Igney & Zollner_Trends Pharmacol Sci 2004

Techniques: Species’ finest blend –
humanized mouse models in
inflammatory skin disease research
Frederik H. Igney, Khusru Asadullah and Thomas M. Zollner
Schering AG, CRBA Dermatology, Berlin, Germany
Differences between humans and mice often hamper
the transfer of promising results from the bench to the
clinic. For ethical reasons, research that involves
patients is limited, and so there is an urgent need for
models that mimic the human situation as closely as
possible. In recent years, there has been considerable
progress in generating humanized mouse models, and
their application to drug discovery has proved fruitful.
So, how can mice be humanized, and how can human-
ized mice be employed in immunology research and drug
discovery? In this article, we answer these questions,
focusing on T-cell-mediated skin diseases as an example.
Inflammatory diseases have a high prevalence in Western
countries. Hence, pharmaceutical companies spend increas-
ing amounts of money to develop drugs for these disorders.
The most expensive phase of drug discovery is clinical trials
but new compounds fail frequently at this stage. Often,
results from animal experiments and clinical outcome do
not correlate because of significant differences in human
and murine immunity [1]. In addition, the complex patho-
physiology of human inflammatory diseases is represented
only partially in classical animal models. Moreover,
research that involves patients is limited; in particular,
it is not possible to induce diseases for scientific purposes.
Thus, there is an urgent need for more-predictive and
reliable animal models. Humanized mouse models seem to
be the answer to this problem because they combine the
advantages of small-animal models with better correlation
in the clinic. Here, we review how mice can be humanized
and discuss the applications of humanized mice in
immunology research and drug discovery, focusing on
T-cell-mediated skin diseases.
How to humanize a mouse
The most important way to humanize animals is to pro-
duce chimeras by xenotransplantation. In general, this
involves transplanting human grafts into immunodefi-
cient mice. A special kind of humanization can also be
obtained by replacing a murine gene with its human
homolog. Both techniques can be combined, for example by
grafting cells into mice that express a human growth
factor. Interspecific chimeras either between sheep and
goats or between mice and rats have been generated by
combining embryonic cells of the respective species.
However, for ethical reasons this technique has not
been and probably will never be developed for human–
mouse chimeras.
Recipient mice
In immune-competent mice, foreign tissue is recognized
and rejected by immune cells. Thus, only immunodeficient
mice can be used for xenotransplantation. The first mouse
strains used were nude, severe-combined-immunodefi-
ciency (SCID) or recombination activating gene 1-knock-
out (Rag1K/K
) and Rag2K/K
mice, each of which have
deficiencies in adaptive immunity [2,3]. Superior hosts for
xenotransplantation are obtained by combining several
immunological defects. Today’s standard models are non-
obese-diabetic/SCID and SCID/beige double mutant mice.
In addition to lacking functional T and B cells, these mice
have deficiencies in natural killer (NK) cells and other
components of innate immunity. Possibly superior
alternatives are mice that possess deletions of both Rag2
and the common cytokine receptor g chain (Rag2K/K
/gc
K/K
mice) and BNX mice, which possess three separate
mutations: the beige, nude and x-linked immunodefi-
ciency (also known as xid or Bruton agammaglobulinemia
tyrosine kinase) mutations [2,3]. For detailed information
on mouse strains see Mouse Genome Informatics
(http://www.informatics.jax.org/). Several other combi-
nations of immune defects are also available. The optimal
mouse strain for xenotransplantation might depend on the
specific application. In general, deficiency in the adaptive
and the innate immune response seems to be beneficial,
and the rule ‘the more defects, the better’ seems to be
valid. However, in practical terms, mice with more
‘complete’ immunodeficiencies tend to be less robust,
which, in turn, increases the risk of them dying as the
experiment progresses.
