title: PD-1-dependent restoration of self-tolerance in the NOD mouse model of diabetes after transient anti-TCRβ mAb therapy.
abstract: OBJECTIVE
  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
  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.
authors: Department of Medical Microbiology and Immunology, University of Toledo College of Medicine, 3000 Arlington Avenue, HEB 263A, Toledo, OH, 43614, USA.
authors: Paul M
authors: PM
authors: Schroder
authors: Mithun
authors: M
authors: Khattar
authors: Caitlin E
authors: CE
authors: Baum
authors: Yoshihiro
authors: Y
authors: Miyahara
authors: Wenhao
authors: W
authors: Chen
authors: Rohit
authors: R
authors: Vyas
authors: Shravan
authors: S
authors: Muralidharan
authors: Beata
authors: B
authors: Mierzejewska
authors: Stanislaw M
authors: SM
authors: Stepkowski
mesh_terms: D064591:Allografts; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001786:Blood Glucose / Q000032:analysis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000097:blood; D003921:Diabetes Mellitus, Experimental / Q000188:drug therapy* / Q000378:metabolism*; D003922:Diabetes Mellitus, Type 1 / Q000378:metabolism / Q000628:therapy; D005260:Female; D005951:Glucose Tolerance Test; D007249:Inflammation; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000276:immunology; D054388:Receptors, CCR / Q000378:metabolism
chemical_list: D000911:Antibodies, Monoclonal; D001786:Blood Glucose; C119309:CC chemokine receptor 9; D016207:Cytokines; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D016693:Receptors, Antigen, T-Cell, alpha-beta; D054388:Receptors, CCR