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Year : 2014  |  Volume : 80  |  Issue : 3  |  Page : 204-213

Severe combined immunodeficiency mouse-psoriatic human skin xenograft model: A modern tool connecting bench to bedside

Smriti Kundu-Raychaudhuri1, Ananya Datta-Mitra1, Christine J Abria2, John Peters2, Siba P Raychaudhuri1,  
1 Research, VA Medical Centre Sacramento; Department of Internal Medicine, Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis School of Medicine, Davis, CA 95616, USA
2 Research, VA Medical Centre Sacramento, University of California, Davis School of Medicine, Davis, CA 95616, USA

Correspondence Address:
Smriti Kundu-Raychaudhuri
VA Medical Center Sacramento, Division of Rheumatology, Allergy and Clinical Immunology, University of California, Davis School of Medicine,10535 Hospital Way, Bldg#807, Mather, CA, 95655
USA

Abstract

Psoriasis is a multifactorial chronic inflammatory disease. Research into the pathogenesis of this disease is hindered by the lack of a proper animal model. Over the past two decades, many scientists were involved in the development of animal models that nearly mirror the immunopathogenesis of psoriasis. One such model, which has opened doors to the study of molecular complexities of psoriasis as well as its treatment, is the severe combined immunodeficiency (SCID) mouse-human skin chimera model. This model not only mirrors the clinical and histopathological features of psoriasis but also help in the study of cell proliferation, angiogenesis, function of T cells, neurogenic inflammation and cytokines involved in inflammatory reactions. In this article, we have reviewed the prospects and the limitations of the SCID mouse model of psoriasis.



How to cite this article:
Kundu-Raychaudhuri S, Datta-Mitra A, Abria CJ, Peters J, Raychaudhuri SP. Severe combined immunodeficiency mouse-psoriatic human skin xenograft model: A modern tool connecting bench to bedside.Indian J Dermatol Venereol Leprol 2014;80:204-213


How to cite this URL:
Kundu-Raychaudhuri S, Datta-Mitra A, Abria CJ, Peters J, Raychaudhuri SP. Severe combined immunodeficiency mouse-psoriatic human skin xenograft model: A modern tool connecting bench to bedside. Indian J Dermatol Venereol Leprol [serial online] 2014 [cited 2019 Jul 21 ];80:204-213
Available from: http://www.ijdvl.com/text.asp?2014/80/3/204/132247


Full Text

 INTRODUCTION



Psoriasis, described in Corpus Hippocraticum, [1] is a chronic inflammatory disease of skin and joints involving a complex interaction of genetic, environmental, and immunologic factors. [2],[3],[4] It affects 2-3% of Caucasians [5],[6] mainly in early adulthood. [7] It is characterized by epidermal hyperplasia (acanthosis) with elongated rete ridges, hypogranulosis, parakeratosis, and CD4 + T lymphocytes predominating in the dermis and CD8 + T lymphocytes infiltrating the epidermis. [8],[9],[10] Due to the heterogeneity of the disease, in spite of intense research, the precise pathogenesis of psoriasis is still uncertain.

Most of the features of psoriasis occur exclusively in humans and are generally absent in animals except in rhesus and cynomolgus monkey. [11],[12]

Thus, research into the pathogenesis of this mysterious disease was greatly handicapped by the need for an appropriate animal model. However, advancement of science and technology has led to the development of numerous murine, non-murine, and in vitro human epidermal models mirroring various aspects of psoriasis. Every model is based on different pathogenetic mechanisms and each one displays similarities as well as differences from psoriasis. [13]

In this article, we will review the efficacy of different animal models in exploring the pathogenesis of psoriasis as well as for development of potential therapeutic agents. We will also highlight in detail the effectiveness of the severe combined immunodeficiency (SCID) mouse psoriasis xenograft model.

 Animal models of psoriasis



Apart from the obvious size difference between human and mouse skin surface area, the fundamental morphological differences between mouse models as opposed to psoriatic skin include absence of parakeratotic scaling and epidermal hypogranulosis and marked follicular hyperplasia rather than true elongation of epidermal rete ridges. [14] Moreover, mouse has an additional subcutaneous muscle layer (panniculus carnosus) that is almost absent in humans which may release myokines that contribute to inflammatory reactions. Commonly, the mouse models of psoriasis can be divided into spontaneous mutant models, genetically engineered murine models, and immune cell transfer and xenotransplantation models [Table 1]. To be an ideal model of psoriasis, the model has to reproduce some histopathologic features with an almost similar pathogenic mechanism to psoriasis and respond similarly to antipsoriatic treatments. [15]{Table 1}

Spontaneous mouse models

Spontaneous mouse mutations that gave rise to psoriasiform phenotypes, the flaky skin (fsn), chronic proliferative dermatitis (cpd), and homozygous asebia (ab/ab) mutant have been used to study pathogenesis of psoriasis. [16],[17] All these mutants show histopathological features of psoriasis such as acanthosis, infiltration of mast cells and macrophages, and angiogenesis in the dermis. [18] However, the deficiency of T cells in these infiltrates [19] and inefficacy of antipsoriatic drugs suggest that these pathological features are not similar to psoriasis.

Genetically engineered mouse models of psoriasis

In the majority of these models, either increased expression or knockout of particular genes is directed to the basal layer of the epidermis, or to the suprabasal layer or to those that target leukocytes or keratinocytes, or those that target vascular endothelium and different cytokines, such as interleukin (IL)-1, IL-6, IL-8, the cytokine 'regulated on activation, normal T-cell expressed and secreted' (RANTES), transforming growth factor (TGF)-α, tumor necrosis factor (TNF)-α, vascular endothelial growth factor (VEGF), and interferon (IFN)-γ, which have been proposed to play an active part in the pathogenesis of psoriasis.

