Anti-CD11a Ameliorates Disease in the Human Psoriatic Skin–SCID Mouse Transplant Model: Comparison of Antibody to CD11a with Cyclosporin A and Clobetasol Propionate

Abstract

SUMMARY:The present study assesses the applicability of human skin-SCID (severe combined immunodeficiency) mouse chimeras in testing antipsoriatic therapeutics. Three agents were examined: (1) a monoclonal antibody to the alpha subunit of leukocyte function associated antigen-1 integrin (CD11a); (2) Cyclosporin A; and (3) clobetasol propionate (Temovate), a potent topical corticosteroid used clinically in the treatment of psoriasis. Skin transplanted to SCID mice from normal human volunteers or from psoriatic lesional skin was allowed to heal for 3 to 5 weeks before application of test reagents. During this period, psoriatic skin, which was 3.8-fold thicker than the corresponding normal skin before transplantation, maintained its phenotype (ie, increased epidermal thickness, rete ridges with blunted ends, and intralesional presence of T lymphocytes). Transplanted normal human skin, however, underwent a hyperplastic response during this period, resulting in a 2.4-fold increase in epidermal thickness. After the healing period, animals transplanted with normal or psoriatic skin were treated for 14 days by daily intraperitoneal injection of either Cyclosporin A or a monoclonal antibody to human CD11a, or by topical application of clobetasol propionate. At the end of the treatment period, the mice were killed and the tissue evaluated morphometrically for changes in epidermal thickness and immunohistologically for the presence of T lymphocytes. Both Cyclosporin A and anti-CD11a reduced the epidermal thickness of transplanted psoriatic skin, whereas neither reagent significantly reduced the thickness of transplanted normal skin. T lymphocytes were detected in the skin from treated animals; there did not seem to be any reduction in the number of T lymphocytes. Clobetasol propionate reduced the epidermal thickness of both normal and psoriatic skin. These data indicate that, in this model, therapies directed against pathophysiologic mechanisms that contribute to psoriasis can be distinguished from treatments that block epidermal hyperplasia occurring as a consequence of xenografting. Our observations provide evidence for the activity of anti-CD11a in an animal model of human psoriasis. (Lab Invest 2001, 81:1253-1261.

BP-1107 [{2-[4-(2,4-Dioxo-thiazolidin-5-ylmethyl)-phenoxy]-ethyl}-methyl-amide]: A Novel Synthetic Thiazolidinedione That Inhibits Epidermal Hyperplasia in Psoriatic Skin-Severe-Combined Immunodeficient Mouse Transplants after Topical Application

“…Treatment was initiated 1 to 2 weeks post-transplantation, depending on how rapidly the tissue healed. The human skin-SCID mouse transplant model has been used previously to study the pathophysiology of psoriasis (Nickoloff et al, 1995;Wrone-Smith and Nickoloff, 1996;Gilhar et al, 1997) and to assess potential antipsoriatic therapies (Ellis et al, 2000;Zeigler et al, 2001;Bhagavathula et al, 2005).…”

“…SCID mice (CB-17 strain; Taconic Farms, Germantown, NY) were used as tissue recipients. One 6-mm punch biopsy was transplanted onto the dorsal surface of a recipient mouse as described previously (Zeigler et al, 2001). In brief, mice were anesthetized, and skin from the dorsal region was shaved.…”

7-Chloro-5-(4-hydroxyphenyl)-1-methyl-3-(naphthalen-2-ylmethyl)-4,5-dihydro-1H-benzo[b][1,4]diazepin-2(3H)-one (Bz-423), a Benzodiazepine, Suppresses Keratinocyte Proliferation and Has Antipsoriatic Activity in the Human Skin-Severe, Combined Immunodeficient Mouse Transplant Model

“…Scid mice (CB-17 strain; Taconic Farms, Germantown, NY) were used as tissue recipients in a human skin-scid mouse transplant model previously used to evaluate potential antipsoriatic agents (Dam et al, 1999;Ellis et al, 2000;Zeigler et al, 2001;Zollner et al, 2002;Villadsen et al, 2003;Bhagavathula et al, 2005a,b). One biopsy from each normal or psoriatic volunteer was transplanted onto the dorsal surface of a recipient mouse as follows.…”

Recent insights into the immunopathogenesis of psoriasis provide new therapeutic opportunities

“…Numerous reports have now described the favorable responses of engrafted psoriatic plaques to a wide range of agents targeting a variety of putative molecular mediators (72,(84)(85)(86). Not only can the SCID-Hu model assist the pharmaceutical and biotechnology industries, but response of grafted human skin to the targeted pathways will also provide valuable new insights into the relevance of specific molecules in maintaining the psoriatic phenotype.…”