Prolongation of islet allograft survival following ex vivo transduction with adenovirus encoding a soluble type 1 TNF receptor-Ig fusion decoy

Gene Therapy
J MachenN Giannoukakis

Abstract

Islet transplantation is a viable long-term therapeutic alternative to daily insulin replacement for type I diabetes. The allogeneic nature of the transplants poses immunological challenges for routine clinical utility. Gene transfer of immunoregulatory molecules and those that improve insulin release kinetics provides rational approaches to facilitate allogeneic islet transplantation as a potential therapy. We have examined the efficacy of a soluble type 1 tumor necrosis factor receptor (TNFR) immunoglobulin-Fc fusion transgene (TNFR-Ig) to protect human islets from cytokine-induced apoptosis in culture, as well as in facilitating allogeneic islet transplants in diabetic mice. Cultured human islets were transduced with an adenoviral vector encoding human TNFR-Ig (Ad-TNFR-Ig). TNFR-Ig protein was secreted by cultured islets, as well as by transduced mouse islet transplants recovered from mouse recipients. Glucose-induced insulin release kinetics were comparable among untransduced, Ad-TNFR-Ig-infected human islets and vector-transduced islets exposed to cytokines. In parallel, Ad-TNFR-Ig-infected islets were protected from cytokine-induced apoptosis activation. Finally, diabetic mice transplanted with allogeneic islets expressin...Continue Reading

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Citations

Nov 11, 2005·American Journal of Therapeutics·Nick Giannoukakis, Massimo Trucco
Sep 29, 2006·Transplantation·Stephen HanleySteven Paraskevas
Aug 12, 2005·Proceedings of the National Academy of Sciences of the United States of America·Eli C LewisCharles A Dinarello
Oct 3, 2015·American Journal of Transplantation : Official Journal of the American Society of Transplantation and the American Society of Transplant Surgeons·H-S LeeJ Yang
Nov 27, 2007·Advanced Drug Delivery Reviews·Yi LaiThomas Linn
Jun 15, 2006·Transplant International : Official Journal of the European Society for Organ Transplantation·Daniel J MooreShaoping Deng
Sep 1, 2007·Journal of Cellular and Molecular Medicine·Beate KuttlerThomas Ritter
Jul 11, 2008·Immunological Reviews·Todd M BruskoJeffrey A Bluestone
May 23, 2006·Pharmacological Reviews·Ajit S Narang, Ram I Mahato
Apr 17, 2021·Drug Discovery Today·Maryam Mahjoubin-TehranAmirhossein Sahebkar

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