title: Prevention of diabetes by manipulation of anti-IGRP autoimmunity: high efficiency of a low-affinity peptide.
abstract: Antigen therapy may hold great promise for the prevention of autoimmunity; however, most clinical trials have failed, suggesting that the principles guiding the choice of treatment remain ill defined. Here, we examine the antidiabetogenic properties of altered peptide ligands of CD8+ T cells recognizing an epitope of islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP206-214), a prevalent population of autoreactive T cells in autoimmune diabetes. We show that islet-associated CD8+ T cells in nonobese diabetic mice recognize numerous IGRP epitopes, and that these cells have a role in the outcome of protocols designed to induce IGRP206-214-specific tolerance. Ligands targeting IGRP206-214-reactive T cells prevented disease, but only at doses that spared low-avidity clonotypes. Notably, near complete depletion of the IGRP206-214-reactive T-cell pool enhanced the recruitment of subdominant specificities and did not blunt diabetogenesis. Thus, peptide therapy in autoimmunity is most effective under conditions that foster occupation of the target organ lymphocyte niche by nonpathogenic, low-avidity clonotypes.
authors.affiliation: Julia McFarlane Diabetes Research Centre, University of Calgary, Faculty of Medicine, 3330 Hospital Drive NW, Calgary, Alberta, Canada T2N 4N1.
authors.forename: Bingye
authors.initials: B
authors.lastname: Han
authors.forename: Pau
authors.initials: P
authors.lastname: Serra
authors.forename: Abdelaziz
authors.initials: A
authors.lastname: Amrani
authors.forename: Jun
authors.initials: J
authors.lastname: Yamanouchi
authors.forename: Athanasius F M
authors.initials: AF
authors.lastname: Marée
authors.forename: Leah
authors.initials: L
authors.lastname: Edelstein-Keshet
authors.forename: Pere
authors.initials: P
authors.lastname: Santamaria
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D002460:Cell Line; D003922:Diabetes Mellitus, Type 1 / Q000517:prevention & control*; D018984:Epitopes, T-Lymphocyte / Q000502:physiology; D005260:Female; D005952:Glucose-6-Phosphatase / Q000276:immunology*; D007515:Islets of Langerhans / Q000276:immunology; D008024:Ligands; D051379:Mice; D016688:Mice, Inbred NOD; D010455:Peptides / Q000494:pharmacology*; D021122:Protein Subunits; D011506:Proteins / Q000276:immunology*
chemical_list: D018984:Epitopes, T-Lymphocyte; D008024:Ligands; D010455:Peptides; D021122:Protein Subunits; D011506:Proteins; D005952:Glucose-6-Phosphatase; C117983:G6pc2 protein, mouse