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Peptide-MHC Class II Dimers as Therapeutics to Modulate Antigen-Specific T Cell Responses in Autoimmune Diabetes¹

Emma L. Masteller^*, Matthew R. Warner^*, Walter Ferlin, Valeria Judkowski, Darcy Wilson, Nicolas Glaichenhaus and Jeffrey A. Bluestone^2,*

^* Diabetes Center, University of California, San Francisco, CA 94143; Centre National de la Recherche Scientifque, University of Nice-Sophia Antipolis, Valbonne, France; and Torrey Pines Institute for Molecular Studies, San Diego, CA 92121

Type 1 diabetes is an autoimmune disorder caused by autoreactive T cells that mediate destruction of insulin-producing cells of the pancreas. Studies have shown that T cell tolerance can be restored by inducing a partial or altered signal through the TCR. To investigate the potential of bivalent peptide-MHC class II/Ig fusion proteins as therapeutics to restore Ag-specific tolerance, we have developed soluble peptide I-A^g7 dimers for use in the nonobese diabetic mouse model of diabetes. I-A^g7 dimers with a linked peptide specific for islet-reactive BDC2.5 TCR transgenic CD4⁺ T cells were shown to specifically bind BDC2.5 T cells as well as a small population of Ag-specific T cells in nonobese diabetic mice. In vivo treatment with BDC2.5 peptide I-A^g7 dimers protected mice from diabetes mediated by the adoptive transfer of diabetogenic BDC2.5 CD4⁺ T cells. The dimer therapy resulted in the activation and increased cell death of transferred BDC2.5 CD4⁺ T cells. Surviving cells were hypoproliferative to challenge by Ag and produced increased levels of IL-10 and decreased levels of IFN- compared with cells from control I-A^g7 dimer-treated mice. Anti-IL-10R therapy reversed the tolerogenic effects of the dimer. Thus, peptide I-A^g7 dimers induce tolerance of BDC2.5 TCR T cells through a combination of the induction of clonal anergy and anti-inflammatory cytokines.

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The JI 2003 171: 4957-4958. [Full Text]  

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