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

Brian T. Fife, Indira Guleria, Melanie Gubbels Bupp, Todd N. Eagar, Qizhi Tang, Helene Bour-Jordan, Hideo Yagita, Miyuki Azuma, Mohamed H. Sayegh, Jeffrey A. Bluestone

Research output: Contribution to journalArticle

215 Citations (Scopus)

Abstract

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. JEM

Original languageEnglish (US)
Pages (from-to)2737-2747
Number of pages11
JournalJournal of Experimental Medicine
Volume203
Issue number12
DOIs
StatePublished - Nov 2006

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Inbred NOD Mouse
Insulin
T-Lymphocytes
Antigens
Cell Proliferation
CTLA-4 Antigen
Cytokines
Therapeutics
Antigen-Presenting Cells
Regulatory T-Lymphocytes
Immunotherapy
Ligands

ASJC Scopus subject areas

  • Immunology

Cite this

Fife, B. T., Guleria, I., Bupp, M. G., Eagar, T. N., Tang, Q., Bour-Jordan, H., ... Bluestone, J. A. (2006). Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway. Journal of Experimental Medicine, 203(12), 2737-2747. https://doi.org/10.1084/jem.20061577

Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway. / Fife, Brian T.; Guleria, Indira; Bupp, Melanie Gubbels; Eagar, Todd N.; Tang, Qizhi; Bour-Jordan, Helene; Yagita, Hideo; Azuma, Miyuki; Sayegh, Mohamed H.; Bluestone, Jeffrey A.

In: Journal of Experimental Medicine, Vol. 203, No. 12, 11.2006, p. 2737-2747.

Research output: Contribution to journalArticle

Fife, BT, Guleria, I, Bupp, MG, Eagar, TN, Tang, Q, Bour-Jordan, H, Yagita, H, Azuma, M, Sayegh, MH & Bluestone, JA 2006, 'Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway', Journal of Experimental Medicine, vol. 203, no. 12, pp. 2737-2747. https://doi.org/10.1084/jem.20061577
Fife, Brian T. ; Guleria, Indira ; Bupp, Melanie Gubbels ; Eagar, Todd N. ; Tang, Qizhi ; Bour-Jordan, Helene ; Yagita, Hideo ; Azuma, Miyuki ; Sayegh, Mohamed H. ; Bluestone, Jeffrey A. / Insulin-induced remission in new-onset NOD mice is maintained by the PD-1-PD-L1 pathway. In: Journal of Experimental Medicine. 2006 ; Vol. 203, No. 12. pp. 2737-2747.
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