title: Prevention of type 1 diabetes in the rat with an allele-specific anti-T-cell receptor antibody: Vβ13 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) 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.
authors.affiliation: Department of Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, USA.
authors.forename: Zhijun
authors.initials: Z
authors.lastname: Liu
authors.forename: Laura
authors.initials: L
authors.lastname: Cort
authors.forename: Ryan
authors.initials: R
authors.lastname: Eberwine
authors.forename: Thomas
authors.initials: T
authors.lastname: Herrmann
authors.forename: Jean H
authors.initials: JH
authors.lastname: Leif
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
authors.forename: Barak
authors.initials: B
authors.lastname: Yahalom
authors.forename: Elizabeth P
authors.initials: EP
authors.lastname: Blankenhorn
authors.forename: John P
authors.initials: JP
authors.lastname: Mordes
mesh_terms: D000483:Alleles; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000276:immunology / Q000517:prevention & control*; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D007515:Islets of Langerhans / Q000166:cytology / Q000378:metabolism; D008297:Male; D011070:Poly I-C / Q000633:toxicity; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics / Q000276:immunology*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D012333:RNA, Messenger; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011070:Poly I-C