title: Safe use of anti-CD154 monoclonal antibody in pig islet xenotransplantation in monkeys.
abstract: Anti-CD154mAb is a powerful co-stimulation blockade agent that is efficacious in preventing rejection, even in xenogeneic settings. It has been used in the majority of successful long-term pig-to-non-human primate islet transplantation models. However, its clinical use was halted as a result of thromboembolic complications that were also observed in preclinical and clinical organ transplantation models. An anti-CD154mAb was administered to 14 streptozotocin-induced diabetic cynomolgus monkey recipients of porcine islets, some of which received the agent for many months. Monkeys were monitored for complications, and blood monitoring was carried out frequently. After euthanasia, multiple biopsies of all organs were examined for histological features of thromboembolism. Anti-CD154mAb prevented rejection of genetically engineered pig islets in all monkeys. No significant complications were attributable specifically to anti-CD154mAb. There was no evidence of thromboembolism in multiple histological sections from all major organs, including the brain. Our data suggest that in diabetic monkeys with pig islet grafts, anti-CD154mAb would appear to be an effective and safe therapy, and is not associated with thromboembolic complications.
authors.affiliation: Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Allegheny Health Network, Pittsburgh, PA, USA.
authors.forename: Rita
authors.initials: R
authors.lastname: Bottino
authors.affiliation: Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Allegheny Health Network, Pittsburgh, PA, USA.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Knoll
authors.affiliation: University of Aberdeen School of Medicine and Dentistry, Aberdeen, Scotland, UK.
authors.forename: Joshua
authors.initials: J
authors.lastname: Graeme-Wilson
authors.affiliation: Division of Laboratory Animal Resources, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: Edwin C
authors.initials: EC
authors.lastname: Klein
authors.affiliation: Revivicor Inc, Blacksburg, VA, USA.
authors.forename: David
authors.initials: D
authors.lastname: Ayares
authors.affiliation: Institute of Cellular Therapeutics, Allegheny-Singer Research Institute, Allegheny Health Network, Pittsburgh, PA, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Trucco
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: David K C
authors.initials: DK
authors.lastname: Cooper
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D023201:CD40 Ligand / Q000276:immunology*; D003921:Diabetes Mellitus, Experimental / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology; D064593:Heterografts / Q000187:drug effects* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D008252:Macaca fascicularis; D013552:Swine; D014183:Transplantation, Heterologous / Q000379:methods
chemical_list: D000911:Antibodies, Monoclonal; D007166:Immunosuppressive Agents; D023201:CD40 Ligand
keywords: anti-CD154mAb; immunosuppression; islets of langerhans; xenotransplantation