CD18 hypomorphic mouse developed a psoriasiform phenotype with predominant lymphocytic infiltration, [20],[21],[22] was nonresponsive to dexamethasone, [23] and was devoid of hyperproliferative keratin expression. Likewise, p40 keratin (K) 14 transgenic mouse, [24],[25] developed skin inflammation similar to eczema and atopic dermatitis, lacking significant cutaneous CD8 + T cell infiltration. αE integrin (CD103) knockout mouse developed cutaneous inflammation with significant ulceration but with very few cutaneous CD8 + T cells compared to psoriasis. [26] In VEGF K14 transgenic mouse, the mice developed a cutaneous inflammatory disease with hyperplasia and inflammation of dermal vasculature, and epidermal acanthosis similar to psoriasis but the lesions were largely vascular and there was dermal infiltration of mast cells. [27],[28] Tie2 transgenic mouse had the same features as VEGF K14 mouse but the lesions were shown to be responsive to cyclosporin A. [29] Similarly, all transgenics targeting epithelial growth factors such as TGF-α, keratinocyte growth factor (KGF), and TGF-β, mimicked the epidermal acanthosis of psoriasis [29],[30],[31] but lesions from K5-TGFβ1 model also appeared to show increased expression of psoriasis-associated genes specifically expressed by T-cells, dendritic cells, and macrophages. [32] In transgenic mouse models overexpressing IL-1α and K14, there was infiltration of macrophages and monocytes within the dermis with acanthosis and parakeratosis. [33] In IFN-γ/involucrin transgenic mice, there was keratinocyte hyperproliferation, major histocompatibility complex (MHC) class II, intercellular adhesion molecule (ICAM)-1 induction and enlargement of dermal capillaries but without epidermal T cell infiltrates. [34] PL/J mouse overexpressing leukocyte β2 integrins, manifested epidermal hyperplasia, hyperkeratosis, parakeratosis, and lymphocyte exocytosis. IL-20 also initiated a psoriasiform lesion in the absence of cutaneous inflammation in K14 promoter epidermal targeted transgenic mice. [35]

K5-Stat3 transgenic mice developed epidermal acanthosis in areas of friction, and also had a dermal CD4 + and epidermal CD8 + lymphocytic infiltrate. [36],[37] The human leukocyte antigen (HLA)-B27/human β2 microglobulin transgenic rat showed epidermal acanthosis with epidermal infiltration of both CD4 + and CD8 + T cells but the incidence of skin lesions was less reliable than the incidence of immune-mediated arthritis and inflammatory bowel disease. Moreover, evidence of response to antipsoriatic treatment was lacking. [38],[39]

Limitations of transgenic model

The main disadvantages of these models are that they are generally produced by manipulation of a single gene, and psoriasis, being a polygenic disease, cannot be accurately reproduced in them. Various features of psoriasis are evident in the above-mentioned transgenic models but none of them demonstrates the true clinical and histological picture of psoriasis.

Immune transfer and xenotransplantation model

The CD45RB Hi CD25 - T cell immune transfer model and the human psoriatic skin xenotransplantation model use SCID mice as the transplant recipients. [40],[41] In the CD45RB Hi T cell immune transfer model, SCID mice are injected with MHC major matched but MHC minor mismatched CD4 + CD45RB Hi CD25 - naive T cells. A chronic persistent cutaneous inflammation mirroring many features of psoriasis were seen when these CD25 - naive T cells were stimulated with lipopolysaccharide (LPS) or IL-12. [40],[42],[43] As in psoriasis, the fundamental pathogenesis of the cutaneous inflammation was Th1-driven, and in contrast to psoriasis, IFNγ did not play a role and no CD8 + lymphocytes were present in the inflammatory infiltrate. Another important finding was the positive response shown by the cutaneous lesions to cyclosporin A, corticosteroids, and anti-IL-12. [40],[42],[43]

The ultimate and possibly the most reliable animal model of psoriasis involved transplantation of human psoriatic skin onto immunodeficient mice. These models permit exploration of disease pathology in a microenvironment simulating its natural background and without graft rejection. However, these models rely on a stable supply of human psoriatic skin and need a well-controlled pathogen-free environment to survive. [41],[44],[45],[46],[47],[48] Among these, nude mice and SCID mice have been used for over two decades. [49],[50],[51] Recently, another model using AGR129 mice has been described.

Epidermal Jun protein deletion model

Deletions of JunB and c-Jun in epidermal cells of mice led to many changes strikingly similar to the histological and molecular features of psoriatic skin as well as arthritis. The disease was noticeable in hairless areas of the skin (ears, paws, and tail), but was also present in hairy back skin, and the symmetrical distribution was suggestive of psoriasis in humans. Arthritic lesions strongly mirrored the inflammatory aspect of psoriatic arthritis along with massive bone destruction. Moreover, the diseased epidermis reflected the changes in the cytokine and chemokine network described for psoriasis. [52]

Nude mice

Initially, athymic nude mice lacking the T cell arm of the immune system were used by investigators. The transplanted psoriatic phenotype persisted for more than 2 months in these mice but in contrast to psoriasis, their histopathology showed absence of parakeratosis and the presence of a granular layer. Moreover, circulating immunoglobulins impaired immunohistochemical assessment. [51]

SCID mice

SCID mice are devoid of humoral and cellular immunity due to a mutation in the DNA dependent protein kinase gene that is required for functional T-cell receptor and immunoglobulin gene rearrangements crucial for T and B cell development. Many investigators have reported that the clinical as well as the histopathological features of psoriasis are maintained on transplanted SCID mice for prolonged periods. [51] The homozygous scid mutation that takes place in the BALB/c mouse affects Variable, Diverse and Joining (V(D)J) gene rearrangement [53] and double-strand break repair. [54],[55] This rearrangement prevents development of mature B and T cells [56] and makes xenogenic transplantation into SCID mice possible without major graft rejection. [57],[58]

 Miscellaneous mouse models of Psoriasis



Imiquimod -induced psoriasis-like mouse model

This model reiterated several signature features of human psoriasis including clinically, hyperkeratosis, erythema, and scaling, and immunologically neutrophil microabscesses and infiltration of γδ T cells and Th17 cells to the skin. [59] This model induced a fast, reproducible, and efficient psoriasis-like pathology, which was based on the IL-23/IL-17 axis. [60] Moreover, Imiquimod (IMQ)-induced skin inflammation was profoundly suppressed in mice with a complete deletion of the IL-17RA receptor as compared with wild type control mice.

 Severe combined immunodeficiency mouse-human skin xenograft model: A valuable tool to explore the immunopathogenesis of psoriasis and a guide for new drug development



0Exploring pathogenesis of psoriasis

The SCID mouse model for psoriasis was first described in 1994. [61] Over the years, it has proved to be a scientific 'gold mine' in the study of pathogenesis of psoriasis.

