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
• Subjects: Adenoviridae - genetics; Animals; Apoptosis - genetics; Apoptosis - immunology; Cysteine Endopeptidases; Cytoprotection - genetics; Cytoprotection - immunology; Diabetes Mellitus, Experimental - immunology; Diabetes Mellitus, Experimental - pathology; Diabetes Mellitus, Experimental - therapy; DNA-Binding Proteins; Gene Transfer Techniques; Genetic Vectors; Graft Survival - genetics; Graft Survival - immunology; Humans; Insulin - biosynthesis; Intracellular Signaling Peptides and Proteins; Islets of Langerhans - immunology; Islets of Langerhans - metabolism; Islets of Langerhans - pathology; Islets of Langerhans Transplantation - immunology; Islets of Langerhans Transplantation - methods; Islets of Langerhans Transplantation - pathology; Male; Mice; Mice, Inbred A; Mice, Inbred C57BL; Nuclear Proteins; Postoperative Period; Protective Agents - metabolism; Protective Agents - therapeutic use; Protective Agents - toxicity; Protein Biosynthesis; Protein Engineering - methods; Proteins - genetics; Proteins - therapeutic use; Proteins - toxicity; Recombinant Proteins - biosynthesis; Recombinant Proteins - genetics; Recombinant Proteins - therapeutic use; Recombinant Proteins - toxicity; Tumor Necrosis Factor alpha-Induced Protein 3
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.170.12.6250

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.