(Journal Article): Genetic engineering of a suboptimal islet graft with A20 preserves beta cell mass and function.
 
Grey ST, Longo C, Shukri T, Patel VI, Csizmadia E, Daniel S, Arvelo MB, Tchipashvili V, Ferran C (Immunobiology Research Center, Department of Surgery and Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA., sgrey@caregroup.harvard.edu )
 
IN: J Immunol 2003; 170(12):6250–6256.-
Impact Factor(s) of J Immunol: 6.486 (2004), 6.702 (2003), 7.065 (2001)

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ABSTRACT: 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-kappaB-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-kappaB 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(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.

TYPE OF PUBLICATION: Original article

Articles citing this article:

• Emamaullee JA, Rajotte RV, Liston P, Korneluk RG, Lakey JR, Shapiro AM, Elliott JF. XIAP overexpression in human islets prevents early posttransplant apoptosis and reduces the islet mass needed to treat diabetes. Diabetes 2005. 54: 2541-2548.
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