Human grafts
It is possible to transplant virtually every tissue of the
human body into immunodeficient mice [4]. In initial
attempts, the human adaptive immune system has been
reconstituted by transplantation of immune cells and
lymphoid organs (Table 1). Careful characterization of
these models reveals an amazing consistency with the
human immune system [5,6]. However, each model shows
Corresponding author: Frederik H. Igney (frederik.igney@schering.de).
Available online 21 August 2004
www.sciencedirect.com 0165-6147/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/j.tips.2004.08.004
Review TRENDS in Pharmacological Sciences Vol.25 No.10 October 2004

its unique deviations from normal immunity, and induc-
ing primary immune responses is difficult in most
models [7,8]. Recently, in a sophisticated model called
SCID–huIC, which uses SCID/beige mice transplanted
with human fetal bone, thymus, skin and autologous
mesenteric lymph nodes, immunization led to a primary
antigen-specific T-cell and B-cell response [8]. Intra-
hepatic injection of CD34C
cord-blood cells into newborn
Rag2K/K
/gc
K/K
mice resulted in the development of B cells,
T cells and dendritic cells, and in the formation of struc-
tured lymphoid organs [9]. Functional immune responses
could be induced with Epstein-Barr virus and tetanus
toxoid. One complication is the reaction of human
lymphocytes against the murine host. Clear signs of a
xenogeneic graft-versus-host disease (GVHD) have been
found, particularly in the huPBL–SCID model [in which
human peripheral blood lymphocytes (huPBLs) are
injected into SCID mice] [6]. Many engrafted T cells
seem to correlate with significant GVHD. By contrast, in
other models, T cells develop tolerance to the murine
background [5].
In addition to the immune system, human skin is
the most frequently transplanted human xenograft [10].
Both healthy and diseased human skin has been used.
Co-engraftment of human immune cells and human skin
offers the opportunity to study their interactions in vivo.
Moreover, engraftment of artificial, human-skin equiva-
lent has been investigated [11]. Further immunologically
important grafts are human bronchi for the study of
asthma, synovial tissue for the study of rheumatoid
arthritis, vaginal and neural tissue for the study of
human immunodeficiency virus (HIV) infection, and
thyroid grafts for the study of Grave’s disease [4].
Employing humanized mice in inflammation research
Humanized mouse models are used in research into all
aspects of immunology. An interesting approach is the
production of human antibodies in mice with a humanized
immune system [12]. Vaccination can be studied by
immunizing mice with a reconstituted human immune
system [8,9], hematopoiesis by transferring human stem
cells [9,13], and allograft rejection by co-transplanting
allogeneic immune cells and grafts [14,15]. In addition to
these basic immunological questions, humanized mice
can be used to investigate diseases by transferring the
respective ‘diseased’ tissues and cells. These disorders
include HIV infection, lymphomas, autoimmune diseases
such as multiple sclerosis, lupus and thyreoditis, and
inflammatory diseases such as asthma and rheumatoid
arthritis [4,13,16]. Moreover, they have been used success-
fully in studies of T-cell-mediated dermatoses. These
diseases share features with immunological disorders in
other organ systems. The skin can, thus, be regarded as
model organ for the investigation of immunological
disorders and for the development of new therapeutic
strategies. Therefore, we focus on skin diseases that
involve T cells and related pathophysiological processes.
T-cell migration to the skin
A crucial step in T-cell-mediated skin and other diseases
is the recruitment of T cells to the respective target organ
[17]. Humanized mouse models are employed to further
elucidate the recruitment of immune cells to inflammatory
sites and to find therapies that interfere specifically with
this process in humans. Initially, either human immune
cells or human skin were transferred to mice, which
provided important insights into the trafficking of immune
cells in response to chemokines [10,18]. Of greater value,
is the combined transplant of both blood and skin
(Figure 1a). Starting w1 week after injection, healthy
human skin is infiltrated and rejected by allogeneic
immune cells. Interestingly, this occurs without signs of
xenogeneic GVHD. This model has been used to analyze
the mechanism of allograft rejection [14,15] and to test the
effect of suppressive therapies such as cyclosporine,
rapamycin, anti-human lymphocyte-function-associated
antigen 3 (LFA3), human LFA3–IgG1 and interleukin 11
(IL-11) [19–21].
