Adenoviral-Mediated Overexpression of Either Membrane-Bound Human FasL or Human Decoy Fas Can Prolong Pig Islet Xenograft Survival in a Rat Transplant Model

Abstract

The success of pancreatic islet transplantation is limited because of the severe shortage of allogeneic pancreas donors. Accordingly, pig islets are considered to be an attractive, promising alternative. However, cell-mediated immunity, especially CD8 + cytotoxic T lymphocyte (CTL)-mediated cytotoxicity, remains a formidable barrier to prevent long-term islet survival in xenograft recipients. Therefore, it is particularly important to explore methods to specifically prevent cell-mediated immunity against pig islets. Our group previously demonstrated that the overexpression of either membrane-bound human FasL or human decoy Fas antigen in pig endothelial cells prevented CTL xenocytotoxicity. In this study, we assessed the cytoprotective effects of adenoviral-mediated overexpression of either membrane-bound human FasL or human decoy Fas antigen in pig islets to inhibit CTL xenocytotoxicity. The CTL-mediated killing of pig islets infected with an adenoviral vector carrying either membrane-bound human FasL or human decoy Fas was significantly reduced compares with that of control pig islets transfected with adenoviral vector encoding enhanced green fluorescent protein (EGFP). Moreover, we transfected pig islets with these molecules to confirm their cytoprotective effects in in vivo studies. The significant long-term survival of pig islets expressing these molecules was elicited through days 3 to 5 posttransplantation. Thus, these results demonstrated that the remodeling of either death receptor or death ligand on pig islets by adenoviral gene transfer prevented innate cellular immunity against xeno-islet grafts facilitating long-term xenograft survival.