Two rodent models of autoimmune type 1 diabetes have been used to investigate the role of insulin as an autoantigen in this disease. In lymphopoenia-induced diabetes in the PVG.RT1u rat, neonatal tolerization with insulin B-chain peptides, but not A-chain peptides, conferred significant protection from disease. After rechallenge of adult rats, neonatally B-chain-tolerized animals showed diminished B-chain-specific T-cell proliferation, interleukin (IL)-2 production, and interferon-gamma (IFN-gamma) production, as compared with control animals. The epitope recognized by the PVG.RT1u rat was mapped to residues 1-18 of the B-chain; T-cell lines specific for this epitope were generated, and these conferred diabetes upon adoptive transfer to irradiated syngeneic recipients. In adult nonobese diabetic (NOD) mice, subcutaneous immunization with B-chain peptide 9-23 emulsified in incomplete Freund's adjuvant (IFA) was also potent at preventing onset of diabetes. In contrast to PVG.RT1u rats, NOD mice recognized an epitope within residues 10-29 of the insulin B-chain. The data implicate insulin as a target autoantigen in type 1 diabetes but do not support a role for molecular mimicry to insulin in the pathogenesis of this disease.

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