Review Paper_ Preclinical Models

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					Vet Pathol 45:563–575 (2008)




                   Review Paper: Preclinical Models of Psoriasis
                                                  D. M. DANILENKO
                       Genentech, Inc., Department of Pathology, South San Francisco, CA

        Abstract. Psoriasis is the most common autoimmune disease in man and is characterized by focal to
     coalescing raised cutaneous plaques with consistent scaling and variable erythema. The specific
     pathogenesis of psoriasis is not completely understood, but the underlying mechanisms involve a complex
     interplay between epidermal keratinocytes, T lymphocytes as well as other leukocytes (including dendritic
     cells and other antigen presenting cells [APCs]), and vascular endothelium. Mirroring the complexity of
     mechanisms that underlie psoriasis, there are a relatively large number of models of psoriasis. Each model
     is based on a slightly different pathogenic mechanism, and each has its similarities to psoriasis as well as its
     limitations. In general, psoriasis models can be very broadly divided on the basis of the pathogenic
     mechanisms that interplay to cause psoriasis, with the addition of several relatively poorly defined
     spontaneous murine mutant models. Other than the spontaneous mutant models, murine models of
     psoriasis can be divided into those that are genetically engineered (transgenic and knockout—with
     manipulation of either the epidermis, leukocytes, or the endothelium), and those that are induced (either by
     immune transfer or by xenotransplantation of skin from psoriatic patients). In addition to the murine
     models, in vitro human epidermal models have recently become more widely utilized. While no one single
     model of psoriasis is ideal, many have proven to be extremely valuable in investigating and better
     understanding the molecular mechanisms that underlie the complex interplay between epidermal
     keratinocytes, the innate and adaptive immune system, and the vascular endothelium in psoriasis.

        Key words:    Animal disease models; human epidermis; in vitro models; mouse; psoriasis.

                      Introduction                            been much recent progress in understanding many
                                                              of its complex underlying mechanisms, which
   Psoriasis is a common inflammatory condition of            involve an interplay between epidermal keratino-
human skin characterized by focal to coalescing               cytes, leukocytes (including dendritic cells and
raised cutaneous plaques with consistent scaling              other antigen presenting cells [APCs]), and vascular
and variable erythema.26 Typical histologic features          endothelium (Fig. 1 illustrates some of the key
of psoriasis include epidermal hyperplasia (acan-             features underlying the pathogenesis of psoria-
thosis) with elongated rete ridges, a less discrete           sis).26,29 Originally, psoriasis was considered to be
epidermal granular layer (hypogranulosis), para-              primarily a disorder of disregulated epidermal
keratosis, and leukocytic infiltration of the dermis          proliferation and differentiation, and indeed,
and epidermis.26,29,34 The cellular composition of            agents such as retinoids and vitamin D analogs
the psoriatic leukocytic infiltrate is variable but           that treat epidermal differentiation defects have
very consistently contains both CD4+ and CD8+ T               shown some efficacy in the treatment of psoria-
lymphocytes, with CD4+ T lymphocytes predomi-                 sis.2,24,32 With the discovery that immunosuppres-
nating in the dermis, and CD8+ T lymphocytes,                 sive agents such as cyclosporin A and corticoste-
particularly those expressing the aEb7 integrin,              roids are often effective in treating psoriasis, the
preferentially infiltrating the epidermis.26,38 Psoria-       pendulum has swung toward psoriasis being
sis is now recognized as the most common                      considered primarily a disorder of the immune
autoimmune disease in man, with a prevalence of               system, with T cells and specifically CD4+ T cells
2–4% worldwide.26,29 While the specific etiology of           felt to play a central role.35,51 Initially, psoriasis was
psoriasis is unknown, a genetic basis has been                believed to primarily be a Th1 T helper cell–
suspected for some time, and a number of different            mediated process, driven by IFNc and related
psoriasis susceptibility gene clusters, designated            cytokines.26,29 More recently it has been shown that
PSORS1, PSORS2 . . . PSORS6, have been identi-                IL-23, a cytokine involved in the development of
fied, underscoring the heterogeneous nature of                the newly defined Th17 T helper cell subset,36 plays
psoriasis.26,34 Similarly, the specific pathogenesis of       a major role in psoriasis.5,22,27,33 Even more recent
psoriasis is still not fully understood, but there has        data suggest that psoriasis is caused by an
                                                           563
564                                                  Danilenko                                        Vet Pathol 45:4, 2008