We have observed that apart from slight morphological variations of the transplanted plaques from mature human plaques, most of the clinical as well as histopathological features of psoriasis are reflected in the grafts. [62] These features persist for 12-16 weeks [Figure 1]. The transplanted plaques are hyperpigmented, rough and dry with few scales and lacking Auspitz's sign. Histological features are similar to psoriasis except that sometimes the granular layer is present. Immunological features reflect chronic plaque psoriasis with presence of CD4 + and CD8 + T cell infiltrates and expression of adhesion molecules like ICAM-1 and vascular cell adhesion molecule (VCAM)-1. [50] Gilhar et al.[63] reported waning of epidermal thickness with loss of HLA-DR expression and decrease in ICAM-1 expression in the transplants after 10 weeks of transplantation. Moreover, after 22 weeks of grafting, apart from persistence of acanthosis and hyperkeratosis there was resolution of Munro's microabscesses, loss of parakeratosis, and decrease in lymphocytic infiltrates in the transplanted grafts. [64] However, in transplanted grafts, all the pathological features of psoriasis could be maintained longer by intradermal or intravenous administration of T cells derived from psoriatic plaques, but not from peripheral blood mononuclear cells (PBMCs). [64] Interestingly, injection of autologous immunocytes activated with Staphylococcus enterotoxins (SEB and SEC2) and IL-2 into non-lesional skin grafts from psoriatic patients induced immunological as well as histopathological features of psoriasis. [47],[48] In another study, administration of PBMC, stimulated by superantigen (staphylococcal superantigen exfoliative toxin) into non-lesional psoriatic skin resulted in histopathological features of psoriasis as well as infiltrates of CD3 positive cells expressing cutaneous lymphocyte associated antigen. [65] According to Nickoloff et al., [46] clinicopathological features of psoriasis can be induced in transplanted normal skin by superantigen activated allogenic immunocytes from psoriatic patients. The role of T cells in the immunopathogenesis of psoriasis was strongly supported by the fact that transplanted non-lesional psoriatic skin on SCID mice could be converted to an active plaque by intradermal injection of antigen activated T cells and the plaques could be cleared after therapy directed against CD4 [66] (monoclonal CD4 antibody) and IL2-R (diphtheria fusion protein). [67] But the factors responsible for T cell activation are still unknown. It was shown that non-lesional skin can be converted to active psoriatic plaque not only by superantigen activated autologous lymphomononuclear cells [66] but also T cells activated with substance P (SP) and nerve growth factor (NGF). [68] Apart from neuropeptide-induced T cell activation, stress-induced onset and exacerbation of psoriasis, [69] upregulation of neuropeptides with proliferation of terminal cutaneous nerves in psoriatic plaques, [70],[71],[72] positive response to capsaicin, somatostatin and peptide T, [73-76] and disappearance of active plaques at sites of local anesthesi a[77] supported the role of neurogenic inflammation in psoriasis. {Figure 1}

Some investigators noted that keratinocytes in lesional and nonlesional psoriatic tissue not only express high levels of NGF [78],[79] but also nerve growth factor receptor (NGF-R) is upregulated in the terminal cutaneous nerves of the lesions. [80] Raychaudhuri et al.[62] further demonstrated that increased levels of NGF in transplanted psoriatic plaques led to marked proliferation of murine cutaneous nerve fibers with upregulation of neuropeptides in transplanted plaques as compared with transplanted normal human skin on SCID mouse. Thus the SCID model has proved to be a very effective model to explore the role of neurogenic inflammation in psoriasis and has opened a door to the development of drugs targeting the NGF/NGF-R system. [73],[74],[81],[82],[83]

In psoriasis there is increased expression of endothelial cell adhesion molecules (E-selectin, ICAM, VCAM), [84],[85],[86],[87] angiogenesis with upregulation of endothelial cell-stimulating angiogenesis factor (ESAF) and VEGF [88],[89] activated T-cells (CD4, CD8, NK cells) infiltrates [90],[91],[92],[93] neutrophils (Munro's and Kogoji microabscess), mast cells, [93],[94] upregulation of chemokines such as IL-8, RANTES, fractalkine, [17],[95],[96],[97] and neuropeptides. [71],[72],[98],[99] Likewise, the transplanted psoriatic plaques in SCID mice, demonstrate upregulation of molecules like p38 MAPK, STAT3, ICAM, CXCR3, fractalkine, IL-8, CD3, CD4, CD8, CD40, CD80, CD86, HLA-DR, OX-40R, K16, Ki67, SP, NGF, and NGF-R. Upregulation of CD80/CD86 supports the role of CD28/B7 co-stimulatory cascades in psoriatic inflammation. [100]

The effector memory T cells play an important role in various autoimmune diseases. The membrane potential of effector memory T cells is maintained by Kv1.3 voltage-gated potassium channels. [101],[102],[103] It has been shown earlier that there was an increased number of Kv1.3 infiltrating T cells in dermis and in the synovial tissue of arthritic joints of psoriatic patients. Gilhar et al.[104] showed that dermal T cell infiltrates of psoriatic plaque of SCID mouse model, expressed Kv1.3 channels, but to a lesser extent than in psoriatic patients. This indicates that stronger and continuous antigenic stimulation may be responsible for the presence of Kv1.3 positive effector memory T cells within psoriatic lesions.

Drug development using the SCID mouse human skin xenograft model

The SCID psoriasis model bridges the gap between late preclinical research and clinical development of novel therapeutic agents. Many investigators regard this model as the perfect model because of the ease of application of drugs directly at the site of lesion, and determination of responsiveness by noting clinical improvement. The drugs with proven efficacy in this model are cyclosporine A, glucocorticosteroids, Vitamin D derivatives (calcipotriol), efalizumab, etanercept, CD80/CD86 antisense oligonucleotide, anti-CTLA4 IgG, a humanized Fc silent anti-CD28 antibody, FR255734, and K252a, a high affinity NGF R blocker. Several of these drugs are already in use for the treatment of psoriasis. Evaluation of efficacy of some novel compounds targeting different pathological aspects of psoriasis are given below.

