Prevention of Type 1 Diabetes in the Rat With an Allele-Specific Anti–T-Cell Receptor Antibody
Vβ13 as a Therapeutic Target and Biomarker
- Zhijun Liu1,
- Laura Cort2,
- Ryan Eberwine2,
- Thomas Herrmann3,
- Jean H. Leif4,
- Dale L. Greiner4,
- Barak Yahalom5,
- Elizabeth P. Blankenhorn2 and
- John P. Mordes1⇓
- 1Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
- 2Department of Microbiology and Immunology, Center for Immunogenetics and Inflammatory Diseases, Drexel University College of Medicine, Philadelphia, Pennsylvania
- 3Institute for Virology and Immunobiology, University of Würzburg, Würzburg, Germany
- 4Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts
- 5Division of Research Development, Biomedical Research Models, Worcester, Massachusetts
- Corresponding author: John P. Mordes, .
In earlier studies of the Iddm14 diabetes susceptibility locus in the rat, we identified an allele of the T-cell receptor (TCR) β-chain, Tcrb-V13S1A1, as a candidate gene. To establish its importance, we treated susceptible rats with a depleting anti-rat Vβ13 monoclonal antibody and then exposed them to either polyinosinic:polycytidylic acid or a diabetogenic virus to induce diabetes. The overall frequency of diabetes in the controls was 74% (n = 50), compared with 17% (n = 30) in the anti-Vβ13–treated animals, with minimal islet pathology in nondiabetic treated animals. T cells isolated from islets on day 5 after starting induction showed a greater proportion of Vβ13+ T cells than did peripheral lymph node T cells. Vβ13 transcripts recovered from day 5 islets revealed focused Jβ usage and less CDR3 diversity than did transcripts from peripheral Vβ13+ T cells. CDR3 usage was not skewed in control Vβ16 CDR3 transcripts. Anti-rat Vβ13 antibody also prevented spontaneous diabetes in BBDP rats. The Iddm14 gene is likely to be Tcrb-V13, indicating that TCR β-chain usage is a determinant of susceptibility to autoimmune diabetes in rats. It may be possible to prevent autoimmune diabetes by targeting a limited element of the T-cell repertoire.
This article contains Supplementary Data online at http://diabetes.diabetesjournals.org/lookup/suppl/doi:10.2337/db11-0867/-/DC1.
Z.L. is currently affiliated with the Department of Medical Microbiology, Weifang Medical University, Shandong, China.
The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
See accompanying commentary, p. 976.
- Received August 25, 2011.
- Accepted December 14, 2011.
- © 2012 by the American Diabetes Association.
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