Long‐Term Controlled Normoglycemia in Diabetic Non‐Human Primates After Transplantation with hCD46 Transgenic Porcine Islets

• Published in: American journal of transplantation Vol. 9; no. 12; pp. 2716 - 2726
• Main Authors: Van Der Windt, D. J., Bottino, R., Casu, A., Campanile, N., Smetanka, C., He, J., Murase, N., Hara, H., Ball, S., Loveland, B. E, Ayares, D., Lakkis, F. G., Cooper, D. K. C., Trucco, M.
• Format: Journal Article
• Language: English
• Published: Malden, USA Blackwell Publishing Inc 01.12.2009; Wiley
• Subjects: Animals; Animals, Genetically Modified; Biological and medical sciences; Blood Glucose - metabolism; Complement regulation; Cynomolgus; diabetes mellitus; Diabetes Mellitus, Experimental - physiopathology; Diabetes Mellitus, Experimental - surgery; Diabetes. Impaired glucose tolerance; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Female; islet xenotransplantation; Islets of Langerhans Transplantation - methods; Macaca fascicularis; Male; Medical sciences; Membrane Cofactor Protein - genetics; non‐human primate; Primates; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Swine; transgenic pigs; Transplantation, Heterologous; Endocrinopathy; Diabetes mellitus; Nonhuman primate; Langerhans islet; Transgenic animal; Complement; transgenic pigs; Heterograft; Long term; Pig; Vertebrata; Regulation(control); Complement regulation; Mammalia; non-human primate; Primates; Graft; Artiodactyla; Ungulata; Endocrine pancreas; islet xenotransplantation
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2009.02850.x

Xenotransplantation of porcine islets into diabetic non‐human primates is characterized by (i) an initial massive graft loss possibly due to the instant blood‐mediated inflammatory reaction and (ii) the requirement of intensive, clinically unfriendly immunosuppressive therapy. We investigated whether the transgenic expression of a human complement‐regulatory protein (hCD46) on porcine islets would improve the outcome of islet xenotransplantation in streptozotocin‐induced diabetic Cynomolgus monkeys. Immunosuppression consisted of thymoglobulin, anti‐CD154 mAb for costimulation blockade, and mycophenolate mofetil. Following the transplantation of islets from wild‐type pigs (n = 2) or from 1,3‐galactosyltransferase gene‐knockout pigs (n = 2), islets survived for a maximum of only 46 days, as evidenced by return to hyperglycemia and the need for exogenous insulin therapy. The transplantation of islets from hCD46 pigs resulted in graft survival and insulin‐independent normoglycemia in four of five monkeys for the 3 months follow‐up of the experiment. One normalized recipient, selected at random, was followed for >12 months. Inhibition of complement activation by the expression of hCD46 on the pig islets did not substantially reduce the initial loss of islet mass, rather was effective in limiting antibody‐mediated rejection. This resulted in a reduced need for immunosuppression to preserve a sufficient islet mass to maintain normoglycemia long‐term. This study demonstrated survival and functional performance of pig islets expressing hCD46 following transplantation in diabetic non‐human primates for three months in four of five recipients.