Rapid T-cell infiltration can be induced in this system
by intradermal injection of chemokines before the onset of
the alloimmune response. For example, tumor necrosis
factor a (TNF-a), CCL3 (macrophage inflammatory pro-
tein 1a) and CCL2 (monocyte chemoattractant protein 1)
attracted high numbers of CD45ROC
CD45RAK
T cells,
whereas CCL5 [RANTES (regulated upon activation,
normal T cells, expressed and presumably secreted)],
Table 1. Reconstitution of the human immune system in micea
Nameb
Mouse strain Human graft Important characteristics Refs
huPBL-SCID SCIDc
PBLs Functional immune system; signs of GVHD [6]
SCID-huThy/Liv SCID Fetal thymus and liver Continued repopulation of lymphoid and myeloid
lineages; no peripheral B cells; tolerance to
murine background
[5]
HID Beige/nude/xid Bone marrow Sustained active hematopoiesis [5]
SCID-hu-bone SCID Fetal bone Sustained active hematopoiesis; no peripheral
T cells
[5]
SCID-huBM/T SCID Fetal thymus and bone Generation of all leukocyte lineages and Ig
classes
[8]
SCID-huIC SCID/beige Fetal bone, thymus, skin
and lymph nodes
Primary, antigen-specific T-cell and B-cell
responses
[8]
Rag2-gc-CD34C
Newborn
Rag2K/K
/gc
K/K
CD34C
cord-blood cells B-cell, T-cell and dendritic-cell development;
structured thymus, spleen, lymph nodes;
functional immune responses
[9]
a
Abbreviations: GVHD, graft-versus-host disease; PBL, peripheral blood lymphocyte; Rag2, recombination activating gene 2; SCID, severe combined immunodeficiency; xid,
x-linked immunodeficiency; gc, common cytokine receptor g chain.
b
Names are either used by the original authors or established in the literature and, in general, represent an abbreviation of the mouse strain and human (hu) grafts used.
c
To date, either non-obese-diabetic (NOD)/SCID or SCID/beige mice are usually used, which seem to be superior to SCID mice for reconstitution with human PBLs.
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CXCL12 (stromal cell-derived factor 1) and CXCL10
(interferon g-inducible protein 10) attracted only low
numbers [22]. In experiments that used autologous skin
and peripheral blood mononuclear cells (PBMCs),
CXCL10, CCL22 (macrophage-derived chemokine),
CCL11 (eotaxin) and CCL5 differentially recruited subsets
of immune cells [23]. Preferential recruitment of T helper 1
(Th1) and Th2-associated cells indicates potential value as
a model for diseases associated with Th1 and Th2 cells.
By using T cells from patients with skin diseases, these
models can be used to delineate the molecules that are
essential for T-cell homing in the respective diseases, and
for testing specific therapies (see below).
Atopic dermatitis
In atopic dermatitis (AD) and type I hypersensitivity
reactions, Th2 cells and IgE provoke a prolonged inflam-
matory response in the skin. In classical animal models,
wild-type mice are sensitized by applying chemical
allergens such as ovalbumin and trimellitic anhydride
and are challenged with the same hapten several days
later. This results in an acute inflammatory response, but
not a chronic Th2-cell response with pronounced skin
inflammation. Moreover, although they have a major
impact on the course of the disease, the allergens applied
and their routes of administration (e.g. subcutaneous
implantation and the use of adjuvants) are often not rele-
vant for human pathophysiology. Thus, translating results
from animal experiments to humans is a crucial issue.
Several aspects of AD and type I hypersensitivity
reactions can be mimicked in humanized mouse
models. Transferring PBLs from atopic patients leads to
IL-4-dependent production of IgE in SCID mice [24].
