Insulin dependent diabetes mellitus (IDDM) is likely to be due to the immunologic destruction of the islets of Langerhans. However, the relative importance of expression of a unique set of islet antigens or of differences in immune responses to those antigens in determining susceptibility to autoimmune diabetes is unknown. To a large extent, the reason for this uncertainty is the difficulty in directly identifying islet antigens expressed in vivo. We have studied the relationship between islet antigen expression, immune responsiveness to islet antigens, and the development of diabetes in diabetes induced by multiple low-doses of streptozotocin (STZ) in mice of the H-2(d) haplotype. We identified the expression of relevant islet antigens by testing the ability of STZ treated islets to induce tolerance to diabetes in C57BL/KsJ mice after intrathymic transplantation. C57BL/KsJ but not BALB/cByJ mice developed hyperglycaemia and insulitis following STZ treatment. Interferon-γ transcription was detected in intrapancreatic lymphocytes from C57BL/KsJ mice but at lower levels in cells from BALB/cByJ. IL-4 levels 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 islets from resistant BALB/cByJ mice did not induce tolerance to disease in C57BL/KsJ mice even though they did cause tolerance to the alloantigens. (C57BL/KsJ x BALB/cByJ)F1 mice developed hyperglycaemia like the susceptible parent following STZ treatment, and islets from these mice induced tolerance to MDSDM when treated with STZ and transplanted intrathymically into C57BL/KsJ. We conclude the expression of islet antigens and the intrapancreatic responses to STZ treated islets differs between mice that are susceptible and resistant to multi-dose streptozotocin induced diabetes mellitus.
Bibliographical noteFunding Information:
Supported by grant DK44905 from the National Institutes of Health and a grant from the Juvenile Diabetes Foundation International to K.H. E.B. was a recipient of a fellowship award from the Juvenile Diabetes Foundation International. The authors wish to thank Dr Anthony Montag for his evaluation of the histologic section. We would also like to thank Dr Jeffrey Bluestone for his suggestions and helpful comments.
- intrathymic transplantation
- islet antigens