Peptide-MHC class II dimers as therapeutics to modulate antigen-specific T cell responses in autoimmune diabetes.
Type 1 diabetes is an autoimmune disorder caused by autoreactive T cells that mediate destruction of insulin-producing beta 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-gamma 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.
Masteller
Emma L
EL
Diabetes Center, University of California, San Francisco, CA 94143, USA.
Warner
Matthew R
MR
Ferlin
Walter
W
Judkowski
Valeria
V
Wilson
Darcy
D
Glaichenhaus
Nicolas
N
Bluestone
Jeffrey A
JA
D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D019264:Adoptive Transfer; D000595:Amino Acid Sequence; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000637:transplantation; D002460:Cell Line; D002478:Cells, Cultured; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control*; D019281:Dimerization; D015536:Down-Regulation / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000008:administration & dosage / Q000235:genetics / Q000627:therapeutic use*; D007108:Immune Tolerance; D016753:Interleukin-10 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D018716:Molecular Mimicry / Q000235:genetics / Q000276:immunology; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000096:biosynthesis / Q000737:chemistry; D014162:Transfection
D000276:Adjuvants, Immunologic; D018984:Epitopes, T-Lymphocyte; D000949:Histocompatibility Antigens Class II; C407099:I-A g7 antigen; D010446:Peptide Fragments; D011993:Recombinant Fusion Proteins; D016753:Interleukin-10