   Fig. 1. Schematic diagram illustrating some of the key features that make up our current understanding of the
pathogenesis of psoriasis. Psoriasis in genetically susceptible individuals is believed to be triggered by specific
stimuli, such as trauma or bacterial infections, which in turn induce resident dendritic cells (DC), macrophages, and
T cells to produce cytokines that initiate a cascade of events leading to the hallmarks of psoriasis: immune cell
activation, disregulated epidermal acanthosis, and angiogenesis. IL-12 produced by DC and macrophages induces a
Th1 immune response, characterized by production of IFNc, while IL-23 from DC and macrophages induces a
Th17 immune response, characterized by production of IL-17 and IL-22. These cytokines, in turn, induce the
changes characteristic of psoriatic epidermal keratinocytes, including upregulation of NF-kB, induction of nuclear
pStat3, and induction of psoriasin. Macrophages activated by TNF-a produce additional cytokines that induce
psoriatic epidermal changes, as well as VEGF, which stimulates angiogenesis. Activated macrophages and psoriatic
keratinocytes also produce chemokines that recruit leukocytes from the vasculature to infiltrate the developing
psoriatic plaque. DC 5 dendritic cell; IFNc 5 interferon gamma; IL 5 interleukin; NF-kB 5 nuclear factor-kappa
B; pStat3 5 phospho-signal transducer and activator of transcription 3; Th 5 helper T cell; TNF-a 5 tumor
necrosis factor-a; VEGF 5 vascular endothelial growth factor.

interaction between epidermal keratinocytes and            lated epidermal acanthosis, dermal and epidermal
the immune system,32,39,41 and that one possible           leukocytic infiltration, and dilation of dermal
candidate linking the immune system and epider-            blood vessels—lesions that are maintained by
mal keratinocytes is IL-22, a T-cell-derived cyto-         the complex interplay between T cells and their
kine that is produced by Th17 polarized T cells            cytokines, other leukocytes, vascular endothelium,
that are stimulated by IL-23,56 but that acts              and epidermal keratinocytes.26,29 As noted above,
on epidermal keratinocytes to induce acanthosis            epidermal keratinocytes as well as vascular endo-
and differentiation toward a psoriatic pheno-              thelial cells are active participants in the psori-
type.7,33,40 Regardless of the specific underlying         atic inflammatory process via secretion of cyto-
pathogenesis, psoriasis is characterized by disregu-       kines and growth factors, and the upregulation
Vet Pathol 45:4, 2008                           Psoriasis Models                                            565

of signaling and adhesion molecules on their              lesions that do respond to corticosteroids, the
surfaces.26,29                                            pathogenesis of these lesions is unknown, and they
   Mirroring the complexity of mechanisms that            do not express all of the features of psoriasis, such
underlie psoriasis, there are a relatively large          as lack of an epidermal T-cell infiltrate and the lack
number of models of psoriasis. While most of              of hyperproliferative keratin expression.47 In addi-
these are murine models, there are also several non-      tion, these mice have a limited useful lifespan
murine and a few in vitro human epidermal models          because of nonregenerative anemia and the massive
(Table 1). Each model is based on a slightly              papillomatous hyperplasia of their forestomachs.47
different pathogenic mechanism, and each has its          Another spontaneous mouse model that has been
strong points/similarities to psoriasis, as well as its   relatively well described is the chronic proliferative
limitations, not the least of which are the funda-        dermatitis mouse (Sharpincpdm/Sharpincpdm), a
mental morphologic differences between human              mouse that develops marked eosinophilic inflam-
psoriatic skin and murine psoriasis models (except-       mation in a number of tissues, including the skin,
ing xenotransplantation models).29,34,42 Morpholog-       which leads to marked acanthosis.17,18,45 Unlike
ic differences in murine models versus psoriatic          psoriasis, however, the inflammation in this model
skin include lack of parakeratotic scaling and            is driven by Th2 cytokines such as IL-4, IL-5, and
epidermal hypogranulosis, and marked follicular           IL-13, and lesions respond to IL-12 treatments.18
hyperplasia rather than true exaggeration of epi-         For these reasons, this model is not felt to be very
dermal rete ridges (Figs. 2, 3). In general, murine       representative of psoriasis, which is predominantly
models of psoriasis can be broadly divided on the         a Th1- and Th17-driven disease, and which has
basis of the pathogenic mechanisms that interplay         been shown to respond to an anti-IL-12 (and anti-
to cause psoriasis, with the addition of a few            IL-23) p40 MAb.22,49
relatively poorly defined spontaneous mutant
models. Aside from these spontaneous models,                        Genetically Engineered Models
murine models of psoriasis can be divided into               Genetically engineered mice and rats are the
those that are genetically engineered (transgenic         largest category of psoriasis models and include
and knockout—with manipulation of the epider-             both transgenics and knockouts. In this review, I
mis, leukocytes, or the endothelium), and those           have divided these into 3 broad categories: those
that are induced (either by immune cell transfer or       that target epidermal keratinocytes, those that
by xenotransplantation). In general, to be consid-        target leukocytes, and those that target vascular
ered as a useful model of psoriasis, the model has to     endothelium. The CD18 hypomorphic mouse is a
either share some histopathologic features with           genetically engineered model that targets leuko-
psoriasis, have a pathogenesis and/or disease             cytes. This mouse does not completely lack the
mechanism that is similar to psoriasis, and/or            CD18 b2 integrin, but rather has decreased
respond similarly to therapeutic agents that psori-       expression of this common b2 chain of the
asis has been demonstrated to respond to. The ideal       leukointegrin adhesion molecule complex. When
psoriasis model would have all 3 features. Howev-         on a PL/J strain background, these CD18 hypo-
er, as mentioned earlier, psoriasis is a heteroge-        morphic mice, PL.129S7-Itgb2tm1Bay, develop a
neous disease with a complex pathogenesis, There-         psoriasiform inflammatory skin condition with a
fore, identifying a single model of psoriasis that        predominantly lymphocytic infiltration.3,10,23 While
completely mirrors all aspects of psoriasis is very       lesions in these mice are responsive to dexameth-
likely not possible. A discussion of the most widely      asone,10 their pathogenesis has not been well
accepted models of psoriasis follows in the               characterized. In addition, unlike psoriasis, these
subsequent sections.                                      mice exhibit nonpsoriasiform epidermal hyperplasia
                                                          with lack of hyperproliferative keratin expression.
                        Spontaneous Models
                                                          Therefore, this model has not been widely used for
   There are a number of different spontaneously          efficacy testing of potential therapeutic agents.
occurring mouse models of psoriasis, none of which           Another genetically engineered mouse model
are very well understood mechanistically.42 Flaky         that develops cutaneous inflammation with some
skin mice (Ttcfsn/Ttcfsn) are probably the best           features similar to psoriasis is the p40 keratin 14
described, and have a spontaneous mutation that           (K14) transgenic mouse, Tg(KRT14-Il12b)1Tsk, in
induces proliferation and hyperkeratosis of strati-       which the p40 subunit of both IL-12 and IL-23 is
fied squamous epithelia, including the nonglandu-         overexpressed via the K14 promoter in basal
lar forestomach.46 While these mice have interest-        epidermal keratinocytes.24,25 These mice develop
ing squamous proliferative and inflammatory               cutaneous inflammation that is felt to be more
566                                               Danilenko                                         Vet Pathol 45:4, 2008



