The lack of adequate human organs has created a strong interest in the use of non-human organs for clinical transplantation. However, vigorous immune responses prevent the successful transplantation of non-human organs into humans. In particular, antibodies against a single carbohydrate epitope, Gal-a1,3-Gal, appear to be the major cause of xenograft injury and rejection in the pig-to-primate model. This project focuses on understanding the mechanisms by which anti-Gal antibodies cause graft rejection, and on the definition of novel approaches to control them. We have generated a series of anti-Gal IgG antibodies, and will transfuse these antibodies into mice receiving a rat heart xenotransplant. We will define the immunological and biochemical events that are triggered by anti-Gal antibodies that lead to graft rejection, and attempt to inhibit the rejection by inhibition of specific immunological functions. In addition, we will explore a novel approach of inducing resistance to antibody-mediated injury by pre-treating grafts with low doses of anti-Gal antibodies. We will define the immunological and biochemical events that mediate this resistant state. These studies are directly relevant to the long-term goal of inducing long-term survival of non-human grafts in humans.