Human IgE is also produced in SCID mice after recon-
stitution with PBLs from allergic patients and immuniz-
ation with the respective allergen [25,26]. Ex vivo
stimulation of splenocytes with allergen, IL-2 and
antigen-presenting cells gives rise to Th2-like T cells
[26]. After intraperitoneal and intradermal injection of
PBMCs from AD patients into SCID mice, topical
stimulation with superantigen and a relevant allergen
induced weak, epidermal inflammation that resembled
TRENDS in Pharmacological Sciences
Infiltration
Skin
T cells
Therapy
Therapy
Lesional
pso skin
(a)
Human
PBMCs
Activation
+/– therapy
No therapy
Therapy
No therapy
No therapy
SCID
(b)
Induction
Non-lesional
pso skin
SCID
(c)
4 weeks
Chemokines
SCID
(i)
(ii)
(i)
(ii)
(i)
(ii)
Figure 1. Humanized mouse models. (a) Humanized mouse model of T-cell migration. Human skin from a healthy donor is transplanted onto immunodeficient mice such as
severe combined immunodeficiency (SCID) mice. After engraftment, mice are injected with either autologous or allogeneic T cells. Intradermal injection of chemokines
induces infiltration of immune cells and allows testing of therapies that interfere with this process. Usually, T-cell infiltration is determined by immunohistology. Sections
show CD3 staining of human skin with (i) and without (ii) T-cell infiltration. Scale bars Z 100 mm. (b) Humanized mouse model of psoriasis (pso). Lesional skin from a patient
with pso is transplanted onto immunodeficient mice, and either topical or systemic therapy is studied. Scale bars Z 250 mm. (c) Induction of pso in non-lesional skin. Non-
lesional skin from a psoriasis patient is transplanted onto immunodeficient mice. After engraftment pso can be induced by intradermal injection of pre-activated autologous
immunocytes or superantigen. Therapy can be applied either to the immunocytes before injection or directly to the lesional skin. Scale bars Z 250 mm. Sections in (b) and (c)
show hematoxylin and eosin staining of human lesional psoriatic (i) and non-lesional (ii) skin on SCID mice. Abbreviation: PBMCs, peripheral blood mononuclear cells.
Review TRENDS in Pharmacological Sciences Vol.25 No.10 October 2004 545

AD [27]. SCID mice reconstituted with human serum
that contains anti-allergen IgE antibodies have positive
immediate-type skin test responses to intradermal injec-
tion of allergen [28]. These mice also develop increased
airway responsiveness.
To determine the molecules involved in skin homing
of T cells in AD, and to interfere specifically with this
process, human PBMCs and Th2 clones derived from
either lesions or blood of patients with AD have been
transferred into mice transplanted with allogeneic human
skin (Figure 1a) [29,30]. Th2 clones were selectively
recruited to the skin by injection of CCL17 and CCL22,
which are ligands of the Th2-associated chemokine
receptor CCR4, and by CCL2, but not by CXCL10, CCL1
or CCL11. Normal human PBMCs were attracted by CCL2
and CXCL10. Infiltration in response to CCL22 was
dependent on E-selectin (CD62E) and was inhibited by
either an anti-CD62E antibody or a CD62E antagonist.
Infiltration can also be blocked by an anti-leukocyte
function-associated molecule 1 (LFA-1) antibody and an
LFA-1 inhibitor [29,30]. By contrast, results from other
animal experiments and clinical observations indicate
that blocking CD62E alone is not sufficient for therapeutic
efficacy [29,30]
In addition, skin from allergic patients transplanted to
SCID mice is sensitive to an early-phase skin-prick test
with the relevant allergen [31]. In SCID mice engrafted
with skin and autologous PBMCs from allergic patients, a
profound, allergic, cutaneous reaction is induced by intra-
dermal injection of allergen. The skin is infiltrated by
CD4C
and CD45ROC
cells, basophils and murine eosino-
phils. The cutaneous reaction is not observed with grafts
from non-atopic donors. Administering anti-CCR3 anti-
body selectively reduces the accumulation of eosinophils
but not CD4C
cells and basophils [31].
