There is a need for safe and effective therapies for inflammatory skin diseases. Current topical and systemic treatment of psoriasis is effective but suffers from side-effects or is inconvenient. The therapeutic armamentarium for atopic dermatitis is very limited and far from satisfactory. In vivo preclinical data are presented for SDZ ASM 981, a novel ascomycin macrolactam derivative with high anti-inflammatory activity. Anti-inflammatory activity was observed in mouse, rat and pig models of allergic contact dermatitis. In the pig model, topical SDZ ASM 981 was as effective as the ultrapotent corticosteroid clobetasol-17-propionate, and when compared with a series of commercial topical corticosteroid preparations, 0.1% SDZ ASM 981 had equivalent efficacy to clobetasol-17-propionate (0.05%), the most potent product on the market. Unlike the corticosteroid, however, SDZ ASM 981 did not cause skin atrophy in pigs. SDZ ASM 981 potently inhibited allergic contact dermatitis in mice and rats when given systemically, and oral treatment was more effective than cyclosporin A in rats. Furthermore, SDZ ASM 981 has a low potential for affecting systemic immune responses, as demonstrated in rat models of localized graft vs. host reaction and allogeneic kidney transplantation. Preclinical results suggest that SDZ ASM 981 has the potential to be a well-tolerated and effective drug for topical as well as oral treatment of inflammatory skin diseases.
Background. The aims of this study were to evaluate the efficacy of US Food and Drug Administration-approved drugs in genetically engineered pig-to-baboon kidney xenotransplantation and compare the results with those using an anti-CD40 monoclonal antibody (mAb)-based regimen. Methods. Ten life-supporting kidney transplants were carried out in baboons using α1,3-galactosyltransferase gene-knockout/CD46 pigs with various other genetic manipulations aimed at controlling coagulation dysregulation. Eight transplants resulted in informative data. Immunosuppressive therapy consisted of induction with antithymocyte globulin and anti-CD20mAb, and maintenance based on either (1) CTLA4-Ig and/or tacrolimus (+rapamycin or mycophenolate mofetil) (GroupA [US Food and Drug Administration-approved regimens], n = 4) or (2) anti-CD40mAb + rapamycin (GroupB, n = 4). All baboons received corticosteroids, interleukin-6R blockade, and tumor necrosis factor-α blockade. Baboons were followed by clinical and laboratory monitoring of kidney function, coagulation, and immune parameters. At euthanasia, morphological and immunohistochemical studies were performed on the kidney grafts. Results. The median survival in GroupB was 186 days (range 90–260), which was significantly longer than in GroupA; median 14 days (range 12–32) (P < 0.01). Only GroupA baboons developed consumptive coagulopathy and the histopathological features of thrombotic microangiopathic glomerulopathy and interstitial arterial vasculitis. Conclusions. Recognizing that the pig donors in each group differed in some genetic modifications, these data indicate that maintenance immunosuppression including anti-CD40mAb may be important to prevent pig kidney graft failure.
Pigs deficient in three glycosyltransferase enzymes (triple‐knockout [TKO] pigs) and expressing “protective” human transgenes are likely sources of organs for transplantation into human recipients. Testing of human sera against red blood cells (RBCs) and peripheral blood mononuclear cells (PBMCs) from TKO pigs has revealed minimal evidence of natural antibody binding. However, unlike humans, baboons exhibit natural antibody binding to TKO pig cells. The xenoantigen specificities of these natural antibodies are postulated to be one or more carbohydrate moieties exposed when N‐glycolylneuraminic acid (Neu5Gc) is deleted. The aim of this study was to compare the survival of renal grafts in baboons from pigs that either expressed Neu5Gc (GTKO pigs; Group1, n = 5) or did not express Neu5Gc (GTKO/CMAHKO [DKO] or TKO pigs; Group2, n = 5). An anti‐CD40mAb‐based immunosuppressive regimen was administered in both groups. Group1 kidneys functioned for 90‐260 days (median 237, mean 196 days), with histopathological features of antibody‐mediated rejection in two kidneys. Group2 kidneys functioned for 0‐183 days (median 35, mean 57), with all of the grafts exhibiting histologic features of antibody‐mediated rejection. These findings suggest that the absence of expression of Neu5Gc on pig kidneys impacts graft survival in baboon recipients.
Recent advances in the histophysiology of the normal thymus have revealed its complex architecture, showing distinct microenvironments at the light and electron microscopic level. The epithelium comprising the major component of the thymic stroma is not only involved in the positive selection of thymocytes, but also in their negative selection. Dendritic cells, however, are more efficient than epithelial cells in mediating negative selection. Thymocytes are dependent on the epithelium for normal development. Conversely, epithelial cells need the presence of thymocytes to maintain their integrity. The thymus rapidly responds to immunotoxic injury. Both the thymocytes and the nonlymphoid compartment of the organ can be targets of exposure. Disturbance of positive and negative thymocyte selection may have a major impact on the immunological function of the thymus. Suppression of peripheral T-cell-dependent immunity as a consequence of thymus toxicity is primarily seen after perinatal exposure when the thymus is most active. Autoimmunity may be another manifestation of chemically mediated thymus toxicity. Although the regenerative capacity of thymus structure is remarkable, it remains to be clarified whether this also applies to thymus function. In-depth mechanistic studies on chemical-induced dysfunction of the thymus have been conducted with the environmental contaminants 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and bis(tri-n-butyltin)oxide (TBTO) as well as the pharmaceutical immunosuppressant cyclosporine (CsA). Each of these compounds exerts a differential effect on the morphology of the thymus, depending on the cellular targets for toxicity. TCDD and TBTO exposure results in cortical lymphodepletion, albeit by different mechanisms. An important feature of TCDD-mediated thymus toxicity is the disruption of epithelial cells in the cortex. TBTO primarily induces cortical thymocyte cell death. In contrast CsA administration results in major alterations in the medulla, the cortex remaining largely intact. Medullary epithelial cells and dendritic cells are particularly sensitive to CsA. The differential effects of these three immunotoxicants suggest unique susceptibilities of the various cell types and regions that make up the thymus.
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