| Abstract: | BACKGROUND: Mutating the insulin B:9-23 peptide prevents diabetes in NOD mice. Thus, the trimolecular complex of I-A$^{\rm{g7}}$-insulin B:9-23 peptide-TCR may be essential for the development of spontaneous diabetes. Pathogenic T cells recognize the B:9-23 peptide presented by I-A$^{\rm{g7}}$ in what is termed register 3, with the B22 basic amino acid (arginine) of the peptide bound in pocket 9 of I-A$^{\rm{g7}}$. Our hypothesis is that immunization with an insulin B:12-22 peptide linked to I-A$^{\rm{g7}}$ in register 3 (I-A$^{\rm{g7}}$-B:RE#3 complex) can induce specific antibodies to the complex, block pathogenic TCRs, and thus prevent diabetes. METHODS: We immunized young NOD mice with recombinant I-A$^{\rm{g7}}$-B:RE#3 protein, in which two amino acids of the peptide were mutated to fix the peptide in register 3, and investigated the induced antibodies targeted to the peptide in register 3. RESULTS: Specific antibodies targeting I-A$^{\rm{g7}}$-B:RE#3 but not I-A$^{\rm{g7}}$-HEL were identified in the sera of I-A$^{\rm{g7}}$-B:RE#3 immunized mice. The sera inhibited B:9-23-induced T-cell responses in vitro. I-A$^{\rm{g7}}$-B:RE#3 immunization delayed progression to diabetes (versus PBS, p = 0.0005), while immunization with I-A$^{\rm{g7}}$-HEL control complex did not. CONCLUSIONS: Immunization with I-A$^{\rm{g7}}$-B:RE#3 complex significantly delays the development of insulin autoantibodies and the onset of diabetes in NOD mice, which is associated with the induction of I-A$^{\rm{g7}}$-B:RE#3 antibodies. Copyright © 2011 John Wiley & Sons, Ltd. |
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