PD-1-dependent restoration of self-tolerance in the NOD mouse model of diabetes after transient anti-TCRβ mAb therapy.

Published

Journal Article

T cells play a major role in the pathogenesis of type 1 diabetes, and there is great interest in developing curative immunotherapies targeting these cells. In this study, a monoclonal antibody (mAb) targeting the T cell receptor β-chain (TCRβ) was investigated for its ability to prevent and reverse disease in mouse models of diabetes.RIP-OVA(hi) (C57BL/6-Tg(Ins2-OVA)59Wehi/WehiJ) mice adoptively transferred with ovalbumin-specific T cells (an induced model of diabetes) and NOD mice (a spontaneous model of diabetes) were used to test anti-TCRβ mAb therapy as a means of preventing and reversing type 1 diabetes.A single dose of anti-TCRβ completely prevented disease in RIP-OVA(hi) mice without inducing the release of inflammatory cytokines. Transient anti-TCRβ therapy prevented diabetes in 90% of NOD mice and reversed the disease after its onset in 73% of NOD mice. Long after the remission of type 1 diabetes, the anti-TCRβ treated mice were able to reject BALB/c skin allografts with normal kinetics while maintaining normoglycaemia. Treatment did not cause significant reductions in lymphocyte numbers in the spleen or pancreatic lymph nodes, but did result in a decreased percentage of chemokine receptor 9 (CCR9) positive, CD8(+) T cells. Notably, anti-TCRβ therapy increased the expression of programmed death 1 (PD-1) on the surface of the T cells; PD-1 expression is important for maintaining anti-TCRβ-induced self-tolerance, as type 1 diabetes recurs in mice following a blockade of PD-1 signalling.Anti-TCRβ mAb is a safe and effective immunotherapy that results in reduced numbers of CCR9(+) T cells, an increased expression of PD-1 on T cells and the restoration of self-tolerance in NOD mice.

Full Text

Duke Authors

Cited Authors

  • Schroder, PM; Khattar, M; Baum, CE; Miyahara, Y; Chen, W; Vyas, R; Muralidharan, S; Mierzejewska, B; Stepkowski, SM

Published Date

  • June 2015

Published In

Volume / Issue

  • 58 / 6

Start / End Page

  • 1309 - 1318

PubMed ID

  • 25794782

Pubmed Central ID

  • 25794782

Electronic International Standard Serial Number (EISSN)

  • 1432-0428

International Standard Serial Number (ISSN)

  • 0012-186X

Digital Object Identifier (DOI)

  • 10.1007/s00125-015-3564-1

Language

  • eng