Cyclosporin prophylaxis induces long-term prevention of diabetes, and inhibits lymphocytic infiltration in multiple target tissues in the high-risk BB rat.

Spontaneous insulin-dependent diabetes mellitus (IDDM) and other autoimmune manifestations, such as lymphocytic thyroiditis and atrophic gastritis, develop in diabetes-prone (high-risk) lines of Wistar-derived BioBreeding (BB) rats. To examine whether Cyclosporin A (CsA) would abrogate multiple autoimmune manifestations in BB rats, we treated them prophylactically with CsA from 5-6 weeks to 23-25 weeks of age. IDDM developed in 0/58 CsA-treated rats; 47% (29 out of 62) of sex- and age-matched controls treated with vehicle developed IDDM (p less than 0.001). CsA-treated rats had no or minimal lymphocytic infiltration and parenchymal changes in the pancreas, stomach and thyroid at the time of cessation of treatment. IDDM, glycosuria and hyperglycemia developed in 0/22 rats followed up to 370 days of age (up to 210 days following the cessation of CsA therapy); histologic examination of their islets was normal. We conclude that CsA completely abrogates the development of clinical IDDM in the BB rat, and that it inhibits or abolishes lymphocyte infiltration in several organs against which there is autoimmunity. The data also suggest that the protective effect of CsA persists well past the duration of therapy, and that cell-mediated autoimmunity (with or without humoral immunity) may be an important pathogenetic mechanism in the destruction of beta cells in the BB rat.

Immunosuppression in autoimmune disease: the double-edged sword.

We have developed a protocol of prophylactic cyclosporin A administration which confers complete and permanent protection against insulin-dependent diabetes mellitus in diabetes-prone BioBreeding rats. Spontaneous insulin-dependent diabetes mellitus developed in about 50% of BioBreeding rats, between 10 and 18 weeks of age. Prophylactic cyclosporin A (10 mg/kg/day p.o.), started at 6 weeks of age and terminated at 21 weeks of age, completely prevented insulin-dependent diabetes mellitus: 0% (0/25) cyclosporin A-treated compared to 46% (11/24) control rats developed insulin-dependent diabetes mellitus (p less than 0.001). Protection against insulin-dependent diabetes mellitus was lifelong, provided cyclosporin A prophylaxis was initiated when insulitis was minimal or absent, and pancreatic insulin content was normal. Cyclosporin A prophylaxis initiated later, but still before the onset of clinical symptoms (8-9 weeks), and terminated at 22-23 weeks, was only partially effective; 5/20 (25%) of cyclosporin A-treated rats developed insulin-dependent diabetes mellitus, compared to 60% (12/20) of controls (p less than 0.05). Cyclosporin A prophylaxis started at the appropriate time (6 weeks) but terminated prematurely (17-19 weeks of age) was not effective; insulin-dependent diabetes mellitus developed in 20% (3/15), compared to 50% (7/14) controls (p greater than 0.05); insulin-dependent diabetes mellitus developed after cessation of therapy. We conclude that effective and permanent moderate-dose cyclosporin A prophylaxis of insulin-dependent diabetes mellitus in BioBreeding rats requires (1) early initiation of treatment, when islet morphology and hormone content are still normal; and (2) prolonged treatment, with continuation of prophylaxis past the end of the at-risk period.(ABSTRACT TRUNCATED AT 250 WORDS)