title: Immunosuppression With CD40 Costimulatory Blockade Plus Rapamycin for Simultaneous Islet-Kidney Transplantation in Nonhuman Primates.
abstract: The lack of a reliable immunosuppressive regimen that effectively suppresses both renal and islet allograft rejection without islet toxicity hampers a wider clinical application of simultaneous islet-kidney transplantation (SIK). Seven MHC-mismatched SIKs were performed in diabetic cynomolgus monkeys. Two recipients received rabbit antithymocyte globulin (ATG) induction followed by daily tacrolimus and rapamycin (ATG/Tac/Rapa), and five recipients were treated with anti-CD40 monoclonal antibody (mAb) and rapamycin (aCD40/Rapa). Anti-inflammatory therapy, including anti-interleukin-6 receptor mAb and anti-tumor necrosis factor-α mAb, was given in both groups. The ATG/Tac/Rapa recipients failed to achieve long-term islet allograft survival (19 and 26 days) due to poor islet engraftment and cytomegalovirus pneumonia. In contrast, the aCD40/Rapa regimen provided long-term islet and kidney allograft survival (90, 94, >120, >120, and >120 days), with only one recipient developing evidence of allograft rejection. The aCD40/Rapa regimen was also tested in four kidney-alone transplant recipients. All four recipients achieved long-term renal allograft survival (100% at day 120), which was superior to renal allograft survival (62.9% at day 120) with triple immunosuppressive regimen (tacrolimus, mycophenolate mofetil, and steroids). The combination of anti-CD40 mAb and rapamycin is an effective and nontoxic immunosuppressive regimen that uses only clinically available agents for kidney and islet recipients.
authors: Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors: T
authors: T
authors: Oura
authors: Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors: K
authors: K
authors: Hotta
authors: Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors: J
authors: J
authors: Lei
authors: Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors: J
authors: J
authors: Markmann
authors: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors: I
authors: I
authors: Rosales
authors: Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors: A
authors: A
authors: Dehnadi
authors: Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors: K
authors: K
authors: Kawai
authors: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors: D
authors: D
authors: Ndishabandi
authors: Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors: R-N
authors: RN
authors: Smith
authors: Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors: A B
authors: AB
authors: Cosimi
authors: Department of Surgery, Center for Transplantation Sciences, Massachusetts General Hospital, Harvard Medical School, Boston, MA.
authors: T
authors: T
authors: Kawai
mesh_terms: D000818:Animals; D000961:Antilymphocyte Serum / Q000627:therapeutic use*; D023201:CD40 Ligand / Q000037:antagonists & inhibitors; D003920:Diabetes Mellitus / Q000601:surgery*; D004359:Drug Therapy, Combination; D006085:Graft Survival / Q000187:drug effects*; D007108:Immune Tolerance; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016381:Islets of Langerhans Transplantation; D016030:Kidney Transplantation; D008252:Macaca fascicularis; D011817:Rabbits; D020123:Sirolimus / Q000627:therapeutic use*; D014184:Transplantation, Homologous
chemical_list: D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D023201:CD40 Ligand; D020123:Sirolimus
keywords: animal models: nonhuman primate; costimulation; fusion proteins and monoclonal antibodies; immunosuppressant; immunosuppression/immune modulation; islet transplantation; islets of Langerhans; kidney transplantation/nephrology; mechanistic target of rapamycin: sirolimus; translational research/science