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Prevention of type 1 diabetes in the rat with an allele-specific anti-T-cell receptor antibody: V?13 as a therapeutic target and biomarker.

ABSTRACT: In earlier studies of the Iddm14 diabetes susceptibility locus in the rat, we identified an allele of the T-cell receptor (TCR) ?-chain, Tcrb-V13S1A1, as a candidate gene. To establish its importance, we treated susceptible rats with a depleting anti-rat V?13 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-V?13-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 V?13(+) T cells than did peripheral lymph node T cells. V?13 transcripts recovered from day 5 islets revealed focused J? usage and less CDR3 diversity than did transcripts from peripheral V?13(+) T cells. CDR3 usage was not skewed in control V?16 CDR3 transcripts. Anti-rat V?13 antibody also prevented spontaneous diabetes in BBDP rats. The Iddm14 gene is likely to be Tcrb-V13, indicating that TCR ?-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.


PROVIDER: S-EPMC3331757 | BioStudies | 2012-01-01T00:00:00Z

REPOSITORIES: biostudies

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