Drugs targeting proliferation and differentiation

The effectiveness of calcipotriol as an antipsoriatic agent has mainly been attributed to its effects on epidermal proliferation and differentiation [105],[106],[107] although the effects on skin infiltrating T cells are also relevant to its mode of action. [108],[109] There was a reduction of CD3 + CD4 + CD8 + memory T cells in psoriatic skin [110] as well as significant reduction in biomarkers of epidermal proliferation, differentiation, and lymphocyte infiltration. [110],[111],[112] Likewise, in a study with K252a, a high affinity NGF-R blocker, we have shown that within 2 weeks of administration in SCID mouse psoriatic xenograft model, it reduced clinical, immunological as well as pathological characteristics of psoriasis. [113]

Drugs targeting angiogenesis

Both pro-angiogenic factors like VEGF and anti-angiogenic factors like pigment epithelium-derived factor (PEDF) are upregulated in psoriasis. Abe et al.[114] demonstrated high levels of PEDF in psoriatic epidermis as well as dermis but it may not be sufficient to counteract effects of VEGF on angiogenesis. In SCID mice, local application of PEDF resulted in reduction of acanthosis attributed to reduced angiogenesis and basal cell proliferation.

Drugs targeting T cell activation and cytokine upregulation

Using this model we have demonstrated that targeting the CD28/B7 cascade in psoriasis with a humanized anti-CD28 monoclonal antibody for a month led to significant thinning of epidermis, reduced HLA-DR-positive lymphocytic infiltrates and also decreased length of rete pegs. [115] In another study, using CTLA4IgG, we have shown that there was significant improvement of transplanted psoriatic plaques, reduction in length of rete pegs and reduction in number of lympho-mononuclear cells and HLA-DR. [100]

Targeting the voltage sensitive Kv1.3 channels in effector memory T cells in psoriasis will be an effective novel therapeutic option in the near future. It has been shown that ShK, a potent and selective blocker of Kv1.3, is a potential therapeutic option for autoimmune diseases. [101],[102],[115],[116],[117] Gilhar et al. found that there was suppression of development of psoriatic features in the SCID mice model by ShK. It also reduced T cell infiltrates and cytokine (IFN-γ and TNF-α) production. However, there was incomplete recovery of the  psoriasiform grafts with ShK treatment. This may be due to production of TNF-α by keratinocytes, [118] Langerhans cells, [119] and mast cells, [120] which most likely are not affected by ShK. The effects of the clinically efficacious anti-TNF-α biologic, etanercept have also been demonstrated in the psoriasis xenograft SCID mouse model. Etanercept induced significant reduction in epidermal thickness as well as a decrease in the number of proliferative cells. [121] Thus, drugs effective in SCID mice have the potential to be highly effective antipsoriatic agents in humans later on.

 Limitations of this model



SCID mouse psoriasis xenograft model is relatively expensive. Due to immunodeficiency, mice are prone to infections so they require a pathogen-free environment for maintenance. Moreover, a localized cutaneous infection may occur after transplantation of skin. Up to 20% of CB17 SCID mice become 'leaky', that is, the genetic defect is reversed leading to immunocompetence. [57] These mice then fail to accept the human skin graft. Selective inbreeding is recommended as the leakiness among SCID colonies decreases exponentially in the F2 and F3 generation compared with F1. [122] The SCID beige [123] and C3H SCID, [124] two new strains of SCID mice, have a more severe immune defect than CB17 SCID mice and do not show 'leakiness'.

 AGR129 mice



This is the most recent xenotransplantation model used for studying pathogenesis of psoriasis. [45] These AGR 129 mice are triple knockout mice deficient in type I and type II IFN receptors and also lack the recombinase activating gene-2 gene. They do not have T and B cells and have immature NK cells with severely impaired cytotoxic activity both in vitro and in vivo. They develop psoriatic lesions spontaneously when psoriatic skin is grafted onto them. [44]

 Future perspectives



The tremendous advancement of science and technology including genetic engineering and xenotransplantation has given significant insights into the pathology and treatment of several immune-mediated diseases such as psoriasis, rheumatoid arthritis, and atopic dermatitis. The SCID mouse-human skin chimeras are a valuable animal model not only to study the pathogenesis but also to discover new drugs for the treatment of this enigmatic disease. Incorporation of human skin on SCID mice has demonstrated a significant role of the immune system in inflammatory processes of psoriasis. This model also made it possible to investigate the molecular and cellular events associated with key biological processes such as cell proliferation, angiogenesis, homing in of T cells in target tissues, neurogenic inflammation and cytokine/chemokine cascades involved in an inflammatory reaction. Moreover, humanization of SCID mouse has made it possible to develop potential novel therapeutic agents against chronic inflammatory diseases such as psoriasis.

 ACKNOWLEDGMENT



This work was supported by resources from the VA Northern California Health Care System, Sacramento.

