Xenotransplantation: state of the art

Organ transplantation is unfortunately limited by the number of cadaveric human donor organs that become available. Xenotransplantation - the transplantation of organs and tissues between animal species - would supply an unlimited number of organs and offer many other advantages. The leading candidate as a source of organs for xenotransplantation is the pig, as it is anatomically and physiologically similar to man. However, organ transplantation between distantly related species results in hyperacute rejection (HAR) of the transplant, which consists of a violent immune response involving the complement system, unleashed when organs are transplanted between distant relatives, such as pigs and humans. HAR destroys the blood vessels in the transplanted organs and kills them within minutes. Complement attack is due to the antibody-mediated activation of the complement cascade (human anti-pig antibodies have been identified as being directed against Gal-a1-3galactose epitopes on pig vascular endothelium), and this phenomenon is physiologically subjected to negative regulation by a set of species-specific proteins, known as regulators of complement activation (RCA), such as decay accelerating factor (DAF), membrane cofactor protein (MCP) and CD59. If human RCA are expressed by mammalian cells in vitro, the cells are protected against the lysis by human complement. Therefore the incorporation of human RCA into a xenogeneic organ by transgenesis should protect the transplanted organ or tissue from in vivo lysis by human complement. Major efforts are being made to overcome this hyperacute rejection. Methods being investigated include: i. depletion or inhibition of recipient antibodies or complement; ii. development of immunological tolerance to pig organs in the recipient; and iii. development of transgenic pigs that do not express the a-Gal epitope and/or express a human complement inhibiting protein (i.e., DAF). A small number of research teams, including our group, have embarked on programs to produce transgenic pigs for one of the human RCA, in the attempt to produce animals whose organs may be suitable for transplantation into humans.