Anti-Gal and Anti-Non Gal Antibody Barriers in Xenotransplantation

The many studies on the immune mechanisms contributing to xenograft rejection have identified two types of antibodies (Abs) that form barriers to transplantation of xenografts into humans: 1. Natural and induced anti-Gal Abs, and 2. Induced anti-non gal Abs. The formidable barrier of anti-Gal Abs seems to have been removed by the generation of 1,3galactosyltransferase (1,3GT) knockout (KO) pigs. However, the second immune barrier of anti-non gal Abs may be even more formidable than that of anti-Gal Abs. The antinon gal Ab barrier was not fully appreciated in the 1990’s when much of the research was focused on overcoming the first barrier of anti-Gal mediated hyperacute rejection of pig xenografts. The anti-non gal Ab barrier still presents a challenge that requires the development of novel immunological treatments which prevent the production of these Abs. It is possible that without overcoming the anti-non gal Ab barrier it may be difficult to progress in clinical xenotransplantation beyond the use of short term bridge xenografts. Both the anti-Gal and anti-non gal barriers have been the focus of many studies in nonprimate mammal and in monkeys. This chapter does not intend to review the vast literature on anti-Gal and anti-non gal immune response in experimental animal models, but aims primarily to describe the information gained in studying anti-Gal and anti-non gal Ab response in humans. Although xenotransplantation is rarely performed in humans, I have had the opportunity of collaborating with several groups that introduced xenogeneic cells or tissues expressing -gal epitopes into humans and study anti-Gal and anti-non gal Ab response in the sera of such patients. I believe that the information gained in these studies may contribute to the understanding of the immune response to -gal epitopes and to xenoantigens that induce the anti-non gal Ab response in humans.