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Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway.

  • Author(s): Fife, Brian T
  • Guleria, Indira
  • Gubbels Bupp, Melanie
  • Eagar, Todd N
  • Tang, Qizhi
  • Bour-Jordan, Helene
  • Yagita, Hideo
  • Azuma, Miyuki
  • Sayegh, Mohamed H
  • Bluestone, Jeffrey A
  • et al.

The past decade has seen a significant increase in the number of potentially tolerogenic therapies for treatment of new-onset diabetes. However, most treatments are antigen nonspecific, and the mechanism for the maintenance of long-term tolerance remains unclear. In this study, we developed an antigen-specific therapy, insulin-coupled antigen-presenting cells, to treat diabetes in nonobese diabetic mice after disease onset. Using this approach, we demonstrate disease remission, inhibition of pathogenic T cell proliferation, decreased cytokine production, and induction of anergy. Moreover, we show that robust long-term tolerance depends on the programmed death 1 (PD-1)-programmed death ligand (PD-L)1 pathway, not the distinct cytotoxic T lymphocyte-associated antigen 4 pathway. Anti-PD-1 and anti-PD-L1, but not anti-PD-L2, reversed tolerance weeks after tolerogenic therapy by promoting antigen-specific T cell proliferation and inflammatory cytokine production directly in infiltrated tissues. PD-1-PD-L1 blockade did not limit T regulatory cell activity, suggesting direct effects on pathogenic T cells. Finally, we describe a critical role for PD-1-PD-L1 in another powerful immunotherapy model using anti-CD3, suggesting that PD-1-PD-L1 interactions form part of a common pathway to selectively maintain tolerance within the target tissues.

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