Improved survival of biolistically transfected mouse islet allografts expressing CTLA4-Ig or soluble Fas ligand

Background, Pancreatic islet transplantation is limited because of immune rejection of the transplanted tissue. Long-term survival of allogeneic pancreatic islet grafts in the absence of systemic immunosuppressive agents should be possible by transfecting the islets directly with DNA encoding immunoregulatory molecules. Localized production of these molecules should affect only the immune cells that come into the vicinity of the foreign tissue. We investigated whether local expression of human CTLA4-Ig or soluble human Fas ligand from biolistically transfected mouse islets would have a protective effect on allograft survival. Methods. Isolated CBA (H2(k)) islets were biolistically transfected using the gene gun. The experimental groups were naked gold particles (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 product was confirmed by screening islet culture supernatants for protein production using a sandwich ELISA, The blasted islets were transplanted under the kidney capsule of alloxan-diabetic BALB/c (H2(d)) recipients. Results. Control grafts survived for 23 days, on average. CTLA4-Ig-transfected islets showed a bimodal distribution: 50% of cases survived greater than or equal to 46 days and 50% were similar to the controls. In the soluble human Fas ligand group, 80% of grafts survived greater than or equal to 50 days. There was no correlation between graft survival times and pretransplant levels of protein production. Conclusion. Our results indicate that local production of human CTLA4-Ig or soluble human Fas ligand by biolistically transfected islets can promote allograft survival. This approach should be valuable as a potential immunoprotective therapeutic strategy in tissue transplantation.