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Cell Mass and Function1
* Immunobiology Research Center,
Department of Surgery and Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; and
Section on Islet Transplantation and Cell Biology, Joslin Diabetes Center, Boston, MA 02115
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 
cell inflammatory response (up-regulation of NF-
B-dependent genes such as inos) result in cell destruction in the early post-transplantation period. Genetic engineering of islets with anti-inflammatory and antiapoptotic genes may prevent cell loss and primary nonfunction. We have shown in vitro that A20 inhibits NF-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/AF1 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 cell mass and are protected from cell death. These data demonstrate that A20 is an ideal cytoprotective gene therapy candidate for islet transplantation.
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