The severe shortage of organ donors currently limits the number of transplants performed. As an example, in the United States, 82,149 patients (updated on July 4, 2003) are currently waiting for a life-saving organ and approximately 17 patients on the waiting list die each day (reports from United Network for Organ Sharing). The ultimate goal of our proposal is to solve the problem of this supply-demand disparity by xenotransplantation (xenografts) from pigs, the most suitable donor species for humans. As xenografts are subject to vigorous rejection, the amount of immunosuppressive drugs for overcoming xenograft rejection is likely to destroy the host immune system that the body needs to fight viruses/bacteria and eradicate cancer cells, thus rendering the recipient at a high risk for infections and cancers. It would then be highly desirable to control only the immune responses that are responsible for the rejection while preserving host immunocompetence.
The focus of this project is to understand the mechanisms of xenograft rejection by macrophages. Macrophages, a major component of the immune system, are activated first when the body is exposed to foreign antigens. Normally, macrophages are restrained from activation by the patient’s own tissues because self-tissues express a number of molecules that deliver inhibitory signalling by engaging specific receptors on macrophages. In this proposal, we intend to identify the counterpart molecules of pigs, which are essential to maintain the inactive status of macrophages, but fail to function in humans with respect to inhibiting human macrophage activation. The ultimate aim is to genetically modify pigs to overcome macrophage-mediated rejection. Information obtained from these studies may guide the development of effective strategies for preventing porcine xenograft rejection in patients, so that xenotransplantation from pigs can be used clinically to save the lives of patients who are waiting for a life-saving organ.