Prevention of type 1 diabetes in the rat with an allele-specific anti-T-cell receptor antibody: Vß13 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) ß-chain, Tcrb-V13S1A1, as a candidate gene. To establish its importance, we treated susceptible rats with a depleting anti-rat Vß13 monoclonal antibody and then exposed them to either polyinosinicpolycytidylic 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-Vß13-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 Vß13(+) T cells than did peripheral lymph node T cells. Vß13 transcripts recovered from day 5 islets revealed focused Jß usage and less CDR3 diversity than did transcripts from peripheral Vß13(+) T cells. CDR3 usage was not skewed in control Vß16 CDR3 transcripts. Anti-rat Vß13 antibody also prevented spontaneous diabetes in BBDP rats. The Iddm14 gene is likely to be Tcrb-V13, indicating that TCR ß-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.