                               Table 1. Animal and in vitro models of psoriasis.

                                                                                         Increased     Leukocytic
            Model                    Acanthosis    Altered Epidermal Differentiation   Vascularization Infiltration
Spontaneous Models
  Flaky Skin (Ttcfsn/Ttcfsn)       Yes           Focal parakeratosis                      Yes             Yes
  Chronic Proliferative Dermatitis Yes           Focal parakeratosis                      Yes             Yes
    (Sharpincpdm/Sharpincpdm)
Genetically Engineered Models Targeting the Immune System
  PL/J CD18 b2 Integrin            Yes           Focal parakeratosis                      Yes             Yes
    Hypomorphic
  K14.p40 (IL-12 and IL-23)        Yes           No                                       Yes             Yes
    Transgenic
  HLA-B27/b2 Microglobulin         Yes           No                                       Yes             Yes
    Transgenic Rat
  aE (CD103) Knockout              Yes           No                                       Yes             Yes
Targeting Vascular Endothelium
  K14.VEGF Transgenic             Yes              Epidermal expression of                Yes             Yes
                                                     hyperproliferative keratins
  pTek-tTA.Tie2 Double            Yes              No data                                Yes             Yes
    Transgenic
Targeting Epidermal Keratinocytes
  K14.TGF-a Transgenic            Yes              Parakeratosis; altered                 No data         In some
                                                     differentiation                                       animals
  K14.KGF Transgenic              Yes              Epidermal expression of                Yes             No
                                                     hyperproliferative keratins
  K5.TGFb1 Transgenic             Yes              Parakeratosis                          Yes             Yes
  K14.IL-20 Transgenic            Yes              Epidermal expression of                No              No
                                                     hyperproliferative keratins
  IKK2 Epidermal Deletion         Yes              Epidermal expression of                Yes             Yes
                                                     hyperproliferative keratins

  K5.Stat3 Transgenic             Yes              Epidermal expression of                Yes             Yes
                                                     hyperproliferative keratins
  JunB/c-Jun Inducible            Yes              Parakeratosis; upregulation of         Yes             Yes
    Epidermal Deletion                               S100A8 and S100A9
Immune Transfer Model
  CD45RBHi + LPS & IL-12          Yes              Epidermal expression of                Yes             Yes
   in SCID Mice                                      hyperproliferative keratins
Xenotransplantation Models
  SCID Xenotransplantation        Yes              Epidermal expression of                Yes             Yes
                                                     hyperproliferative keratins
  AGR129 Xenotransplantation      Yes              Epidermal expression of                Yes             Yes
                                                     hyperproliferative keratins
In vitro Models
  Reconstituted Human             Yes              Epidermal expression of                No              No
     Epidermis (RHE) Using                           hyperproliferative keratins
     Psoriatic Keratinocytes
  RHE Using Normal Human          Yes when        Epidermal expression of                 No              No
     Keratinocytes                  treated with    hyperproliferative keratins
                                    specific        and S100A7 (psoriasin) when
                                    cytokines or    treated with IL-20 subfamily
                                    growth factors cytokines or oncostatin-M
Vet Pathol 45:4, 2008                                Psoriasis Models                                                     567


                                                    Table 1. Extended.

