title: Vaccination with single chain antigen receptors for islet-derived peptides presented on I-A(g7) delays diabetes in NOD mice by inducing anergy in self-reactiveT-cells.
abstract: To develop a vaccination approach for prevention of type 1 diabetes (T1D) that selectively attenuates self-reactive T-cells targeting specific autoantigens, we selected phage-displayed single chain antigen receptor libraries for clones binding to a complex of the NOD classII MHC I-A(g7) and epitopes derived from the islet autoantigen RegII. Libraries were generated from B-cell receptor repertoires of classII-mismatched mice immunized with RegII-pulsed NOD antigen presenting cells or from T-cell receptor repertoires in pancreatic lymph nodes of NOD mice. Both approaches yielded clones recognizing a RegII-derived epitope in the context of I-A(g7), which activated autoreactive CD4(+) T-cells. A receptor with different specificity was obtained by converting the BDC2.5 TCR into single chain form. B- but not T-cells from donors vaccinated with the clones transferred protection from diabetes to NOD-SCID recipients if the specificity of the diabetes inducer cell and the single chain receptor were matched. B-cells and antibodies from donors vaccinated with the BDC2.5 single chain receptor induced a state of profound anergy in T-cells of BDC2.5 TCR transgenic NOD recipients while B-cells from donors vaccinated with a single chain receptor specific for I-A(g7) RegII peptide complexes induced only partial non-responsiveness. Vaccination of normal NOD mice with receptors recognizing I-A(g7) RegII peptide complexes or with the BDC2.5 single chain receptor delayed onset of T1D. Thus anti-idiotypic vaccination can be successfully applied to T1D with vaccines either generated from self-reactive T-cell clones or derived from antigen receptor libraries.
authors.affiliation: Department of Internal Medicine, Yale University, School of Medicine, New Haven, Connecticut, United States of America. werner.gurr@yale.edu
authors.forename: Werner
authors.initials: W
authors.lastname: Gurr
authors.forename: Margaret
authors.initials: M
authors.lastname: Shaw
authors.forename: Raimund I
authors.initials: RI
authors.lastname: Herzog
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Li
authors.forename: Robert
authors.initials: R
authors.lastname: Sherwin
mesh_terms: D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000276:immunology; D017635:Clonal Anergy / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology / Q000517:prevention & control; D005260:Female; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D014611:Vaccination / Q000379:methods*
chemical_list: D000888:Antibodies, Anti-Idiotypic; D011948:Receptors, Antigen, T-Cell
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