| First Author | Schroder PM | Year | 2015 |
| Journal | Diabetologia | Volume | 58 |
| Issue | 6 | Pages | 1309-18 |
| PubMed ID | 25794782 | Mgi Jnum | J:220839 |
| Mgi Id | MGI:5636547 | Doi | 10.1007/s00125-015-3564-1 |
| Citation | Schroder PM, et al. (2015) PD-1-dependent restoration of self-tolerance in the NOD mouse model of diabetes after transient anti-TCRbeta mAb therapy. Diabetologia 58(6):1309-18 |
| abstractText | AIMS/HYPOTHESIS: 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 beta-chain (TCRbeta) was investigated for its ability to prevent and reverse disease in mouse models of diabetes. METHODS: 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-TCRbeta mAb therapy as a means of preventing and reversing type 1 diabetes. RESULTS: A single dose of anti-TCRbeta completely prevented disease in RIP-OVA(hi) mice without inducing the release of inflammatory cytokines. Transient anti-TCRbeta 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-TCRbeta 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-TCRbeta 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-TCRbeta-induced self-tolerance, as type 1 diabetes recurs in mice following a blockade of PD-1 signalling. CONCLUSIONS/INTERPRETATION: Anti-TCRbeta 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. |
