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

By M. Ansari, A. Salama, Tanuja Chitnis, R. N. Smith, H. Yagita, H. Akiba, Tomohide Yamazaki, M. Azuma, H. Iwai, S. Khoury and 2 more. Journal of Experimental Medicine, 2003

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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 γ–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.

Subfields: Genetics, Immunology

View Paper: https://www.semanticscholar.org/paper/4ce033ad604573b9a9e176f5f81e768fdc7c1aa7

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Citations in the corpus

• Mechanisms of immune evasion by tumors. (2006, background): “In murine models of experimental autoimmune encephalomyelitis (EAE) and diabetes, anti‐PD1 antagonist antibodies enhance disease progression (Ansari et al., 2003; Salama et al., 2003).”
• Irradiation and anti-PD-L1 treatment synergistically promote antitumor immunity in mice. (2014, positive): “Evidence for a tissue-protective role of PD-L1 is revealed through the association of upregulated PD-L1 expression and amelioration of autoimmunity in several models, such as EAE and autoimmune diabetes (16, 17).”
• The function of programmed cell death 1 and its ligands in regulating autoimmunity and infection (2007, background): “Administration of anti-PD-1 or anti-PD-L1 to 1- to 10-week-old prediabetic NOD female and male mice leads to the rapid onset of diabetes and is associated with more IFN-γ-producing splenic T cells that recognize an islet antige”
• Co-inhibitory molecules of the B7–CD28 family in the control of T-cell immunity (2004, background): “Antagonist PD1-specific antibodies were found to accelerate experimental autoimmune encephalomyelitis (EAE), autoimmune diabetes, GVHD and hapten-induced contact hypersensitivity in mouse model”
• Blockade of B7-H1 and PD-1 by monoclonal antibodies potentiates cancer therapeutic immunity. (2005, background): “In addition, infusion of neutralizing monoclonal antibody (mAb) against PD-1 increased incidence of experimental autoimmune encephalitis and experimental diabetes (20, 21).”
• PD-1 and PD-1 ligands: from discovery to clinical application. (2007, background): “In agreement with these observations, antibody blockade of PD-1‐PD-L pathway in prediabetic NOD mice induces type I diabetes within 10 days ( 47 ).”
• The PD-1 Pathway in Tolerance and Autoimmunity (2010, background): “Blocking PD-L2 (clone TY25) does not alter diabetes progression in either NOD mice or in the RIP-OVA transfer model of peripheral tolerance (55, 150).”
• Inhibitory B7-family molecules in the tumour microenvironment (2008, background): “B7-H1-deficient NOD mice also develop diabetes more rapidly than wild-type NOD mic”
• Interactions between programmed death-1 and programmed death ligand-1 promote tolerance by blocking the T cell receptor-induced stop signal (2009, background): “Similarly, blocking PD-1–PD-L1 interactions accelerates spontaneous autoimmune diabete”
• Control of peripheral T‐cell tolerance and autoimmunity via the CTLA‐4 and PD‐1 pathways (2008, background): “PD-L1 is expressed on leukocytes, nonhematopoietic cells, and in non-lymphoid tissues including islets (21, 24, 25), while PD-L2 is expressed exclusively on DCs and monocytes (21, 22, 26, 27).”