Hepatocyte expression of soluble donor MHC class I antigen via gene transfer inhibits multiple aspects of the antidonor immune response in fully sensitized rat transplant recipients

Abstract

Sensitized organ transplant recipients face an increased risk of hyperacute rejection (HAR) due to donor major histocompatibility complex (MHC) class I antigen (Ag) preexposure. We recently reported a novel donor-specific strategy to address this problem, whereby soluble donor MHC class I Ag gene therapy prevented HAR of heart allografts in passively sensitized rats. Here, we tested this same approach in presensitized rat recipients with a fully preactivated humoral and cellular immune response. Our gene therapy method involved liposomal transfection of cultured recipient (Lewis-RT1.A 1) hepatocytes with DNA encoding secretable donor MHC class I Ag, RT1.A a. Control-transfected or RT1.A a-transfected hepatocytes were implanted intrasplenically into Lewis rats presensitized with three skin transplants. Subsequently, antidonor antibody, cytotoxic T lymphocyte (CTL), and helper T lymphocyte (HTL) assays were performed. Additionally, the effectiveness of our gene therapy on the prevention of ACI (RT1 a) heart HAR was evaluated. Results indicated that soluble MHC not only decreased cytotoxic antibody levels, but also suppressed antidonor CTL and HTL responses; furthermore, HAR of heart allografts was prevented in all recipients. Therefore, soluble donor MHC class I gene therapy can inhibit multiple aspects of the primed antidonor immune response in actively presensitized rats. Development of this strategy in presensitized humans could improve organ transplant outcome.