                                                                                                Reflects Human
T-cell Infiltration                Pathogenesis                 Response to Therapy                Situation     References

                                                                                                                         46
Strain-dependent        Uncertain                         Only steroids                            No
                                                                                                                      17,18
No data                 Uncertain; Th2 cytokine driven    Steroids, IL-12                          No



Yes                     Uncertain; CD4+ T-cell mediated Only steroids                              No               3,10,23


                                                                                                                      24,25
Yes                     Overexpression of IL-23 in          No data                                No
                         epidermis
                                                                                                                      47,52
Yes                     Overexpression of HLA linked        No data                                No
                         to spondylo-arthropathies
                                                                                                                         44
Yes                     Uncertain, possibly increased sus- No data                                 No
                         ceptibility to bacterial infection
                                                                                                                      12,53
No data                 VEGF overexpression               Only VEGFR1-VEGFR2-Ig                    No
                                                            fusion protein; no data for other
                                                                                                                         50
Yes                     Tie2 overexpression               Cyclosporin A                            No


                                                                                                                         49
In some animals         TGF-a overexpression              No data                                  No
                                                                                                                         15
No                      KGF overexpression                No data                                  No
                                                                                                                         28
Yes                     TGFb1 overexpression              No data                                  No
                                                                                                                          6
No                      IL-20 overexpression; neonatal    No data                                  No
                          lethal
                                                                                                                      37,45
Yes                     Disregulation of epidermal        Soluble TNF receptor fusion              Possibly
                          cytokine regulatory network.      protein
                          T cells not required
Yes                     pStat3 overexpression. CD4+       Only Stat3 Decoy Oligo, no               Possibly              41

                          cells required                   data for other
                                                                                                                         55
Yes                     Induction of Jun regulated        No data                                  Possibly
                          cytokines in keratinocytes;
                          T cells not required
Yes                     Activated Th1 polarized CD4+      Steroids and cyclosporin A               No              19,20,43

                          T cells traffic to sites of
                          immune stimulation
                                                                                                                  4,35,51,54
Yes                     Human psoriatic skin with         Anti-CD11a                               Yes
                         activated human CD4+ T cells
                                                                                                                       9,31
Yes                     Human psoriatic skin with         Anti-TNF and soluble TNF                 Yes
                         proliferation of resident         receptor fusion protein
                         human CD4+ T cells
                                                                                                                          1
No                      In vitro manipulation             No data                                 Partially

                                                                                                                   7,8,13,40
No                      In vitro manipulation             No data                                 Partially



similar to eczema and atopic dermatitis, lacking a            (CD103) knockout mouse, Itgaetm1Cmp, also devel-
significant cutaneous CD8+ T-cell infiltration, and           ops a cutaneous inflammatory disease. The aE
so are not considered to be a particularly useful             integrin complexes with the b7 chain and is thought
model for psoriasis. Similarly, the aE integrin               to play a role in cutaneous and mucosal immunity
568                                                  Danilenko                                        Vet Pathol 45:4, 2008




    Fig. 2. Skin; human psoriatic skin illustrating exaggerated epidermal rete ridges exhibiting epidermal
hypogranulosis (asterisks) with extensive parakeratotic scaling (PS). HE. Bar 5 100 mm in a and 50 mm in b.
    Fig. 3. Skin; CD45RBHi CD252 T-cell immune transfer mouse model. In contrast to the human psoriatic skin
illustrated in Fig. 1, the epidermis in this mouse model has follicular hyperplasia rather than exaggerated epidermal
rete ridges, exhibits epidermal hypergranulosis (arrows) rather than hypogranulosis, and lacks the parakeratotic
scaling that is one of the hallmarks of a psoriatic plaque. HE. Bar 5 100 mm in a and 50 mm in b.


through interaction with its counter receptor, E           Tg(HLA-B*2705, B2M)33-3Trg.48,53 This rat over-
cadherin.44 In addition, aEb7 is preferentially            expresses a form of human leukocyte antigen
expressed by the CD8+ T cells that infiltrate the          (HLA)-B27 that has been linked to spondyloar-
psoriatic epidermis.38 However, the cutaneous              thropathies.21 HLA-B27 transgenic rats develop
inflammatory condition that aE knockout mice               epidermal acanthosis with epidermal infiltration of
develop is not felt to mimic psoriasis closely             both CD4+ and CD8+ T cells, as well as immune-
enough, having significant ulceration and very             mediated arthritis and inflammatory bowel dis-
few cutaneous CD8+ T cells, for these mice to be           ease.48,53 The occurrence of psoriatic skin lesions is
a useful psoriasis model. Still, these mice have a         less consistent than is the occurrence of the other
phenotype that does shed some light on the                 immune-mediated disorders,48,53 and there have
potential functions of the aEb7 integrin complex           been no published reports of therapeutic efficacy
in cutaneous inflammatory disease.44                       testing for the psoriatic lesions. Therefore, while
   Another genetically engineered animal model             this model has attained some utility as a model of
that targets the immune system more broadly is the         HLA-B27 associated autoimmune disease, it has
HLA-B27/human b2 microglobulin transgenic rat,             not gained widespread use as a model of psoriasis.
Vet Pathol 45:4, 2008                           Psoriasis Models                                             569

