Peptide and major histocompatibility complex-specific breaking of humoral tolerance to native insulin with the B9-23 peptide in diabetes-prone and normal mice

NOD mice spontaneously develop anti-insulin autoantibodies and diabetes. A dominant peptide recognized by T-cell clones from NOD mice is insulin B- ch ain peptide B9-23. When administered subcutaneously to NOD mice, this pepti de decreases the development of diabetes, In this study, we evaluated the a utoantibody response to native insulin after administration of the B9-23 pe ptide. In NOD mice, administration of the B9-23 peptide in incomplete Freun d's adjuvant enhanced their insulin autoantibody response with a higher lev el and longer persistence. Induction of insulin autoantibodies with the B9- 23 peptide was observed in non-diabetes-prone BALB/c mice and NOR mice with in 2 weeks of administration, but this was not observed in C57BL/6 mice, A series of A-chain, other B-chain, and proinsulin peptides did not induce in sulin autoantibodies, Induced anti-insulin autoantibodies could not be abso rbed with the peptide alone but could be absorbed with native insulin. The B13-23 peptide Cone of two identified epitopes within B9-23) when administe red to BALB/c mice, induced autoantibodies, whereas peptide B9-16 did not. Induction of autoantibodies mapped to the major histocompatibility complex (MHC) rather than to the background genes, Both splenocytes with I-A(d)/I-E -d or I-Ag-7/I-E-null presented the B9-23 peptide to NOD islet-derived T-ce ll clones. Finally, administration of the B9-23 peptide to BALB/c mice, eve n without adjuvant, could induce insulin autoantibodies, Our results indica te that B-cell tolerance to intact insulin is readily broken with the prese ntation of the B9-23 insulin peptide, depending on the host's specific MHC.