References

1Nickoloff BJ, Nestle FO. Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities. J Clin Invest 2004;113:1664-75.
2Raychaudhuri SP, Gross J. A comparative study of pediatric onset psoriasis with adult onset psoriasis. Pediatr Dermatol 2000;17:174-8.
3Gladman DD, Anhorn KA, Schachter RK, Mervart H. HLA antigens in psoriatic arthritis. J Rheumatol 1986;13:586-92.
4Sakkas LI, Loqueman N, Bird H, Vaughan RW, Welsh KI, Panayi GS. HLA class II and T cell receptor gene polymorphisms in psoriatic arthritis and psoriasis. J Rheumatol 1990;17:1487-90.
5Gelfand JM, Stern RS, Nijsten T, Feldman SR, Thomas J, Kist J, et al. The prevalence of psoriasis in African Americans: Results from a population-based study. J Am Acad Dermatol 2005;52:23-6.
6Menter A, Gottlieb A, Feldman SR, Van Voorhees AS, Leonardi CL, Gordon KB, et al. Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol 2008;58:826-50.
7Nograles KE, Brasington RD, Bowcock AM. New insights into the pathogenesis and genetics of psoriatic arthritis. Nat Clin Pract Rheumatol 2009;5:83-91.
8Krueger JG, Bowcock A. Psoriasis pathophysiology: Current concepts of pathogenesis. Ann Rheum Dis 2005;64 Suppl 2:ii30-6.
9Lowes MA, Bowcock AM, Krueger JG. Pathogenesis and therapy of psoriasis. Nature 2007;445:866-73.
10Pauls K, Schon M, Kubitza RC, Homey B, Wiesenborn A, Lehmann P, et al. Role of integrin alphaE (CD103) beta7 for tissue-specific epidermal localization of CD8 + T lymphocytes. J Invest Dermatol 2001;117:569-75.
11Lowe NJ, Breeding J, Kean C, Cohn ML. Psoriasiform dermatosis in a rhesus monkey. J Invest Dermatol 1981;76:141-3.
12Zanolli MD, Jayo MJ, Jayo JM, Blaine D, Hall J, Jorizzo JL. Evaluation of psoriatic plaques that spontaneously developed in a cynomolgus monkey (Macaca fascicularis). Acta Derm Venereol Suppl (Stockh) 1989;146:58.
13Schon MP. Animal models of psoriasis-what can we learn from them? J Invest Dermatol 1999;112:405-10.
14Danilenko DM. Review paper: preclinical models of psoriasis. Vet Pathol 2008;45:563-75.
15Gudjonsson JE, Johnston A, Dyson M, Valdimarsson H, Elder JT. Mouse models of psoriasis. J Invest Dermatol 2007;127:1292-308.
16Sundberg JP, King LE Jr. Mouse mutations as animal models and biomedical tools for dermatological research. J Invest Dermatol 1996;106:368-76.
17Raychaudhuri SP, Jiang WY, Farber EM. Cellular localization of fractalkine at sites of inflammation: Antigen-presenting cells in psoriasis express high levels of fractalkine. Br J Dermatol 2001;144:1105-13.
18Sundberg JP, Beamer WG, Shultz LD, Dunstan RW. Inherited mouse mutations as models of human adnexal, cornification, and papulosquamous dermatoses. J Invest Dermatol 1990;95 Suppl 5:62S-3.
19Wilkinson DI, Karasek MA. Skin lipids of a normal and mutant (asebic) mouse strain. J Invest Dermatol 1966;47:449-55.
20Barlow SC, Collins RG, Ball NJ, Weaver CT, Schoeb TR, Bullard DC. Psoriasiform dermatitis susceptibility in Itgb2(tm1Bay) PL/J mice requires low-level CD18 expression and at least two additional loci for progression to severe disease. Am J Pathol 2003;163:197-202.
21Bullard DC, Scharffetter-Kochanek K, McArthur MJ, Chosay JG, McBride ME, Montgomery CA, et al. A polygenic mouse model of psoriasiform skin disease in CD18-deficient mice. Proc Natl Acad Sci U S A 1996;93:2116-21.
22Kess D, Peters T, Zamek J, Wickenhauser C, Tawadros S, Loser K, et al. CD4 + T cell-associated pathophysiology critically depends on CD18 gene dose effects in a murine model of psoriasis. J Immunol 2003;171:5697-706.
23Kopp T, Kieffer JD, Rot A, Strommer S, Stingl G, Kupper TS. Inflammatory skin disease in K14/p40 transgenic mice: Evidence for interleukin-12-like activities of p40. J Invest Dermatol 2001;117:618-26.
24Kopp T, Lenz P, Bello-Fernandez C, Kastelein RA, Kupper TS, Stingl G. IL-23 production by cosecretion of endogenous p19 and transgenic p40 in keratin 14/p40 transgenic mice: Evidence for enhanced cutaneous immunity. J Immunol 2003;170:5438-44.
25Schon MP, Schon M, Warren HB, Donohue JP, Parker CM. Cutaneous inflammatory disorder in integrin alphaE (CD103)-deficient mice. J Immunol 2000;165:6583-9.
26Detmar M, Brown LF, Schon MP, Elicker BM, Velasco P, Richard L, et al. Increased microvascular density and enhanced leukocyte rolling and adhesion in the skin of VEGF transgenic mice. J Invest Dermatol 1998;111:1-6.
27Xia YP, Li B, Hylton D, Detmar M, Yancopoulos GD, Rudge JS. Transgenic delivery of VEGF to mouse skin leads to an inflammatory condition resembling human psoriasis. Blood 2003;102:161-8.
28Vassar R, Fuchs E. Transgenic mice provide new insights into the role of TGF-alpha during epidermal development and differentiation. Genes Dev 1991;5:714-27.
29Guo L, Yu QC, Fuchs E. Targeting expression of keratinocyte growth factor to keratinocytes elicits striking changes in epithelial differentiation in transgenic mice. EMBO J 1993;12:973-86.
30Li AG, Wang D, Feng XH, Wang XJ. Latent TGFbeta1 overexpression in keratinocytes results in a severe psoriasis-like skin disorder. EMBO J 2004;23:1770-81.
31Groves RW, Mizutani H, Kieffer JD, Kupper TS. Inflammatory skin disease in transgenic mice that express high levels of interleukin 1 alpha in basal epidermis. Proc Natl Acad Sci U S A 1995;92:11874-8.
32Swindell WR, Johnston A, Carbajal S, Han G, Wohn C, Lu J, et al. Genome-wide expression profiling of five mouse models identifies similarities and differences with human psoriasis. PLoS One 2011;6:e18266.
33Carroll JM, Crompton T, Seery JP, Watt FM. Transgenic mice expressing IFN-gamma in the epidermis have eczema, hair hypopigmentation, and hair loss. J Invest Dermatol 1997;108:412-22.
34Blumberg H, Conklin D, Xu WF, Grossmann A, Brender T, Carollo S, et al. Interleukin 20: Discovery, receptor identification, and role in epidermal function. Cell 2001;104:9-19.
