CYCLOSPORINE DEPRESSES PANCREATIC-ISLET EXPRESSION OF ANTIGENS FOR ISLET-CELL AUTOANTIBODIES IN NONOBESE DIABETIC MICE

An unexpected observation led us to investigate whether a short course (7 days) of oral cyclosporin (CsA) at different doses (5, 10, 20 or 4 0 mg/kg/day) in nonobese diabetic (NOD) mice could modify the expressi on of islet antigens related to the autoimmune process. Analysis was p erformed on the last day of CsA administration, and then up to 60 days after CsA withdrawal. Antigen modulation was analysed by indirect imm unofluorescence using islet-cell antibody (ICA)-positive human sera fo r ICA antigens, and by immunoperoxidase for glutamic acid decarboxylas e 67 Kd (GAD67). Concomitantly, beta-cell function was evaluated by in vivo glucose tolerance and insulin response from isolated islets. The severity of insulitis and histological damage to islets was quantifie d. We measured splenocyte and thymocyte subsets by cytofluorometry (CD 4(+) CD8(-), CD4(-) CD8(+), and double-positive thymocytes; Thy1-2(+), CD3(+), CD4(+), and CD8(+) spleen cells) and determined splenocyte mi togenesis in response to concanavalin A. Even when the lowest dose (5 mg/kg) was used, CsA concentrated in the islets. A graded reduction of ICA antigens was detected, showing no effect for 5 mg/kg/day but a si gnificant dose-dependent reduction (P<0.01) with 10, 20 and 40 mg/kg/d ay. GAD67 expression was also reduced P<0.03) in a CsA dose-dependent manner. On the other hand, only treatment with the highest CsA dose (4 0 mg/kg/day) induced glucose intolerance in vivo (P<0.02), decreased i nsulin sensitivity to glucose from isolated islets (P<0.03), reduced i nsulitis (P<0.03), and altered thymocyte and splenocyte phenotypes and mitogenesis (P<0.02). Moreover, the reversibility of the different ef fects was different: islet antigens were not completely recovered 2 mo nths after CsA withdrawal, whereas other immunologic and metabolic eff ects obtained with the highest CsA dose were reversed within 15 days. Thus, a short course of low CsA doses in NOD mice produced a pancreati c concentration of the drug which reduced the expression of certain is let antigens for several weeks, whereas major effects on immunological parameters and islet insulin release occurred only with higher CsA do ses and improved more rapidly. (C) 1996 Academic Press Limited