Department of Surgery; Division of Transplantation
Keith Reemtsma Lecture: Xenotransplantation - The Past and the Future
Mark A. Hardy1.
1Transplantation Program, New York, NY, United States
Since the first renal transplant between twins in 1954 the development of new immunosuppressive agents expanded the field to include transplantation of almost all organs and tissues. Keith Reemtsma, my chief and one of my mentors foresaw in 1964 that soon there may be an unachievable need for donor organs. He focused his, and the interests of others, on xenotransplantation and confirmed its feasibility by performing the first successful xenotransplant of a chimpanzee kidney to man which lasted more than 9 months. When it was soon realized that, in addition to the enormous immunologic barriers, various species of NHP are protected and may be the bearers of deadly zoonotic viruses transmissible to humans, it became clear that a new species must be selected for xenotransplantation. The swine was selected because it has many progenies (6-8), fast turnover (144 day gestation), comes in variety of sizes, from infant size to monster size and shares with humans the physiology of many of its organs. It is also bacteriologically very clean and most importantly can be genetically modified.
To make xenograft prolonged survival a safe reality one of the first questions that needs to be answered is what are the mechanisms of xenograft rejection that could be manipulated pharmacologically in the recipient or genetically in the donor. These will be briefly discussed and include: 1) direct presentation of donor antigens to recipient T cells by donor antigen presenting cells (APC's) whose transplantation peptide ligands differ significantly from the recipient's T-cell receptors; 2) indirect pathway of xenograft derived peptide recognition by recipient APC's may be more important than direct recognition and may be perhaps more easily manipulated, but may also be associated with highly destructive increase in antibody responses to the donor xenograft; 3) the critical interaction of T cells with the innate immune response of the host to produce an array of cytokines that activate macrophages and killer cells, both of which are critical in xenograft rejection; 4) anti-xenograft antibody responses against porcine antigens that, although primarily directed against Gal antigens, have some cross-reactivity with human antigens most probably related to endothelial cell antigens that are difficult to identify as dominant and therefore difficult to target for genetic deletion; 5) since the major damage in xenotransplantation is related to inflammation, thrombosis, platelet aggregation and coagulation, the use of transgenic pigs with increased expression of human complement inhibitory proteins such hDAF (decay accelerator factor), CD59 (membrane attack complex inhibitor) or hMCP (human membrane cofactor protein) may ameliorate the vascular component of rejection; 6) other targets slated for immuno-manipulation are B-cells and plasma cells which so far have resisted attempts at depletion with anti-CD 20 (mixed response for B-cells) or for plasma cells with Bortezomib; 7) NK cells interfere with xenotransplantation both directly and through antibody-dependent cell-mediated cytotoxicity and this can be inhibited by using human class I HLA which has now led to production of transgenic human HLA-E expressing swine whose cells are not destroyed by human NK cells. These are only some of the biologic problems that are being addressed in many laboratories around the world.
Other major approaches that may offer more rapid and successful translational results are to adopt and develop various recently described tolerance models. Initial transplantation of the donor thymus suggests that it is possible to "educate" the recipient cells in the "thymic school" to subsequently recognize the donor organ as "self". In line with this it may be possible to use only recipient professional APC's primed with donor xenogeneic antigens to accomplish a similar education using the recipient's thymus as the "school" for the recipient's T cells. Finally using the mixed chimerism model of allografting approach and applying it to xenotransplantation is also a possibility that has not been sufficiently explored.
13:30 - 15:00
|Special Lectures||Keith Reemtsma Lecture: Xenotransplantation - The Past and the Future||Plenary Room 1|