Genetic engineering of a suboptimal islet graft with A20 preserves beta cell mass and function.

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Grey, ST; Longo, C; Shukri, T; Patel, VI; Csizmadia, E; Daniel, S; Arvelo, MB; Tchipashvili, V; Ferran, C

Published Date

  • June 15, 2003

Published In

Volume / Issue

  • 170 / 12

Start / End Page

  • 6250 - 6256

PubMed ID

  • 12794157

Pubmed Central ID

  • 12794157

International Standard Serial Number (ISSN)

  • 0022-1767

Digital Object Identifier (DOI)

  • 10.4049/jimmunol.170.12.6250

Language

  • eng

Conference Location

  • United States