35Sano S, Chan KS, Carbajal S, Clifford J, Peavey M, Kiguchi K, et al. Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model. Nat Med 2005;11:43-9.
36Pittelkow MR. Psoriasis: More than skin deep. Nat Med 2005;11:17-8.
37Taurog JD, Maika SD, Simmons WA, Breban M, Hammer RE. Susceptibility to inflammatory disease in HLA-B27 transgenic rat lines correlates with the level of B27 expression. J Immunol 1993;150:4168-78.
38Yanagisawa H, Richardson JA, Taurog JD, Hammer RE. Characterization of psoriasiform and alopecic skin lesions in HLA-B27 transgenic rats. Am J Pathol 1995;147:955-64.
39Schon MP, Detmar M, Parker CM. Murine psoriasis-like disorder induced by naive CD4 + T cells. Nat Med 1997;3:183-8.
40Zeigler M, Chi Y, Tumas DB, Bodary S, Tang H, Varani J. Anti-CD11a ameliorates disease in the human psoriatic skin-SCID mouse transplant model: Comparison of antibody to CD11a with Cyclosporin A and clobetasol propionate. Lab Invest 2001;81:1253-61.
41Hong K, Chu A, Ludviksson BR, Berg EL, Ehrhardt RO. IL-12, independently of IFN-gamma, plays a crucial role in the pathogenesis of a murine psoriasis-like skin disorder. J Immunol 1999;162:7480-91.
42Hong K, Berg EL, Ehrhardt RO. Persistence of pathogenic CD4 + Th1-like cells in vivo in the absence of IL-12 but in the presence of autoantigen. J Immunol 2001;166:4765-72.
43Bhagavathula N, Nerusu KC, Fisher GJ, Liu G, Thakur AB, Gemmell L, et al. Amphiregulin and epidermal hyperplasia: Amphiregulin is required to maintain the psoriatic phenotype of human skin grafts on severe combined immunodeficient mice. Am J Pathol 2005;166:1009-16.
44Boyman O, Hefti HP, Conrad C, Nickoloff BJ, Suter M, Nestle FO. Spontaneous development of psoriasis in a new animal model shows an essential role for resident T cells and tumor necrosis factor-alpha. J Exp Med 2004;199:731-6.
45Nestle FO, Conrad C, Tun-Kyi A, Homey B, Gombert M, Boyman O, et al. Plasmacytoid predendritic cells initiate psoriasis through interferon-alpha production. J Exp Med 2005;202:135-43.
46Nickoloff BJ, Wrone-Smith T. Injection of pre-psoriatic skin with CD4 + T cells induces psoriasis. Am J Pathol 1999;155:145-58.
47Wrone-Smith T, Nickoloff BJ. Dermal injection of immunocytes induces psoriasis. J Clin Invest 1996;98:1878-87.
48Boehncke WH, Schon MP. Animal models of psoriasis. Clin Dermatol 2007;25:596-605.
49Krueger GG, Chambers DA, Shelby J. Involved and uninvolved skin from psoriatic subjects: Are they equally diseased? Assessment by skin transplanted to congenitally athymic (nude) mice. J Clin Invest 1981;68:1548-57.
50Nickoloff BJ, Kunkel SL, Burdick M, Strieter RM. Severe combined immunodeficiency mouse and human psoriatic skin chimeras. Validation of a new animal model. Am J Pathol 1995;146:580-8.
51Haftek M, Ortonne JP, Staquet MJ, Viac J, Thivolet J. Normal and psoriatic human skin grafts on "nude" mice: Morphological and immunochemical studies. J Invest Dermatol 1981;76:48-52.
52Zenz R, Eferl R, Kenner L, Florin L, Hummerich L, Mehic D, et al. Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins. Nature 2005;437:369-75.
53Schuler W, Weiler IJ, Schuler A, Phillips RA, Rosenberg N, Mak TW, et al. Rearrangement of antigen receptor genes is defective in mice with severe combined immune deficiency. Cell 1986;46:963-72.
54Fulop GM, Phillips RA. The scid mutation in mice causes a general defect in DNA repair. Nature 1990;347:479-82.
55Roth DB, Menetski JP, Nakajima PB, Bosma MJ, Gellert M. V(D)J recombination: Broken DNA molecules with covalently sealed (hairpin) coding ends in scid mouse thymocytes. Cell 1992;70:983-91.
56Bosma MJ, Carroll AM. The SCID mouse mutant: Definition, characterization, and potential uses. Annu Rev Immunol 1991;9:323-50.
57Mosier DE, Gulizia RJ, Baird SM, Wilson DB. Transfer of a functional human immune system to mice with severe combined immunodeficiency. Nature 1988;335:256-9.
58McCune JM, Namikawa R, Kaneshima H, Shultz LD, Lieberman M, Weissman IL. The SCID-hu mouse: Murine model for the analysis of human hematolymphoid differentiation and function. Science 1988;241:1632-9.
59van der Fits L, Mourits S, Voerman JS, Kant M, Boon L, Laman JD, et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23/IL-17 axis. J Immunol 2009;182:5836-45.
60Shear NH, Prinz J, Papp K, Langley RG, Gulliver WP. Targeting the interleukin-12/23 cytokine family in the treatment of psoriatic disease. J Cutan Med Surg 2008;12 Suppl 1:S1-10.
61Boehncke WH, Sterry W, Hainzl A, Scheffold W, Kaufmann R. Psoriasiform architecture of murine epidermis overlying human psoriatic dermis transplanted onto SCID mice. Arch Dermatol Res 1994;286:325-30.
62Raychaudhuri SP, Dutt S, Raychaudhuri SK, Sanyal M, Farber EM. Severe combined immunodeficiency mouse-human skin chimeras: A unique animal model for the study of psoriasis and cutaneous inflammation. Br J Dermatol 2001;144:931-9.
63Gilhar A, David M, Ullmann Y, Berkutski T, Kalish RS. T-lymphocyte dependence of psoriatic pathology in human psoriatic skin grafted to SCID mice. J Invest Dermatol 1997;109:283-8.
64Sugai J, Iizuka M, Kawakubo Y, Ozawa A, Ohkido M, Ueyama Y, et al. Histological and immunocytochemical studies of human psoriatic lesions transplanted onto SCID mice. J Dermatol Sci 1998;17:85-92.
65Boehncke WH, Zollner TM, Dressel D, Kaufmann R. Induction of psoriasiform inflammation by a bacterial superantigen in the SCID-hu xenogeneic transplantation model. J Cutan Pathol 1997;24:1-7.
66Morel P, Revillard JP, Nicolas JF, Wijdenes J, Rizova H, Thivolet J. Anti-CD4 monoclonal antibody therapy in severe psoriasis. J Autoimmun 1992;5:465-77.
