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This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: jimmunol.0901616v1 183/7/4809    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Related articles in The JI Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Google Scholar Articles by Li, L. Articles by Tisch, R. PubMed PubMed Citation Articles by Li, L. Articles by Tisch, R. Pubmed/NCBI databases Substance via MeSH Medline Plus Health Information Diabetes Type 1

Suppression of Ongoing T Cell-Mediated Autoimmunity by Peptide-MHC Class II Dimer Vaccination¹

Department of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599

Tissue-specific autoimmune diseases such as type 1 diabetes (T1D) are characterized by T cell-driven pathology. Administration of autoantigenic peptides provides a strategy to selectively target the pathogenic T cell response. Indeed, treatment with β cell peptides effectively prevents T1D in NOD mice. However, the efficacy of peptide immunotherapy generally wanes as β cell autoimmunity progresses and islet inflammation increases. With the goal of enhancing the efficacy of peptide immunotherapy, soluble (s)IA^g7-Ig dimers covalently linked to β cell autoantigen-derived peptides were tested for the capacity to suppress late preclinical T1D. NOD female mice with established β cell autoimmunity were vaccinated i.v. with a short course of sIA^g7-Ig dimers tethered to peptides derived from glutamic acid decarboxylase (GAD)65 (sIA^g7-pGAD65). Treatment with sIA^g7-pGAD65 dimers and the equivalent of only 7 µg of native peptide effectively blocked the progression of insulitis and the development of diabetes. Furthermore, suppression of T1D was dependent on β cell-specific IL-10-secreting CD4⁺ T cells, although the frequency of GAD65-specific FoxP3-expressing CD4⁺ T cells was also increased in sIA^g7-pGAD65 dimer vaccinated NOD mice. These results demonstrate that MHC class II-Ig dimer vaccination is a robust approach to suppress ongoing T cell-mediated autoimmunity, and may provide a superior strategy of adjuvant-free peptide-based immunotherapy to induce immunoregulatory T cells.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Grant R01AI058014 from the National Institutes of Health, Grant 1-2008-452 from the Juvenile Diabetes Research Foundation, and Grant 7-04-RA-121 from the American Diabetes Association. B.W. was supported by the 1-04-CD-09 American Diabetes Association Career Development Award.

² Address correspondence and reprint requests to Dr. Roland Tisch, Department of Microbiology and Immunology, Mary Ellen Jones Building, Room 635, Campus Box 7290, University of North Carolina, Chapel Hill, NC 27599-7290. E-mail address: rmtisch{at}med.unc.edu

³ Abbreviations used in this paper: T1D, type 1 diabetes; HEL, hen egg lysozyme; MHCII, MHC class II; HA, hemagglutinin; GAD, glutamic acid decarboxylase; Treg, immunoregulatory T; aTreg; adaptive Treg; PLN, pancreatic lymph node; MLN, mesenteric lymph node.

⁴ The online version of this article contains supplemental material.

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The JI 2009 183: 4143-4144. [Full Text]