PD-1-dependent restoration of self-tolerance in the NOD mouse model of diabetes after transient anti-TCR[beta] mAb therapy

• Published in: Diabetologia 2015-06, Vol.58 (6), p.1309
• Main Authors: Schroder, Paul M, Khattar, Mithun, Baum, Caitlin E, Miyahara, Yoshihiro, Chen, Wenhao, Vyas, Rohit, Muralidharan, Shravan, Mierzejewska, Beata, Stepkowski, Stanislaw M
• Format: Article
• Language: English
• Subjects: Chemokines; Clinical trials; Diabetes; Immunology; Immunotherapy; Laboratory animals; Ligands; Lymphocytes; Monoclonal antibodies; Pathogenesis; Peptides; T cell receptors
• ISSN: 0012-186X; 1432-0428
• DOI: 10.1007/s00125-015-3564-1

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 (TCR[beta]) was investigated for its ability to prevent and reverse disease in mouse models of diabetes. RIP-OVA^sup 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-TCR[beta] mAb therapy as a means of preventing and reversing type 1 diabetes. A single dose of anti-TCR[beta] completely prevented disease in RIP-OVA^sup hi^ mice without inducing the release of inflammatory cytokines. Transient anti-TCR[beta] 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-TCR[beta] 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^sup +^ T cells. Notably, anti-TCR[beta] 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-TCR[beta]-induced self-tolerance, as type 1 diabetes recurs in mice following a blockade of PD-1 signalling. Anti-TCR[beta] mAb is a safe and effective immunotherapy that results in reduced numbers of CCR9^sup +^ T cells, an increased expression of PD-1 on T cells and the restoration of self-tolerance in NOD mice.