title: Blockade of the PD-1/PD-1L pathway reverses the protective effect of anti-CD40L therapy in a rat to mouse concordant islet xenotransplantation model.
abstract: BACKGROUND
  We have previously demonstrated that costimulatory blockade with anti-CD40L monoclonal antibody (mAb) prolongs the survival of non-vascularized concordant rat to mouse islet xenografts. Here, we examine whether signaling through the PD-1/PD-1L pathway is required for the anti-CD40L therapy to prolong concordant islet graft survival using a novel anti-murine PD-1 mAb (clone 4F10).
  
  
  METHODS
  C57BL/6 mice received a cellular concordant islet xenograft under the left kidney capsule and four experimental groups were prepared. Group I: untreated control; group II: recipient mice were treated with three doses of 0.5 mg of anti-CD40L mAb (clone MR1) on days 0, 2 and 4; group III: mice were treated with 0.5 mg of anti-PD-1 (CD279) mAb (clone 4F10) every other day for 8 days; and finally group IV: mice received the combined treatment that consisted of anti-CD40L plus anti-PD-1 mAb.
  
  
  RESULTS
  Concordant islet xenografts transplanted in control untreated mice showed a median survival time (MST) of 17 +/- 7.43 days, whereas anti-CD40L treatment led to a significant prolongation of graft survival (MST: 154 +/- 65.56, P < 0.0001). The administration of anti-PD-1 alone significantly accelerated graft rejection compared to non-treated controls (MST: 10 +/- 2.24 vs. MST: 17 +/- 7.43, P < 0.0004). Remarkably, the combined administration of anti-CD40L and anti-PD-1 reversed the protective effect obtained with anti-CD40L alone (anti-CD40L, MST: 154 +/- 65.56 vs. anti-CD40L plus anti-PD-1, MST: 10 +/- 7.72, P < 0.0002).
  
  
  CONCLUSIONS
  Overall, our data indicate that the PD-1/PD-1L pathway is required for the achievement of prolonged graft survival in anti-CD40L-treated mice in a setting of rat to mouse concordant islet xenotransplantation.
authors.affiliation: Department of General Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Mai
authors.forename: Maria-Luisa
authors.initials: ML
authors.lastname: del Rio
authors.forename: Jiong
authors.initials: J
authors.lastname: Tian
authors.forename: Pablo
authors.initials: P
authors.lastname: Ramirez
authors.forename: Leo
authors.initials: L
authors.lastname: Buhler
authors.forename: Jose-Ignacio
authors.initials: JI
authors.lastname: Rodriguez-Barbosa
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation / Q000276:immunology*; D018122:B7-1 Antigen / Q000276:immunology*; D060890:B7-H1 Antigen; D023201:CD40 Ligand / Q000037:antagonists & inhibitors / Q000276:immunology*; D006224:Cricetinae; D003412:Cricetulus / Q000276:immunology; D003920:Diabetes Mellitus / Q000139:chemically induced; D004195:Disease Models, Animal; D006085:Graft Survival / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000276:immunology* / Q000379:methods; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D010455:Peptides / Q000037:antagonists & inhibitors / Q000276:immunology*; D061026:Programmed Cell Death 1 Receptor; D051381:Rats; D017207:Rats, Sprague-Dawley; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D014183:Transplantation, Heterologous / Q000276:immunology* / Q000379:methods
chemical_list: D000911:Antibodies, Monoclonal; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; D023201:CD40 Ligand