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

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Deng, R; Khattar, M; Xie, A; Schroder, PM; He, X; Chen, W; Stepkowski, SM

Published Date

  • June 2014

Published In

Volume / Issue

  • 97 / 12

Start / End Page

  • 1216 - 1224

PubMed ID

  • 24854475

Electronic International Standard Serial Number (EISSN)

  • 1534-6080

International Standard Serial Number (ISSN)

  • 0041-1337

Digital Object Identifier (DOI)

  • 10.1097/tp.0000000000000120

Language

  • eng