67Gottlieb SL, Gilleaudeau P, Johnson R, Estes L, Woodworth TG, Gottlieb AB, et al. Response of psoriasis to a lymphocyte-selective toxin (DAB389IL-2) suggests a primary immune, but not keratinocyte, pathogenic basis. Nat Med 1995;1:442-7.
68Farber EM, Raychaudhuri SP. Is psoriasis a neuroimmunologic disease? Int J Dermatol 1999;38:12-5.
69Farber EM, Nickoloff BJ, Recht B, Fraki JE. Stress, symmetry, and psoriasis: Possible role of neuropeptides. J Am Acad Dermatol 1986;14:305-11.
70Naukkarinen A, Nickoloff BJ, Farber EM. Quantification of cutaneous sensory nerves and their substance P content in psoriasis. J Invest Dermatol 1989;92:126-9.
71Wallengren J, Ekman R, Sundler F. Occurrence and distribution of neuropeptides in the human skin. An immunocytochemical and immunochemical study on normal skin and blister fluid from inflamed skin. Acta Derm Venereol 1987;67:185-92.
72Jiang WY, Raychaudhuri SP, Farber EM. Double-labeled immunofluorescence study of cutaneous nerves in psoriasis. Int J Dermatol 1998;37:572-4.
73Bernstein JE, Parish LC, Rapaport M, Rosenbaum MM, Roenigk HH Jr. Effects of topically applied capsaicin on moderate and severe psoriasis vulgaris. J Am Acad Dermatol 1986;15:504-7.
74Camisa C, O'Dorisio TM, Maceyko RF, Schacht GE, Mekhjian HS, Howe BA. Treatment of psoriasis with chronic subcutaneous administration of somatostatin analog 201-995 (sandostatin). I. An open-label pilot study. Cleve Clin J Med 1990;57:71-6.
75Farber EM, Cohen EN, Trozak DJ, Wilkinson DI. Peptide T improves psoriasis when infused into lesions in nanogram amounts. J Am Acad Dermatol 1991;25:658-64.
76Wetterberg L, Alexius B, Saaf J, Sonnerborg A, Britton S, Pert C. Peptide T in treatment of AIDS. Lancet 1987;1:159.
77Raychaudhuri SP, Farber EM. Are sensory nerves essential for the development of psoriatic lesions? J Am Acad Dermatol 1993;28:488-9.
78Raychaudhuri SP, Jiang WY, Farber EM. Psoriatic keratinocytes express high levels of nerve growth factor. Acta Derm Venereol 1998;78:84-6.
79Fantini F, Magnoni C, Bracci-Laudiero L, Pincelli CT. Nerve growth factor is increased in psoriatic skin. J Invest Dermatol 1995;105:854-5.
80Raychaudhuri SP, Jiang WY, Smoller BR, Farber EM. Nerve growth factor and its receptor system in psoriasis. Br J Dermatol 2000;143:198-200.
81Fitzgerald M. Capsaicin and sensory neurones--A review. Pain 1983;15:109-30.
82Snider RM, Constantine JW, Lowe JA 3 rd , Longo KP, Lebel WS, Woody HA, et al. A potent nonpeptide antagonist of the substance P (NK1) receptor. Science 1991;251:435-7.
83Petzelbauer P, Pober JS, Keh A, Braverman IM. Inducibility and expression of microvascular endothelial adhesion molecules in lesional, perilesional, and uninvolved skin of psoriatic patients. J Invest Dermatol 1994;103:300-5.
84Lee ML, To T, Nicholson E, Schrieber L. Endothelial cell adhesion molecules in psoriasis. Australas J Dermatol 1994;35:65-70.
85Paukkonen K, Naukkarinen A, Horsmanheimo M. The development of manifest psoriatic lesions is linked with the appearance of ICAM-1 positivity on keratinocytes. Arch Dermatol Res 1995;287:165-70.
86Cooper KD. Skin-infiltrating lymphocytes in normal and disordered skin: Activation signals and functional roles in psoriasis and mycosis fungoides-type cutaneous T cell lymphoma. J Dermatol 1992;19:731-7.
87Das PK, de Boer OJ, Visser A, Verhagen CE, Bos JD, Pals ST. Differential expression of ICAM-1, E-selectin and VCAM-1 by endothelial cells in psoriasis and contact dermatitis. Acta Derm Venereol Suppl (Stockh) 1994;186:21-2.
88Barton SP, Abdullah MS, Marks R. Quantification of microvascular changes in the skin in patients with psoriasis. Br J Dermatol 1992;126:569-74.
89Bhushan M, McLaughlin B, Weiss JB, Griffiths CE. Levels of endothelial cell stimulating angiogenesis factor and vascular endothelial growth factor are elevated in psoriasis. Br J Dermatol 1999;141:1054-60.
90Bos JD, Hulsebosch HJ, Krieg SR, Bakker PM, Cormane RH. Immunocompetent cells in psoriasis. In situ immunophenotyping by monoclonal antibodies. Arch Dermatol Res 1983;275:181-9.
91Paukkonen K, Naukkarinen A, Horsmanheimo M. The development of manifest psoriatic lesions is linked with the invasion of CD8 + T cells and CD11c + macrophages into the epidermis. Arch Dermatol Res 1992;284:375-9.
92Raychaudhuri SP, Jiang WY, Raychaudhuri SK, Krensky AM. Lesional T cells and dermal dendrocytes in psoriasis plaque express increased levels of granulysin. J Am Acad Dermatol 2004;51:1006-8.
93Ackermann L, Harvima IT. Mast cells of psoriatic and atopic dermatitis skin are positive for TNF-alpha and their degranulation is associated with expression of ICAM-1 in the epidermis. Arch Dermatol Res 1998;290:353-9.
94Jiang WY, Chattedee AD, Raychaudhuri SP, Raychaudhuri SK, Farber EM. Mast cell density and IL-8 expression in nonlesional and lesional psoriatic skin. Int J Dermatol 2001;40:699-703.
95Schroder JM, Gregory H, Young J, Christophers E. Neutrophil-activating proteins in psoriasis. J Invest Dermatol 1992;98:241-7.
96Kulke R, Todt-Pingel I, Rademacher D, Rowert J, Schroder JM, Christophers E. Co-localized overexpression of GRO-alpha and IL-8 mRNA is restricted to the suprapapillary layers of psoriatic lesions. J Invest Dermatol 1996;106:526-30.
97Raychaudhuri SP, Jiang WY, Farber EM, Schall TJ, Ruff MR, Pert CB. Upregulation of RANTES in psoriatic keratinocytes: A possible pathogenic mechanism for psoriasis. Acta Derm Venereol 1999;79:9-11.
98Raychaudhuri SP, Raychaudhuri SK. Role of NGF and neurogenic inflammation in the pathogenesis of psoriasis. Prog Brain Res 2004;146:433-7.
99Chan J, Smoller BR, Raychauduri SP, Jiang WY, Farber EM. Intraepidermal nerve fiber expression of calcitonin gene-related peptide, vasoactive intestinal peptide and substance P in psoriasis. Arch Dermatol Res 1997;289:611-6.
