Anti-TCR mAb induces peripheral tolerance to alloantigens and delays islet allograft rejection in autoimmune diabetic NOD mice

Ronghai Deng, Mithun Khattar, Aini Xie, Paul M. Schroder, Xiaoshun He, Wenhao Chen, Stanislaw M. Stepkowski

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Background: Clinical application of islet transplantation to treat type 1 diabetes has been limited by islet allograft destruction by both allogeneic and autoimmune diabetogenic T-cell responses. The current study aims at determining whether an anti-T-cell receptor (TCR) monoclonal antibody (mAb) has potential as a novel and potent induction immunotherapy for islet transplantation. Methods: We have investigated the therapeutic efficacy and mechanisms of action of anti-TCR therapy in four different murine models, which comprise either allo-or autoimmune responses alone or both together. RESULTS: T-cell response to islet allografts was potently abrogated by a brief treatment with an anti-TCRβ mAb (clone H57-597), resulting in long-term survival of BALB/c islet allografts in streptozotocin-induced diabetic B6 mice. Moreover, transient anti-TCR treatment permanently prevented BALB/c skin allograft rejection on Rag1 B6 recipients that were reconstituted with Foxp3 cell-depleted B6 splenocytes, but did not impair the reconstituted cells' ability to reject the later transplanted C3H skin allografts (transplanted at 120 days after BALB/c skin grafting). Transient anti-TCR treatment was also able to completely prevent diabetes onset in NOD.SCID.γc mice that were transferred with lymphocytes from diabetic NOD mice. Next, transient anti-TCR treatment significantly prolonged the survival of transplanted BALB/c islets in overtly diabetic NOD mice, which comprise both allogeneic and autoimmune diabetogenic T-cell responses to the transplanted islets. ConclusionS: Overall, anti-TCR mAb induced peripheral tolerance to specific alloantigens even in the absence of Foxp3-expressing natural regulatory T cells. These findings reveal the potential for using TCR-targeting mAbs as induction immunotherapy for islet transplantation.

Original languageEnglish (US)
Pages (from-to)1216-1224
Number of pages9
JournalTransplantation
Volume97
Issue number12
DOIs
StatePublished - Jun 27 2014

Keywords

  • Autoimmunity
  • Islet transplantation
  • T-cell receptor
  • Tolerance
  • Type 1 diabetes

ASJC Scopus subject areas

  • Transplantation

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