The Journal of Experimental Medicine
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Published 7 July 2003. doi:10.1084/jem.20022125
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© Rockefeller University Press, 0022-1007/2003/7/63 $5.00
The Journal of Experimental Medicine, Volume 198, Number 1, 63-69

The Programmed Death-1 (PD-1) Pathway Regulates Autoimmune Diabetes in Nonobese Diabetic (NOD) Mice

Mohammed Javeed I. Ansari1, Alan D. Salama1,3, Tanuja Chitnis2,3, R. Neal Smith4, Hideo Yagita5, Hisaya Akiba5, Tomohide Yamazaki5, Miyuki Azuma6, Hideyuki Iwai6, Samia J. Khoury2, Hugh Auchincloss, Jr.4 and Mohamed H. Sayegh1,3

1 Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital
2 Centre for Neurologic Diseases, Brigham and Women's Hospital
3 Nephrology Division, The Children's Hospital
4 Department of Surgery and Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02115
5 Department of Immunology, Juntendo University School of Medicine, Tokyo 113-8421, Japan
6 Department of Molecular Immunology, Tokyo Medical and Dental University, Tokyo 113-8549, Japan

Address correspondence to Mohamed H. Sayegh, Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115. Phone: 617-732-5259; Fax: 617-732-5254; E-mail: msayegh{at}rics.bwh.harvard.edu

Programmed death-1 (PD-1) receptor, an inhibitory costimulatory molecule found on activated T cells, has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance. We investigated the role of this pathway in the development of autoimmune diabetes. PD-1 or PD-L1 but not PD-L2 blockade rapidly precipitated diabetes in prediabetic female nonobese diabetic (NOD) mice regardless of age (from 1 to 10-wk-old), although it was most pronounced in the older mice. By contrast, cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) blockade induced disease only in neonates. Male NOD mice also developed diabetes after PD-1–PD-L1 pathway blockade, but NOR mice, congenic to NOD but resistant to the development of diabetes, did not. Insulitis scores were significantly higher and frequency of interferon {gamma}–producing GAD-reactive splenocytes was increased after PD-1–PD-L1 pathway blockade compared with controls. Interestingly, PD-L1 but not PD-L2 was found to be expressed on inflamed islets of NOD mice. These data demonstrate a central role for PD-1–PD-L1 interaction in the regulation of induction and progression of autoimmune diabetes in the NOD mouse and provide the rationale to develop new therapies to target this costimulatory pathway in this disease.

Key Words: diabetes mellitus, insulin-dependent • mice, inbred NOD • autoimmunity • self-tolerance • programmed cell death protein 1


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