Thus, there are humanized mouse models of major
aspects of AD, namely IgE production and migration of
T cells to the skin. However, induction of significant
disease is not yet possible, and therapeutic responsiveness
in these models and in humans does not always correlate.
Delayed-type hypersensitivity and allergic contact
dermatitis
Allergic-contact dermatitis (ACD) is a type IV hypersensi-
tivity reaction that is mediated by antigen-specific effector
T cells. Several classical mouse models for ACD that are
used widely in drug discovery are predictive in certain
respects [32]. However, distinct differences between these
models and the human disease exist, particularly with
regard to the ratio of naive to primed T cells, cellular
infiltration and therapeutic responsiveness. Furthermore,
classical models are mainly models of acute disease,
whereas most humans suffer chronic disease.
Few humanized mouse models for type IV hypersensi-
tivity reactions have been established. A frequent cause of
ACD is allergy to nickel ions. Human skin grafts on SCID
mice injected with autologous, nickel-reactive T-cell lines
have been topically challenged with nickel sulfate, which
leads to a massive accumulation of T cells in the grafts
[33]. Moreover, delayed-type hypersensitivity (DTH) to
either tuberculin or tetanus toxoid can be modeled in
humanized mice [34,35]. Thus, SCID mice have been
transplanted with human skin and reconstituted with
autologous PBMCs from sensitized donors. Intradermal
injection of tetanus toxoid or tuberculin caused the
infiltration of activated T cells, which is similar to the
human reaction.
A different kind of humanized mouse model can be used
for testing human DTH reactions in animals. In this
so-called ‘trans vivo DTH’, human PBMCs were injected
into either the pinnae or footpads of naive immune-
competent or immune-deficient mice. Co-injection of
antigens such as tetanus toxoid and alloantigen induced
a DTH-like swelling. This model has been used to
characterize the immune response of liver-transplant
recipients against donor antigens [36].
None of these models represents the full course of the
disease. In particular, sensitization of human T cells to
relevant antigens in the murine host has not been
achieved. Thus, humanized models have no big advantage
compared with classical models for ACD. Recently
developed models with inducible human immunity
(Rag2–gc–CD34C
and SCID–huIC mice) might prove to
be useful in the future [8,9].
Psoriasis
Psoriasis is a chronic skin disease that is characterized by
infiltration of inflammatory cells and hyperproliferation
of keratinocytes. Many cytokines and T cells have a
prominent role in the pathogenesis of the disease. T cells
might be activated by autoantigens and/or by bacterial
superantigens. In general, psoriasis does not occur spon-
taneously in animals, and transgenic and other mouse
models do not represent the full complexity of the disease.
Thus, psoriasis-like lesions in these models lack typical
cellular infiltrates of human lesions. Because of the lack of
suitable animal models there were early attempts to
transplant human psoriatic skin onto immunodeficient
mice (Figure 1b). Although both lesional and non-lesional
skin grafts change their phenotype in nude mice, they are
quite stable in SCID mice [37]. The gradual loss of psori-
atic features in SCID mice is rescued by injecting either
T cells derived from psoriatic lesions or superantigen-
stimulated PBMCs from patients with psoriasis [38,39].
Split-thickness or full-thickness grafts from human
psoriatic lesions transplanted onto SCID or SCID/beige
mice have been used widely to test anti-psoriatic treat-
ments [40]. To date, drug efficacy observed in the human-
ized murine model and in patients is consistent. Thus,
established treatments are also successful in the SCID
mouse model (Table 2). Therefore, the humanized mouse
model of psoriasis is valuable for preclinical evaluation of
novel, topical and systemic therapeutic strategies. Differ-
ent classes of drugs, such as proteasome inhibitors [41],
selectin inhibitors [42], antibodies [12,43,44] and anti-
sense oligonucleotides [45] (Table 2), reduce the severity of
psoriasis in the mouse xenograft model, measured by
epidermal thickness, grade of parakeratosis, and numbers
of inflammatory cells and proliferating keratinocytes.