   Genetically engineered mouse models of psoria-         as a model of psoriasis.6 Recently however, several
sis that target vascular endothelium include VEGF         genetically engineered mouse models that target
K14 transgenic mice and Tie2 transgenic mice.             epidermal keratinocytes have put the epidermal
Mice overexpressing VEGF epidermally via a K14            keratinocyte back into a central role in the
promoter, Tg(KRT14-Vegfa)1Gdy, develop a very             pathogenesis of psoriasis. These models appear to
vasculocentric cutaneous inflammatory disease             fulfill most of the criteria necessary for a model of
with hyperplastic and inflamed dermal vasculature,        psoriasis to be representative and useful. The first of
and psoriasiform epidermal acanthosis.12,54 Al-           these models targeting epidermal keratinocytes is
though these mice have many vascular, epidermal           the epidermal-specific IKK2 knockout mouse,
and inflammatory features that resemble psoriasis,        Tg(KRT14-cre)1Cgn 3 Ikbkbtm1Mpa, in which
the lesions appear to be largely vascular-based, and      deletion of the IKK2 catalytic subunit of the IkB
there is marked dermal infiltration by mast cells. In     kinase complex (necessary for NF-kB activation by
addition, other than responding to treatment with a       inflammatory stimuli) caused mice to develop
soluble VEGFR1-VEGFR2-Ig fusion protein, data             psoriasiform cutaneous inflammation that shared
demonstrating response to therapeutic candidates          many features of psoriasis, including dependence on
in this model are lacking.12,54 Therefore, there are a    intact TNF signaling, but which was T-cell inde-
number of caveats that limit the usefulness of the        pendent.37,46 A second model targeting epidermal
VEGF K14 transgenic mouse model. Tie2 trans-              keratinocytes is the JunB/c-Jun epidermal inducible
genic mice, Tg(Tek-tTA)1Dmt 3 Tg(TetOS-                   double knockout mouse, Tg(Krt1-5cre/ERT)1lpc 3
Tek)1Dmt, were constructed using a driver trans-          Junbtm3Wag 3 Juntm4Wag.56 JunB is a component of
gene, pTek-tTA, which localizes Tie2, the receptor        the AP-1 transcription factor and has been localized
for angiopoietin-1 and angiopoietin-2, to vascular        to the PSORS6 psoriasis susceptibility locus, while
endothelium as well as to keratinocytes in the            c-Jun is felt to be an antagonist to JunB. Inducible
epidermis and hair follicles.51 Tie2 transgenic mice      deletion of both JunB and c-Jun leads to psoriasi-
also develop a very vasculocentric cutaneous              form cutaneous inflammation, as well as to arthritis
inflammatory disease with vascular hyperplasia            in some mice. The cutaneous inflammation is not
and epidermal acanthosis with inflammation.               dependent on T cells, nor is it dependent on TNF
While many of the same caveats that hold for the          signaling, as both Rag2 knockout mice and TNFR1
VEGF K14 transgenic mice also pertain for the             knockout mice still developed cutaneous lesions.56
Tie2 transgenic mice (vasculocentric inflammation         Interestingly, however, the TNFR1 knockout mice
with many mast cells and incomplete characteriza-         did not develop arthritis.55 A final recent transgenic
tion of epidermal changes), cutaneous lesions in the      model targeting epidermal keratinocytes is the K5-
Tie2 transgenic mice have at least been shown to be       Stat3 transgenic mouse, Tg(KRT5-stat3*A661C*
responsive to a therapeutic that has shown efficacy       N663C)1Jdg, in which Stat3, a transcription factor
in psoriasis, namely cyclosporin A.50                     implicated as playing a major role in signal
   There have been several genetically engineered         transduction in psoriatic keratinocytes, is overex-
mice, all transgenics, that have targeted epithelial      pressed in epidermal keratinocytes.41 In this trans-
growth factors such as TGF-a, KGF, and TGF-b              genic mouse model, mice develop psoriasiform
via K14 or K5 promoters (Tg(TGFa)1Efu,                    epidermal acanthosis that is most pronounced in
Tg(FGF7)2Efu, and Tg(KRT5-TGF-B1)F2020Xjw,                areas of friction, such as the tail head, and that is
respectively) to the basal epidermis, with resulting      accentuated by tape stripping and wounding, all
phenotypes that somewhat mimic the epidermal              features that are similar to psoriasis.41 In addition,
acanthosis of psoriasis because of the disruption of      these mice have a cutaneous lymphocytic infiltrate
normal epidermal growth and differentiation, while        that is predominantly CD4+ in the dermis, and CD8+
generally lacking the inflammatory component of           in the epidermis, another feature that is similar to
psoriasis.15,28,50 While these growth factor trans-       psoriasis.41 Finally, both Stat3 transgenic skin and
genics are not good models of psoriasis, they have        the injection of activated lymphocytes, specifically
proven to be useful in the study of epidermal growth      CD4+ T cells, are necessary to generate a psoriatic
and differentiation.15,28,50 A relatively recently dis-   phenotype in transplanted SCID mice,41 a finding
covered cytokine in the IL-10 family, IL-20, also         that firmly establishes a link between keratinocytes
induces a similar psoriasiform phenotype in K14           and CD4+ T lymphocytes in the pathogenesis of
promoter epidermal targeted transgenic mice,              psoriasis.39 Since phosphorylated Stat3 overexpres-
Tg(KRT14-Il20)1Yac, but again these mice lack             sion has also been detected in the nuclei of psoriatic
cutaneous inflammation, and in addition exhibit           keratinocytes, the link between the K5 Stat3
neonatal lethality, essentially rendering them useless    transgenic mouse and psoriasis is even further
570                                             Danilenko                                    Vet Pathol 45:4, 2008



