EXPRESSION AND IMMUNE-RESPONSE TO ISLET ANTIGENS FOLLOWING TREATMENT WITH LOW-DOSES OF STREPTOZOTOCIN IN H-2(D) MICE

Insulin dependent diabetes mellitus (IDDM) is likely to be due to the immunologic destruction of the islets of Langerhans. However, the rela tive importance of expression of a unique set of islet antigens or of differences in immune responses to those antigens in determining susce ptibility to autoimmune diabetes is unknown. To a large extent the rea son for this uncertainty is the difficulty in directly identifying isl et antigens expressed in vivo. We have studied the relationship betwee n islet antigen expression, immune responsiveness to islet antigens, a nd the development of diabetes in diabetes induced by multiple low-dos es of streptozotocin (STZ) in mice of the H-2(d) haplotype. We identif ied the expression of relevant islet antigens by testing the ability o f STZ treated islets to induce tolerance to diabetes in C57BL/KsJ mice after intrathymic transplantation. C57BL/KsJ but not BALB/cByJ mice d eveloped hyperglycaemia and insulitis following STZ treatment. Interfe ron-gamma transcription was detected in intrapancreatic lymphocytes fr om C57BL/KsJ mice but at lower levels in cells from BALB/cByJ. IL-4 le vels were higher in BALB/cByJ than C57BL/KsJ. Intrathymic STZ-treated islets from syngeneic mice induced tolerance to diabetes in C57BL/KsJ mice following transient depletion of mature peripheral T cells, but i slets from resistant BALB/cByJ mice did not induce tolerance to diseas e in C57BL/KsJ mice even though they did cause tolerance to the alloan tigens. (C57BL/KsJ x BALB/cByJ)F1 mice developed hyperglycaemia like t he susceptible parent following STZ treatment, and islets from these m ice induced tolerance to MDSDM when treated with STZ and transplanted intrathymically into C57BL/KsJ. We conclude the expression of islet an tigens and the intrapancreatic responses to STZ treated islets differs between mice that are susceptible and resistant to multi-dose strepto zotocin induced diabetes mellitus. (C) 1997 Academic Press Limited.