Anti-CD11a therapy and the peroxisome proliferator-
activated receptor g ligand troglitazone also substantially
improved psoriasis in patients [43,46]. By contrast, the

therapeutic effect of the leukotriene inhibitor BAYX1005
(see Chemical names) is disappointing, in both the mouse
model and in humans [47]. Preliminary results indicate
that IL-10 is successful in humans but inefficient in the
humanized mouse model [48]. The inconsistency might be
caused by different biological functions in humans and
mice. For example, IL-10 is produced by both Th1 cells and
Th2 cells and is a strong growth factor for B cells only in
humans [1].
An alternative to transplanting lesional skin is to
induce psoriasis in engrafted, healthy, non-lesional skin
from psoriasis patients (Figure 1c). Induction can be
achieved by intradermal injection of superantigen-stimu-
lated PBMCs from the same patient or by direct injection
of superantigen into the skin [49–51]. More-detailed
analysis reveals that long-term stimulated patient
PBMCs reliably induce psoriasis only in skin from the
same patient [51]. Treating activated PBMCs before
injection into the skin allows immunomodulatory drugs
to be tested [48]. Interestingly, when transplanted onto
mice deficient in Rag2 and type I and II interferon
receptors (AGR mice), non-lesional skin from patients
develops spontaneously into psoriatic lesions without
induction [52].
The humanized SCID mouse model of psoriasis, thus,
seems to be a reliable, versatile model for the human
disease that has striking correlations to human patho-
physiology and response to therapy.
Other T-cell-mediated skin diseases
Humanized mouse models have also been established for
additional T-cell-mediated skin diseases for which no
suitable classical animal model exist. Alopecia areata is a
tissue-restricted autoimmune disease of the hair follicle,
which results in hair loss and baldness. After transplant-
ing human scalp explants from involved areas onto SCID
mice, normal hair regrowth was observed. Injection of
autologous lymphocytes isolated from scalp lesions and
stimulated with hair-follicle homogenate reproduces the
changes that are characteristic of alopecia areata [53,54].
This model has been used to characterize the pathogenetic
T-cell response. Injection of both CD4C
and CD8C
T cells
is necessary to induce significant hair loss [55]. T cells
activated by melanocyte peptides also reduce hair growth,
which indicates that these epitopes can function as auto-
antigens [56]. Immunohistochemical examination of biop-
sies reveals that production of CXCL10 by follicular
epithelium and interferon g by infiltrating T cells is asso-
ciated with hair loss, which supports a Th1-like disease [57].
Another skin disease with potential involvement of
T cells is pustulosis palmaris et plantaris (PPP), a chronic
recurring disorder of the palms and soles that is
characterized by sterile, intra-epidermal pustules. There
seems to be a relationship between PPP and tonsillar focal
infections. SCID mice reconstituted with human tonsillar
mononuclear cells (TMCs) from patients with PPP develop
skin lesions, including fur loss and eruptions around their
cheeks and foreheads [58]. After transplanting uninvolved
patient skin and immediate intraperitoneal injection of
patient TMCs, CD3C
and CD4C
cells infiltrate the graft
and intercellular adhesion molecule 1 is upregulated. This
is not seen after injection with PBLs [58].
Pemphigus foliaceus is an autoimmune, blistering, skin
disease caused by pathogenic autoantibodies against the
glycoprotein desmoglein-1. Injection of either the IgG
fraction from patient serum or related antibodies into
SCID mice transplanted with human skin mimics some
features of the disease [59]. In addition, mice engrafted
with artificial human epidermal equivalents and injected
with patient serum develop pemphigus-like clinical
features [60]. Topical treatment with wheat germ agglu-
tinin inhibits autoantibody binding and prevents acantho-
lysis and blister formation [60].
