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)