Genetic Engineering of a Suboptimal Islet Graft with A20 Preserves {beta} Cell Mass and Function

• Published in: The Journal of immunology (1950) 2003-06, Vol.170 (12), p.6250-6256
• Main Authors: Grey, Shane T, Longo, Christopher, Shukri, Tala, Patel, Virendra I, Csizmadia, Eva, Daniel, Soizic, Arvelo, Maria B, Tchipashvili, Vaja, Ferran, Christiane
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606

Transplantation of an excessive number of islets of Langerhans (two to four pancreata per recipient) into patients with type I diabetes is required to restore euglycemia. Hypoxia, nutrient deprivation, local inflammation, and the [beta] cell inflammatory response (up-regulation of NF-[kappa]B-dependent genes such as inos) result in [beta] cell destruction in the early post- transplantation period. Genetic engineering of islets with anti-inflammatory and antiapoptotic genes may prevent [beta] cell loss and primary nonfunction. We have shown in vitro that A20 inhibits NF-[kappa]B activation in islets and protects from cytokine- and death receptor-mediated apoptosis. In vivo, protection of newly transplanted islets would reduce the number of islets required for successful transplantation. Transplantation of 500 B6/AF sub(1) mouse islets into syngeneic, diabetic recipients resulted in a cure rate of 100% within 5 days. Transplantation of 250 islets resulted in a cure rate of only 20%. Transplantation of 250 islets overexpressing A20 resulted in a cure rate of 75% with a mean time to cure of 5.2 days, comparable to that achieved with 500 islets. A20-expressing islets preserve functional [beta] cell mass and are protected from cell death. These data demonstrate that A20 is an ideal cytoprotective gene therapy candidate for islet transplantation.