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)
Jaworski
M A
MA
Department of Pediatrics, University of Alberta, Edmonton.
Jewell
L D
LD
Honore
L
L
Mehta
J G
JG
Bayens-Simmonds
J
J
McGuire-Clark
P
P
Schouls
J J
JJ
Yap
W Y
WY
D000818:Animals; D003524:Cyclosporins / Q000627:therapeutic use*; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007124:Immunoenzyme Techniques; D007515:Islets of Langerhans / Q000473:pathology; D051381:Rats; D011913:Rats, Inbred BB
D003524:Cyclosporins