100Raychaudhuri SK, Raychaudhuri SP. Scid mouse model of psoriasis: A unique tool for drug development of autoreactive T-cell and th-17 cell-mediated autoimmune diseases. Indian J Dermatol 2010;55:157-60.
101Wulff H, Beeton C, Chandy KG. Potassium channels as therapeutic targets for autoimmune disorders. Curr Opin Drug Discov Dev 2003;6:640-7.
102Wulff H, Calabresi PA, Allie R, Yun S, Pennington M, Beeton C, et al. The voltage-gated Kv1.3 K(+) channel in effector memory T cells as new target for MS. J Clin Invest 2003;111:1703-13.
103Beeton C, Wulff H, Standifer NE, Azam P, Mullen KM, Pennington MW, et al. Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases. Proc Natl Acad Sci U S A 2006;103:17414-9.
104Gilhar A, Bergman R, Assay B, Ullmann Y, Etzioni A. The beneficial effect of blocking Kv1.3 in the psoriasiform SCID mouse model. J Invest Dermatol 2011;131:118-24.
105Jensen AM, Llado MB, Skov L, Hansen ER, Larsen JK, Baadsgaard O. Calcipotriol inhibits the proliferation of hyperproliferative CD29 positive keratinocytes in psoriatic epidermis in the absence of an effect on the function and number of antigen-presenting cells. Br J Dermatol 1998;139:984-91.
106de Jong EM, van de Kerkhof PC. Simultaneous assessment of inflammation and epidermal proliferation in psoriatic plaques during long-term treatment with the vitamin D3 analogue MC903: Modulations and interrelations. Br J Dermatol 1991;124:221-9.
107Glade CP, Van Erp PE, Van De Kerkhof PC. Epidermal cell DNA content and intermediate filaments keratin 10 and vimentin after treatment of psoriasis with calcipotriol cream once daily, twice daily and in combination with clobetasone 17-butyrate cream or betamethasone 17-valerate cream: A comparative flow cytometric study. Br J Dermatol 1996;135:379-84.
108Lamba S, Lebwohl M. Combination therapy with vitamin D analogues. Br J Dermatol 2001;144 Suppl 58:S27-32.
109Berth-Jones J, Fletcher A, Hutchinson PE. Epidermal cytokeratin and immunocyte responses during treatment of psoriasis with calcipotriol and betamethasone valerate. Br J Dermatol 1992;126:356-61.
110Vissers WH, Berends M, Muys L, van Erp PE, de Jong EM, van de Kerkhof PC. The effect of the combination of calcipotriol and betamethasone dipropionate versus both monotherapies on epidermal proliferation, keratinization and T-cell subsets in chronic plaque psoriasis. Exp Dermatol 2004;13:106-12.
111Vissers WH, van Vlijmen I, van Erp PE, de Jong EM, van de Kerkhof PC. Topical treatment of mild to moderate plaque psoriasis with 0.3% tacrolimus gel and 0.5% tacrolimus cream: The effect on SUM score, epidermal proliferation, keratinization, T-cell subsets and HLA-DR expression. Br J Dermatol 2008;158:705-12.
112Korver JE, Vissers WH, van Rens DW, Pasch MC, van Erp PE, Boezeman JB, et al. A double-blind, randomized quantitative comparison of calcitriol ointment and calcipotriol ointment on epidermal cell populations, proliferation and differentiation. Br J Dermatol 2007;156:130-7.
113Raychaudhuri SP, Sanyal M, Weltman H, Kundu-Raychaudhuri S. K252a, a high-affinity nerve growth factor receptor blocker, improves psoriasis: An in vivo study using the severe combined immunodeficient mouse-human skin model. J Invest Dermatol 2004;122:812-9.
114Abe R, Yamagishi S, Fujita Y, Hoshina D, Sasaki M, Nakamura K, et al. Topical application of anti-angiogenic peptides based on pigment epithelium-derived factor can improve psoriasis. J Dermatol Sci 2010;57:183-91.
115Pennington MW, Mahnir VM, Krafte DS, Zaydenberg I, Byrnes ME, Khaytin I, et al. Identification of three separate binding sites on SHK toxin, a potent inhibitor of voltage-dependent potassium channels in human T-lymphocytes and rat brain. Biochem Biophys Res Commun 1996;219:696-701.
116Norton RS, Pennington MW, Wulff H. Potassium channel blockade by the sea anemone toxin ShK for the treatment of multiple sclerosis and other autoimmune diseases. Curr Med Chem 2004;11:3041-52.
117Matheu MP, Beeton C, Garcia A, Chi V, Rangaraju S, Safrina O, et al. Imaging of effector memory T cells during a delayed-type hypersensitivity reaction and suppression by Kv1.3 channel block. Immunity 2008;29:602-14.
118Gilhar A, Yaniv R, Assy B, Serafimovich S, Ullmann Y, Kalish RS. Fas pulls the trigger on psoriasis. Am J Pathol 2006;168:170-5.
119Wang B, Zhuang L, Fujisawa H, Shinder GA, Feliciani C, Shivji GM, et al. Enhanced epidermal Langerhans cell migration in IL-10 knockout mice. J Immunol 1999;162:277-83.
120Biedermann T, Kneilling M, Mailhammer R, Maier K, Sander CA, Kollias G, et al. Mast cells control neutrophil recruitment during T cell-mediated delayed-type hypersensitivity reactions through tumor necrosis factor and macrophage inflammatory protein 2. J Exp Med 2000;192:1441-52.
121Norsgaard H, Svensson L, Hagedorn PH, Moller K, Olsen GM, Labuda T. Translating clinical activity and gene expression signatures of etanercept and ciclosporin to the psoriasis xenograft SCID mouse model. Br J Dermatol 2012;166:649-52.
122Inohara H, Nomura T, Hongyo T, Nakajima H, Kawaguchi T, Fukuda K, et al. Reduction of leaky lymphocyte clones producing immunoglobulins and thymic lymphocytic leukemia by selective inbreeding of SCID (severe combined immunodeficiency) mice. Acta Otolaryngol Suppl 1993;501:107-10.
123Mosier DE, Stell KL, Gulizia RJ, Torbett BE, Gilmore GL. Homozygous scid/scid; beige/beige mice have low levels of spontaneous or neonatal T cell-induced B cell generation. J Exp Med 1993;177:191-4.
124Nonoyama S, Smith FO, Bernstein ID, Ochs HD. Strain-dependent leakiness of mice with severe combined immune deficiency. J Immunol 1993;150:3817-24.

 

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