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

ABSTRACT

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.