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

Nature Medicine volume 11, pages 645–652 (2005)Cite this article

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.

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Figure 1: Agonistic activity of APLs on 8.3-CD8+ T cells.
Figure 2: Differences in the functional avidity of APLs correlate with differences in peptide-MHC–binding avidity and tolerogenic activity.
Figure 3: Antidiabetogenic activity of APLs in wild-type NOD mice.
Figure 4: NRP-V7 and IGRP206-214 cannot blunt progression of diabetes, despite depleting the IGRP206–214-reactive CD8+ T-cell pool.
Figure 5: NOD mice spontaneously mount intraislet CD8+ T-cell responses against multiple IGRP epitopes.
Figure 6: Unlike NRP-I4-treatment, treatment with IGRP206–214 induces increased responses against other IGRP epitopes.

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Acknowledgements

We thank T. Utsugi for Takeda recombinant IL-2, L. Allen, S. Bou, M. Deuma, C. Fehr and T. Trinh for animal care and technical assistance, and T. DiLorenzo, U. Walter and Y. Yang for feedback on the manuscript. This work was supported by the Canadian Institutes of Health Research, the Juvenile Diabetes Research Foundation (JDRF), and the Natural Sciences and Engineering Research Council of Canada. A.A. was supported by the JDRF and the Alberta Heritage Foundation for Medical Research (AHFMR), J.Y. by the JDRF, and P. Serra and B. Han by the AHFMR. A.F.M.M. and L.E.-K. were supported by the Mathematics of Information Technology and Complex Systems (MITACS) Network of Centers of Excellence. P. Santamaria is a Scientist of the AHFMR and a member of MITACS. The JMDRC is supported by the Diabetes Association (Foothills).

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Author notes

  1. Abdelaziz Amrani

    Present address: Service of Immunology, Centre de Recherche Clinique, Université de Sherbrooke, 3001, 12 Avenue N., Sherbrooke, Quebec, J1H 5N4, Canada

  2. Bingye Han and Pau Serra: These authors contributed equally to this work.

Authors and Affiliations

  1. Julia McFarlane Diabetes Research Centre, University of Calgary, Faculty of Medicine, 3330 Hospital Dr. N.W., Calgary, T2N 4N1, Alberta, Canada

    Bingye Han, Pau Serra, Abdelaziz Amrani, Jun Yamanouchi & Pere Santamaria

  2. Department of Theoretical Biology, Utrecht University, Padualaan 8, Utrecht, 3584, CH, The Netherlands

    Athanasius F M Marée

  3. Department of Mathematics, 1984 Mathematics Road, University of British Columbia, Vancouver, V6T 1Z2, British Columbia, Canada

    Leah Edelstein-Keshet

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Correspondence to Pere Santamaria.

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Supplementary information

Supplementary Table 1

IGRP-specific peptide library (PDF 13 kb)

Supplementary Table 2

Amounts of IFN-γ (pg/ml) secreted by islet-derived CD8+ T cells (PDF 33 kb)

Supplementary Table 3

Amounts of IFN-γ (pg/ml) secreted by islet-derived CD8+ T cells (PDF 36 kb)

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Han, B., Serra, P., Amrani, A. et al. Prevention of diabetes by manipulation of anti-IGRP autoimmunity: high efficiency of a low-affinity peptide. Nat Med 11, 645–652 (2005). https://doi.org/10.1038/nm1250

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