strengthened.39,41 Cutaneous lesions in these trans-   skin transplanted onto immunodeficient mice.
genic mice respond to Stat3 decoy oligonucleotides,    However, these models are also the most difficult
suggesting that therapies aimed at this signaling      to utilize, as they rely on having a steady supply
pathway may be of potential clinical benefit.41 A      of human psoriatic skin available. Hence, only a
number of IL-10 family members, including the          few laboratories are able to run these models with
previously mentioned IL-20, as well as IL-6 family     any consistency.4,9,31,35,52,55 In the prototype xe-
members, such as oncostatin M, induce Stat3            notransplantation model, the epidermis and
phosphorylation, and are being investigated as         dermis from a patient with psoriasis is trans-
potential therapeutic targets by a number of           planted onto the flank of a CB.17-Prkdcscid/
investigators.7,8,33,40                                Prkdcscid SCID mouse. As was the case with the
                                                       Stat3 transgenic mice, psoriatic lesions are only
  Immune Transfer and Transplantation Models           induced when activated T cells, and specifically
                                                       CD4+ T cells but not CD8+ T cells, are injected
   This category of models includes the CD45RBHi
                                                       into the transplanted SCID mice.35,52 The trans-
CD252 T-cell immune transfer model and the
                                                       planted epidermis then undergoes psoriasiform
human psoriatic skin xenotransplantation model,
                                                       acanthosis with the induction of proliferation
both using SCID mice as the transplant recipients.
                                                       markers such as keratin 16. In addition, trans-
Both of these models have been relatively exten-
                                                       planted skin becomes infiltrated by lymphocytes,
sively validated in efficacy studies, and thus are
                                                       with primarily CD4+ T cells in the dermis and
frequently favored by investigators hoping to test a
                                                       primarily CD8+ T cells in the epidermis.35,52
novel potential therapeutic entity.43,55
                                                       Intraepidermal microabscesses (Munro’s micro-
   In the CD45RBHi T-cell immune transfer model,
                                                       abscesses) are also sometimes present.52 An anti-
MHC minor mismatched CD4+ CD45RBHi
                                                       CD11a MAb (efalizumab), which has demon-
CD252 naıve T cells (lacking in regulatory T cells)
            ¨                                          strated efficacy in human psoriasis,14,34 has also
are injected into ICR-Prkdcscid/Prkdcscid SCID
                                                       been shown to have efficacy in this mouse
mice, and target areas of antigenic stimulation,       model.54 A variant of this model using symptom-
such as the lower intestinal tract, skin, and lung.    less psoriatic skin transplanted onto AGR129
When these CD252 naıve T cells are stimulated
                         ¨                             mice, 129-Ifnar1tm1Agt 3 Ifngr1tm1Agt 3
with either LPS or IL-12 (SDI mouse, BioSeek,          Rag2tm1Fwa, which lack both interferon type 1
Burlingame, CA), the predominant disease is            and type 2 receptors as well as RAG2, has also
chronic persistent cutaneous inflammation that         recently been described.9,31 In this model, trans-
has many features resembling psoriasis19,20,43         planted symptomless psoriatic skin spontaneous-
(Fig. 3). The underlying pathogenesis of the           ly becomes psoriatic without the addition of
cutaneous inflammation is Th1-driven, similar to       activated T cells because of the proliferation of
psoriasis (although psoriasis is now felt to have a    resident human T cells within the xenograft.9,31
major Th17-driven component), but unlike psori-        An anti-TNF MAb (infliximab) and a soluble
asis, IFNc does not appear to play a major role in     TNF receptor fusion protein (etanercept), both of
the development of lesions in this model.19,20 In      which have been shown to have efficacy in human
addition, since all of the transferred lymphocytes     psoriasis,11,30,34 also demonstrate efficacy in in-
are CD4+, no CD8+ lymphocytes are present in the       hibiting the development of psoriatic lesions in
inflammatory infiltrate, which is unlike psoriasis.    this model.9
To address this limitation, we and other investiga-
tors have added back different lymphocyte subsets                       In Vitro Models
to the cells being immune transferred with relative-
ly good results, such that CD8+ T cells can be            As an alternative to the in vivo models, several
found in the epidermal infiltrate with the mainte-     laboratories, including our own, have begun to use
nance of the severity of the cutaneous inflamma-       reconstituted human epidermal culture model
tion (Khattri and Danilenko, unpublished data).        systems whereby epidermal keratinocytes are
As mentioned above, cutaneous lesions in this          grown to the air-liquid interface and differentiate
model have been shown to respond to a number of        and stratify to mimic the morphology of normal
therapeutic agents, including cyclosporin A, corti-    stratified squamous epidermis. Epidermal kerati-
costeroids, and anti-IL-12.19,20,43                    nocytes in this model can be obtained from
   The final set of animal models of psoriasis are     individuals with psoriasis1 or from normal individ-
probably the most faithful of all to the human         uals and then treated with a variety of cytokines
condition, since these models use human psoriatic      and/or growth factors (e.g., IL-20, IL-22, oncosta-
Vet Pathol 45:4, 2008                             Psoriasis Models                                              571




