title: Porcine Islet-Specific Tolerance Induced by the Combination of Anti-LFA-1 and Anti-CD154 mAbs Is Dependent on PD-1.
abstract: We previously demonstrated that short-term administration of a combination of anti-LFA-1 and anti-CD154 monoclonal antibodies (mAbs) induces tolerance to neonatal porcine islet (NPI) xenografts that is mediated by regulatory T cells (Tregs) in B6 mice. In this study, we examined whether the coinhibitory molecule PD-1 is required for the induction and maintenance of tolerance to NPI xenografts. We also determined whether tolerance to NPI xenografts could be extended to allogeneic mouse or xenogeneic rat islet grafts since we previously demonstrated that tolerance to NPI xenografts could be extended to second-party NPI xenografts. Finally, we determined whether tolerance to NPI xenografts could be extended to allogeneic mouse or second-party porcine skin grafts. Diabetic B6 mice were transplanted with 2,000 NPIs under the kidney capsule and treated with short-term administration of a combination of anti-LFA-1 and anti-CD154 mAbs. Some of these mice were also treated simultaneously with anti-PD-1 mAb at >150 days posttransplantation. Spleen cells from some of the tolerant B6 mice were used for proliferation assays or were injected into B6 rag(-/-) mice with established islet grafts from allogeneic or xenogeneic donors. All B6 mice treated with anti-LFA-1 and anti-CD154 mAbs achieved and maintained normoglycemia until the end of the study; however, some mice that were treated with anti-PD-1 mAb became diabetic. All B6 rag(-/-) mouse recipients of first- and second-party NPIs maintained normoglycemia after reconstitution with spleen cells from tolerant B6 mice, while all B6 rag(-/-) mouse recipients of allogeneic mouse or xenogeneic rat islets rejected their grafts after cell reconstitution. Tolerant B6 mice rejected their allogeneic mouse or xenogeneic second-party porcine skin grafts while remaining normoglycemic until the end of the study. These results show that porcine islet-specific tolerance is dependent on PD-1, which could not be extended to skin grafts.
authors.affiliation: Alberta Diabetes Institute, Surgical-Medical Research Institute, Department of Surgery, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Hossein
authors.initials: H
authors.lastname: Arefanian
authors.forename: Eric B
authors.initials: EB
authors.lastname: Tredget
authors.forename: Dereck C M
authors.initials: DC
authors.lastname: Mok
authors.forename: Qahir
authors.initials: Q
authors.lastname: Ramji
authors.forename: Shahin
authors.initials: S
authors.lastname: Rafati
authors.forename: Jose
authors.initials: J
authors.lastname: Rodriguez-Barbosa
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Korbutt
authors.forename: Ray V
authors.initials: RV
authors.lastname: Rajotte
authors.forename: Ron G
authors.initials: RG
authors.lastname: Gill
authors.forename: Gina R
authors.initials: GR
authors.lastname: Rayat
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D023201:CD40 Ligand / Q000276:immunology; D003920:Diabetes Mellitus / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology / Q000502:physiology*; D007108:Immune Tolerance / Q000276:immunology*; D016381:Islets of Langerhans Transplantation / Q000379:methods; D016169:Lymphocyte Function-Associated Antigen-1 / Q000276:immunology; D008297:Male; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor / Q000378:metabolism*; D016038:Skin Transplantation / Q000379:methods; D013552:Swine; D014183:Transplantation, Heterologous / Q000379:methods
chemical_list: D000911:Antibodies, Monoclonal; D016169:Lymphocyte Function-Associated Antigen-1; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D023201:CD40 Ligand