the reduction of many
diseases.
• Herd immunity protects the most vulnerable members of our population.
 Herd immunity, or community immunity, is when a large part of the population of an
area is immune to a specific disease
 If enough people are resistant to the cause of a disease, such as a virus or bacteria, it
has nowhere to go
 Herd immunity occurs when a sufficient percentage of a population has become
immune to an infection, whether through previous infections or vaccination
 Therefore reducing the likelihood of infection for individuals who lack immunity