   Fig. 4. Skin; in vitro reconstituted human epidermis. Epidermal hyperplasia, induction of epidermal S100A7
(psoriasin) expression, and induction of pStat3 in epidermal keratinocyte nuclei following 4 days in vitro treatment
with IL-20 (b,e,h) and IL-22 (c,f,i) compared with media control (a,d,g). IL-22-treated epidermis also exhibits
hypogranulosis (asterisks in c), a feature frequently evident in psoriatic epidermis. HE (a,b,c), S100A7 (psoriasin)
IHC (d,e,f), pStat3 IHC (g,h,i). Bars 5 50 mm.

tin-M) such that the resulting reconstituted human         pStat37,8,40 (Figs. 3–5), one of the major signal
epidermal model develops phenotypic characteris-           transducers in psoriatic epidermis, as described
tics that can mimic psoriatic epidermis7,8,13,40           previously.41 While these in vitro model systems
(Fig. 4). In both the psoriatic keratinocyte-derived       have obvious limitations in that they lack leuko-
model and the normal human keratinocyte-derived            cytes and blood vessels, they have still proven
model treated with either IL-20, IL-22, or onco-           useful in studying many aspects of the psoriatic
statin-M, keratinocytes exhibit many of the same           epidermis, including keratinocyte differentiation
phenotypic features evident in psoriasis, such as          and response to stimuli.
upregulation of chemokines IL-8 and GRO-a, and
induction of hyperproliferative keratin 16.1,7,8,13,40           Recommendations and Future Directions
Many additional features in common with psoriatic
epidermis are seen in the normal keratinocyte                 While there are a relatively large number of
reconstituted epidermis model treated with cyto-           animal models purported to mimic psoriasis, there
kines such as IL-20, IL-22, or oncostatin-M,               are actually only a small number that meet the
including upregulation of S100 family members              criteria of resembling psoriasis clinically and
such as S100A7/psoriasin, and activation of                pathologically, having a pathogenic mechanism
572                                               Danilenko                                        Vet Pathol 45:4, 2008



