Xenotransplantation: Strategies to Achieve Donor-specific Tolerance and Immune Reconstitution Across Species Barriers Through Mixed Bone Marrow Chimerism.
Background: Allogeneic organ donation will never provide the quantities of organs required for patients with end-stage disease. It is estimated that over 3,000 candidates for a potentially lifesaving sold-organ transplant will die this year while on the waiting list as a result of the donor shortage. A further understanding of the mechanisms of xenoreactivity might make xenotransplantation a viable therapeutic option. This article reviews the benefits of xenotransplantation, including species-specific disease resistance and the potential unlimited supply of donor organs. Methods and Results: Experimental results in rodents have demonstrated that bone marrow stem cells engraft in xenogeneic recipients. Lymphohematopoietic cells arising in a xenogeneic environment undergo normal maturation and negative selection of autoreactive clones. Recipients exhibit donor-specific tolerance to solid-organ and cellular xenografts, yet maintain normal reactivity to third-party antigens. Bone marrow transplantation as a means of developing mixed xenogeneic chimerism and donor-specific tolerance is reviewed. Evidence that baboon cells are resistant to human immunodeficiency virus type 1 and hepatitis B virus is presented, and the rationale for transplantation of baboon hematopoietic stem cells to achieve immune reconstitution in late stage acquired immune deficiency syndrome is discussed. Conclusions: Donor-specific transplantation tolerance induced by mixed xenogeneic chimerism following bone marrow transplantation may provide a means for overcoming barriers to xenotransplantation.
Gammie
JS
Departments of Surgery and Pediatrics, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
Kaufman
CL
Michaels
MG
Ildstad
ST