title: Blockade of the programmed death-1 (PD1) pathway undermines potent genetic protection from type 1 diabetes.
abstract: OBJECTIVE
  Inhibition of PD1-PDL1 signaling in NOD mice accelerates onset of type 1 diabetes implicating this pathway in suppressing the emergence of pancreatic beta cell reactive T-cells. However, the molecular mechanism by which PD1 signaling protects from type 1 diabetes is not clear. We hypothesized that differential susceptibility of Idd mouse strains to type 1 diabetes when challenged with anti PDL1 will identify genomic loci that collaborate with PD1 signaling in suppressing type 1 diabetes.
  
  
  METHODS
  Anti PDL1 was administered to NOD and various Idd mouse strains at 10 weeks of age and onset of disease was monitored by measuring blood glucose levels. Additionally, histological evaluation of the pancreas was performed to determine degree of insulitis. Statistical analysis of the data was performed using Log-Rank and Student's t-test.
  
  
  RESULTS
  Blockade of PDL1 rapidly precipitated type 1 diabetes in nearly all NOD Idd congenic strains tested, despite the fact that all are moderately (Idd5, Idd3 and Idd10/18) or highly (Idd3/10/18 and Idd9) protected from spontaneous type 1 diabetes by virtue of their protective Idd genes. Only the Idd3/5 strain, which is nearly 100% protected from spontaneous disease, remained normoglycemic following PDL1 blockade.
  
  
  CONCLUSIONS
  These results indicate that multiple Idd loci collaborate with PD1 signaling. Anti PDL1 treatment undermines a large portion of the genetic protection mediated by Idd genes in the NOD model of type 1 diabetes. Basal insulitis correlated with higher susceptibility to type 1 diabetes. These findings have important implications since the PD1 pathway is a target for immunotherapy.
authors.affiliation: Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School Renal Division, Boston, Massachusetts, United States of America.
authors.forename: Nora M
authors.initials: NM
authors.lastname: Kochupurakkal
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Annie J
authors.initials: AJ
authors.lastname: Kruger
authors.affiliation: Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School Renal Division, Boston, Massachusetts, United States of America.
authors.forename: Sudipta
authors.initials: S
authors.lastname: Tripathi
authors.affiliation: Center for Neurologic Diseases, Brigham and Women's Hospital, Boston, Massachusetts, United States of America.
authors.forename: Bing
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School Renal Division, Boston, Massachusetts, United States of America.
authors.forename: La Tonya
authors.initials: LT
authors.lastname: Adams
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Rainbow
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Aldo
authors.initials: A
authors.lastname: Rossini
authors.affiliation: Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts, United States of America.
authors.forename: Dale L
authors.initials: DL
authors.lastname: Greiner
authors.affiliation: Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School Renal Division, Boston, Massachusetts, United States of America.
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.affiliation: Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Linda S
authors.initials: LS
authors.lastname: Wicker
authors.affiliation: Transplantation Research Center, Brigham and Women's Hospital and Children's Hospital Boston, Harvard Medical School Renal Division, Boston, Massachusetts, United States of America.
authors.forename: Indira
authors.initials: I
authors.lastname: Guleria
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D060890:B7-H1 Antigen / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics / Q000378:metabolism* / Q000628:therapy*; D005260:Female; D020022:Genetic Predisposition to Disease; D007167:Immunotherapy; D051379:Mice; D016688:Mice, Inbred NOD; D061026:Programmed Cell Death 1 Receptor; D015398:Signal Transduction
chemical_list: D060890:B7-H1 Antigen; D061026:Programmed Cell Death 1 Receptor