ISLET T-CELLS SECRETING IFN-GAMMA IN NOD MOUSE DIABETES - ARREST BY P277 PEPTIDE TREATMENT

Non-obese diabetic (NOD) mice spontaneously develop insulin-dependent (type 1) diabetes mellitus (IDDM) caused by T cells which destroy the insulin-producing islet beta-cells. Since cytokines are involved in th is autoimmune beta-cell damage, we used an ELISPOT assay to enumerate the islet-associated T cells that secreted interferon-gamma (IFN-gamma ), tumor necrosis factor-alpha (TNF-alpha) or interleukin-4 (IL-4). We used mitogenic anti-CD3 antibody to activate all the T cells capable of responding, irrespective of their antigen specificity. We found tha t NOD females, more susceptible than males to IDDM, accumulated islet IFN-gamma producers more rapidly with age than did the males. Accelera tion of male IDDM by cyclophosphamide led to a marked increase in IFN- gamma secreting islet T cells. In contrast, a decrease in IFN-gamma-pr oducing islet T cells was associated with arrest of IDDM by administra tion of peptide p277 of the 60 kDa heat-shock protein (hsp60) to 12-we ek-old female NOD mice. The p277-treated mice later manifested a great er number of islets and fewer leukocytes per islet than did the mice t reated with a bacterial hsp60 peptide. Thus, the development of diabet es could be correlated with the accumulation in the islets of T cells producing IFN-gamma, and destructive insulitis could be downregulated by the administration of a single peptide. (C) 1998 Academic Press Lim ited.