Survival of adult islet grafts from transgenic pigs with N‐acetylglucosaminyltransferase‐III (GnT‐III) in cynomolgus monkeys

Abstract

Because of a severe shortage of human donor pancreases, pig islets are considered to be an attractive donor source. Our previous in vitro study revealed that adult pig islets have strong non-Galalpha1-3Galbeta1-4GlcNAc-R (alpha-Gal) antigenicity, including the Hanganutziu-Deicher (H-D) antigen, especially in N-linked sugars. In this study, the issue of whether islets from N-acetylglucosaminyltransferase-III (GnT-III) transgenic pigs can prolong their survival in cynomolgus monkeys was examined. Adult pig islets were isolated from transgenic pigs with GnT-III and wild-type genes. GnT-III enzyme activity in pig islets was measured by high performance liquid chromatography (HPLC). The antigenicity of the islets to human natural antibodies was examined by flow cytometry. Pig islets were transplanted under the kidney capsule of streptozotocin-induced diabetic monkeys. After transplantation, blood samples were obtained and plasma insulin levels were monitored on a daily basis. While GnT-III was barely expressed in wild-type islets, it was expressed at high levels in islets from transgenic pigs, and xenoantigenicity was significantly reduced. There was a trend for islets isolated from GnT-III-transgenic pigs to survive longer than those from wild-type pigs in cynomolgus monkeys (wild type: 1, 1, and 3 days; GnT-III: 1, >3, 4 and 5 days). Humoral and histological studies indicated up-regulated anti-pig islet antibodies and a relatively high deposition in islet grafts from wild-type pigs, respectively. A reduction in xenoantigenicity by GnT-III may have prolonged the survival of porcine islets, suggesting the importance of non-alpha-Gal and non-H-D antigens, as they relate to N-linked sugars in the early rejection of porcine islets in the monkey. This approach may be useful in the clinical xenotransplantation of islets in the future.