Prevention of diabetes by manipulation of anti-IGRP autoimmunity: High efficiency of a low-affinity peptide

Han, B., Serra, P., Amrani, A., Yamanouchi, J., Maree, A.F.M. ORCID: https://orcid.org/0000-0003-2689-2484, Edelstein-Keshet, L. and Santamaria, P. 2005. Prevention of diabetes by manipulation of anti-IGRP autoimmunity: High efficiency of a low-affinity peptide. Nature Medicine 11 (6) , pp. 645-652. 10.1038/nm1250

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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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Biosciences
Publisher:	Nature Publishing Group
ISSN:	1078-8956
Date of Acceptance:	21 April 2005
Last Modified:	25 Oct 2022 13:19
URI:	https://orca.cardiff.ac.uk/id/eprint/119495

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