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

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 antig...

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Detalles Bibliográficos
Autores principales: 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.
Formato: Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2006
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2118162/
https://www.ncbi.nlm.nih.gov/pubmed/17116737
http://dx.doi.org/10.1084/jem.20061577
Descripción
Sumario: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.