Cyclosporin depresses pancreatic islet expression of antigens for islet cell autoantibodies in non obese 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 40 mg/kg/day) in nonobese diabetic (NOD) mice could modify the expression of islet antigens related to the autoimmune process. Analysis was performed on the last day of CsA administration, and then up to 60 days after CsA withdrawal. Antigen modulation was analysed by indirect immunofluorescence using islet-cell antibody (ICA)-positive human sera for ICA antigens, and by immunoperoxidase for glutamic acid decarboxylase 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 quantified. We measured splenocyte and thymocyte subsets by cytofluorometry (CD4+ CD8-, CD4- CD8+, and double-positive thymocytes; Thy1-2+, CD3+, CD4+, and CD8+ spleen cells) and determined splenocyte mitogenesis 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 significant dose-dependent reduction (P < 0.01) with 10, 20 and 40 mg/kg/day. 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 (40 mg/kg/day) induced glucose intolerance in vivo (P < 0.02), decreased insulin sensitivity to glucose from isolated islets (P < 0.03), reduced insulitis (P < 0.03), and altered thymocyte and splenocyte phenotypes and mitogenesis (P < 0.02). Moreover, the reversibility of the different effects was different: islet antigens were not completely recovered 2 months after CsA withdrawal, whereas other immunologic and metabolic effects obtained with the highest CsA dose were reversed within 15 days. Thus, a short course of low CsA doses in NOD mice produced a pancreatic concentration of the drug which reduced the expression of certain islet antigens for several weeks, whereas major effects on immunological parameters and islet insulin release occurred only with higher CsA doses and improved more rapidly.
el Mansour
A
A
Laboratory of cellular and molecular Immuno-Endocrinology associated to IRNA/ENVN, University School of Medicine, Nantes, France.
Martignat
L
L
Maugendre
S
S
Senecat
O
O
Gouin
E
E
Saï
P
P
D000818:Animals; D015703:Antigens, CD / Q000096:biosynthesis; D001323:Autoantibodies / Q000276:immunology; D001324:Autoantigens / Q000096:biosynthesis*; D048429:Cell Size; D016572:Cyclosporine / Q000494:pharmacology*; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D019084:Fluorescent Antibody Technique, Indirect; D007150:Immunohistochemistry; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects* / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016176:T-Lymphocyte Subsets / Q000276:immunology
D015703:Antigens, CD; D001323:Autoantibodies; D001324:Autoantigens; D007328:Insulin; D016572:Cyclosporine