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01.06.2015 | Article

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

verfasst von: Paul M. Schroder, Mithun Khattar, Caitlin E. Baum, Yoshihiro Miyahara, Wenhao Chen, Rohit Vyas, Shravan Muralidharan, Beata Mierzejewska, Stanislaw M. Stepkowski

Erschienen in: Diabetologia | Ausgabe 6/2015

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Abstract

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 β-chain (TCRβ) 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-TCRβ mAb therapy as a means of preventing and reversing type 1 diabetes.

Results

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.

Conclusions/interpretation

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.

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Titel: PD-1-dependent restoration of self-tolerance in the NOD mouse model of diabetes after transient anti-TCRβ mAb therapy
verfasst von: Paul M. Schroder
Mithun Khattar
Caitlin E. Baum
Yoshihiro Miyahara
Wenhao Chen
Rohit Vyas
Shravan Muralidharan
Beata Mierzejewska
Stanislaw M. Stepkowski
Publikationsdatum: 01.06.2015
Verlag: Springer Berlin Heidelberg
Erschienen in: Diabetologia / Ausgabe 6/2015
Print ISSN: 0012-186X
Elektronische ISSN: 1432-0428
DOI: https://doi.org/10.1007/s00125-015-3564-1

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