title: The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice.
abstract: 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.
authors.affiliation: Laboratory of Immunogenetics and Transplantation, Brigham and Women's Hospital, Boston, MA 02115, USA.
authors.forename: Mohammed Javeed I
authors.initials: MJ
authors.lastname: Ansari
authors.forename: Alan D
authors.initials: AD
authors.lastname: Salama
authors.forename: Tanuja
authors.initials: T
authors.lastname: Chitnis
authors.forename: R Neal
authors.initials: RN
authors.lastname: Smith
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Hisaya
authors.initials: H
authors.lastname: Akiba
authors.forename: Tomohide
authors.initials: T
authors.lastname: Yamazaki
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Iwai
authors.forename: Samia J
authors.initials: SJ
authors.lastname: Khoury
authors.forename: Hugh
authors.initials: H
authors.lastname: Auchincloss
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
mesh_terms: D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000502:physiology; D000954:Antigens, Surface / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins / Q000502:physiology; D060908:CTLA-4 Antigen; D003922:Diabetes Mellitus, Type 1 / Q000209:etiology* / Q000473:pathology; D005260:Female; D007371:Interferon-gamma / Q000096:biosynthesis; D008562:Membrane Glycoproteins; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D010179:Pancreas / Q000473:pathology; D010455:Peptides / Q000502:physiology; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; D001798:Blood Proteins; D060908:CTLA-4 Antigen; C498919:Cd274 protein, mouse; C556707:Ctla4 protein, mouse; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; C556978:Pdcd1lg2 protein, mouse; D010455:Peptides; D061027:Programmed Cell Death 1 Ligand 2 Protein; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma