IMPROVED SURVIVAL OF BIOLISTICALLY TRANSFECTED MOUSE ISLET ALLOGRAFTSEXPRESSING CTLA4-IG OR SOLUBLE FAS LIGAND

Background, Pancreatic islet transplantation is limited because of imm une rejection of the transplanted tissue. Long-term survival of alloge neic pancreatic islet grafts in the absence of systemic immunosuppress ive agents should be possible by transfecting the islets directly with DNA encoding immunoregulatory molecules. Localized production of thes e molecules should affect only the immune cells that come into the vic inity of the foreign tissue. We investigated whether local expression of human CTLA4-Ig or soluble human Fas ligand from biolistically trans fected mouse islets would have a protective effect on allograft surviv al. Methods. Isolated CBA (H2(k)) islets were biolistically transfecte d using the gene gun. The experimental groups were naked gold particle s (n=6), empty vector DNA (n=5), DNA encoding human CTLA4-Ig (n=8), or soluble human Fas ligand (n=5). Secretion of the transfected gene pro duct was confirmed by screening islet culture supernatants for protein production using a sandwich ELISA, The blasted islets were transplant ed under the kidney capsule of alloxan-diabetic BALB/c (H2(d)) recipie nts. Results. Control grafts survived for 23 days, on average. CTLA4-I g-transfected islets showed a bimodal distribution: 50% of cases survi ved greater than or equal to 46 days and 50% were similar to the contr ols. In the soluble human Fas ligand group, 80% of grafts survived gre ater than or equal to 50 days. There was no correlation between graft survival times and pretransplant levels of protein production. Conclus ion. Our results indicate that local production of human CTLA4-Ig or s oluble human Fas ligand by biolistically transfected islets can promot e allograft survival. This approach should be valuable as a potential immunoprotective therapeutic strategy in tissue transplantation.