In a more general approach, human skin grafted on
SCID mice has been transduced with adenoviral vectors
coding for 37 different genes that are potentially involved
in skin diseases [61]. Depending on the gene, infiltration of
inflammatory cells, changes in vascular density, matrix
Table 2. Psoriasis treatment tested in SCID mouse modelsa
Class Drugb
Efficacyc
Refs
Modeld
Patient
Established drugs
Calcineurin inhibitor Cyclosporin A C C [43,48]
Glucocorticoids Dexamethasone C C [41,47]
Clobetasol propionate C C [43]
Vitamin D3 1a,25-Dihydroxycholecalciferol C C [48]
Compounds in development
Proteasome inhibitor PS519 C ? [41]
Selectin inhibitor Efomycine M C ? [42]
Leukotriene synthesis inhibitor BAYX1005 K K [47]
PPAR-g ligands Troglitazone C C [46]
NGF receptor blocker K252a C ? [44]
Antibodies Anti-CD11a, efalizumab C C [43]
Anti-IL-15 C ? [12]
Anti-NGF C ? [44]
Antisense oligonucleotides IGF-I C ? [45]
Cytokines IL-10 K (C) [48]
a
Abbreviations: IGF-I, insulin-like growth factor I; IL-15, interleukin 15; NGF, nerve growth factor; PPAR, peroxisome proliferator-activated receptor; SCID, severe combined
immunodeficiency.
b
See Chemical names.
c
C, good response; (C), moderate response; K, bad or no response; ?, unknown response.
d
Human lesional psoriatic skin was transplanted onto immuodeficient mice and drug efficacy determined after either systemic or topical therapy.

formation, proliferation and epidermal hyperplasia have
been observed.
Concluding remarks
Major progress has been achieved in grafting human
tissues into immunocompromised mice. Transfering either
tissues or cells from patients yields models for complex
diseases that do not occur normally in animals. These
models are invaluable for unraveling the pathophysiology
of diseases and for preclinical testing of novel therapeutic
strategies. Humanized mouse models are one step closer
to the patient and promise better correlation with the
clinical outcome than classical animal models. It might
even be possible to test the suitability of a therapy for an
individual patient before clinical application, thus, con-
tributing to customized medicine.
However, this closeness to the clinical situation brings
similar shortcomings. Thus, the number of animals in
each experiment is restricted because patient material is
limited and inter-individual variability is relatively high,
which makes statistical evaluation difficult. Moreover, the
use of different immunodeficient mouse strains usually
leads to different results, which can make comparison and
interpretation of the outcomes difficult. There are also
restrictions with regard to practicability and costs; timely
and sufficient supply of fresh patient material is crucial
but challenging, and housing and handling immunodefi-
cient mice is more complex than conventional animal
husbandry.
Therefore, humanized animal models are not appro-
priate for high-throughput screening. In drug discovery
they are particularly useful as an intermediate step
between late-preclinical research and clinical develop-
ment, and for target validation and compound character-
ization for complex diseases.
The future will bring more sophisticated models that
mimic some aspects of the human situation more closely.
These models will narrow the gap between the bench and
the clinic and, thus, benefit patients.
Acknowledgements
We apologize for not citing many excellent papers because of space
limitations.
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Chemical names
BAYX1005: (R)-2–4-[(quinolin-2-yl-methoxy) phenyl]-2cyclopentyl
acetic acid
K252a: (9S,10R,12R)-2,3,9,10,11,12-hexahydro-10-hydroxy-9-methyl-
1-oxo-9,12-epoxy-1H-diindolo[1,2,3-fg:30
,20
,10
-kl]pyrrolo[3,4-i][1,6]
benzodiazocine-10-carboxylic acid methyl ester
PS519: [1R-[1S,4R,5S]]-1-(1-hydroxy-2-methylpropyl)-4-n-propyl-6-
oxa-2-azabicyclo[3.2.0]heptane-3,7-dione

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