that is known to play a significant role in psoriasis,   plantation models more faithfully mimic human
and having been validated by showing a response          psoriasis, our laboratory has used the SCID
to therapies that psoriasis is known to respond to.      CD45RBHi CD252 T-cell immune transfer model
Only two sets of models currently meet these             more widely for initial screening, as greater
criteria: the ICR-Prkdcscid/Prkdcscid SCID mouse         numbers of mice can be used, and more treatment
CD45RBHi CD252 T-cell immune transfer model,             effect parameters can be evaluated. Once a
and the 2 human psoriatic skin xenotransplanta-          potential therapeutic has shown evidence of effica-
tion onto immunodeficient mouse models, CB.17-           cy in this model, we will then generally attempt to
Prkdcscid/Prkdcscid and AGR129. Of these 2, the          confirm this effect in one or both of the xenotrans-
human psoriatic skin xenotransplantation models          plantation models.
are the most faithful to human psoriasis, but the           While only the 2 sets of models described above
difficulties in obtaining human psoriatic skin for       are widely used for efficacy testing of potential
transplantation limits the widespread utility of         therapeutics, several recently described genetically
these models. The CD45RBHi CD252 immune                  engineered mouse models hold promise for studying
transfer model has gained relatively widespread use      many aspects of psoriasis pathogenesis and may also
but has several limitations: As is the case for all      eventually turn out to be useful models for efficacy
mouse models, the morphology of lesions in this          testing (this will only be determined after repeated
model does not completely mimic the epidermal            evaluations). The K5-Stat3 transgenic mouse,
changes in psoriasis; in addition, the leukocytic        Tg(KRT5-stat3*A661C*N663C)1Jdg, while cur-
infiltrate lacks CD8+ T cells unless they are            rently not meeting the criterion of having been
specifically added back in.                              validated via efficacy testing with a therapeutic
   Despite these limitations, both models are            known to affect psoriasis, nonetheless shows much
relatively commonly used for evaluation of poten-        promise as a potentially useful model of psoriasis,
tial therapeutic agents, as human therapeutics with      particularly as it appears to link keratinocytes and
demonstrated efficacy in psoriasis have also shown       infiltrating T-lymphocytes in the pathogenesis of
efficacy in these models (both small molecules such      psoriatic lesions.39,41 In addition, while having the
as cyclosporin A and biologics such as anti-TNFs         limitations imposed by the differences inherent
and anti-CD11a).9,43,55 While both sets of models        between mouse and human skin, the morphology
have been used for efficacy testing of potential         of lesions in this model nonetheless appear to
therapeutics, the pros and cons of each somewhat         relatively faithfully mimic those evident in psoriatic
balance each other out. The xenotransplantation          skin.41 While this model does hold promise patho-
models are more biologically faithful to psoriasis,      logically and mechanistically, it still remains to be
but the difficulties in obtaining human psoriatic        validated by testing whether its cutaneous lesions
skin to transplant generally limits the number of        will respond to additional therapeutic agents, such
animals that can be used in a study. In contrast, the    as cyclosporin A, anti-LFA-1, anti-TNFs, and
number of SCID CD45RBHi CD252 T-cell im-                 others. Another recently described mouse model,
mune transfer model mice that can be used in a           the epidermal JunB/c-Jun epidermal inducible dou-
study can be much greater (we generally try to use       ble knockout mouse, Tg(Krt1-5cre/ERT)1lpc 3
10–12 mice per treatment group), thereby allowing        Junbtm3Wag 3 Juntm4Wag, also develops psoriasiform
for much more meaningful statistical analysis of         cutaneous inflammation, as well as arthritis in some
differences in treatment effects. In the xenotrans-      mice.55 As is the case for the Stat3 knockout mice,
plantation models, only the transplanted skin can        this model has the same limitations imposed by
be evaluated for treatment effects, and generally        differences between mouse and human skin, and also
only histologic evaluation is done (epidermal            remains to be validated by testing whether its
thickness is the primary measurement that has            cutaneous lesions will respond to antipsoriatic
been used).9,55 In contrast, in the SCID CD45RBHi        therapeutic agents. Still, it is also a valuable model
CD252 T-cell immune transfer model treatment             for studying the mechanisms common to the
effects are evaluated from a number of different         development of both epidermal and joint lesions in
sites (ears, nasal planum, paws) and evaluation of       psoriasis, as well as for investigating the role that the
both gross appearance (degree of alopecia, scaling,      epidermal keratinocyte plays in the pathogenesis of
hyperemia) as well as histologic appearance (epi-        psoriasis independent of infiltrating activated T cells.
dermal thickness, degree of inflammatory infiltra-          Thus, in summary, new models of psoriasis
tion and vascular hyperplasia)9,20,43 can be evaluat-    continue to be developed even as existing ones are
ed (also Khattri and Danilenko, unpublished              refined. While no single model of psoriasis is ideal,
observations). Therefore, while the xenotrans-           many have proven to be extremely valuable in
Vet Pathol 45:4, 2008                             Psoriasis Models                                              573

investigating and better understanding the molec-            8 Boniface K, Diveu C, Morel F, Pedretti N, Froger J,
ular pathogenic mechanisms that underlie the                   Ravon E, Garcia M, Venereau E, Preisser L,
complex interplay between epidermal keratino-                  Guignouard E, Guillet G, Dagregorio G, Pene J, `
cytes, the innate and adaptive immune system,                  Moles JP, Yssel H, Chevalier S, Bernard FX, Gascan
and the vascular endothelium in psoriasis.                     H, Lecron JC: Oncostatin M secreted by skin
                                                               infiltrating T lymphocytes is a potent keratinocyte
                        Acknowledgements                       activator involved in skin inflammation. J Immunol
                                                               178:4615–4622, 2007
  I would like to sincerely thank Roli Khattri, Steve        9 Boyman O, Hefti HP, Conrad C, Nickoloff BJ, Suter
Hurst, and Susan Sa of Genentech for their review of           M, Nestle FO: Spontaneous development of psori-
and comments on this manuscript. I would also like to          asis in a new animal model shows an essential role
thank Chris Harrison and Heather Abanto (Gardiner-             for resident T cells and tumor necrosis factor-alpha.
Caldwell Pacific, San Bruno, CA) for their technical           J Exp Med 199:731–736, 2004
expertise in the illustration of Fig. 1. Portions of this   10 Bullard DC, Scharffetter-Kochanek K, McArthur
manuscript were presented at the 56th Annual Meeting           MJ, Chosay JG, McBride ME, Montgomery CA,
of the American College of Veterinary Pathologists             Beaudet AL: A polygenic mouse model of psoriasi-
(December 2005), and were published in extended                form skin disease in CD18-deficient mice. Proc Natl
abstract form on pages 88–91 of the Conference                 Acad Sci USA 93:2116–2121, 1996
Proceedings.                                                11 Chaudhari U, Romano P, Mulcahy LD, Dooley
                                                               LT, Baker DG, Gottlieb AB: Efficacy and safety
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Request reprints from D. M. Danilenko, Genentech, Inc., Department of Pathology, One DNA Way, MS 72B,
South San Francisco, CA 94080 (USA). E-mail: danilenko.dimitry@gene.com.

				
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