Xenotransplantation is the transplantation of organs, tissues, or cells between different species (e.g., pig to human). It offers great potential in resolving the inadequate number of available human organs and cells for clinical transplantation. For a number of physiologic and logistic reasons, the pig is being investigated as a source of organs and cells for this purpose. There are several immunologic barriers that need to be overcome; these are in part related to the presence of natural antipig antibodies in humans that develop during infancy. These include hyperacute and acute humoral rejection, as well as the development of a thrombotic microangiopathy in the graft that may be associated with a consumptive coagulopathy in the recipient.

The most successful approach to overcoming these barriers is by genetically engineering the pig to provide it with resistance to the human humoral and cellular immune responses. Organs and cells from pigs that (1) do not express the important antigen Galα1,3Ga l (the major target for human antipig antibodies) and/or (2) express a human complement-regulatory protein (e.g., CD46, CD55) do not exhibit hyperacute rejection. Pigs that express a human antithrombotic gene (e.g., thrombomodulin, endothelial protein C receptor, or CD39) are also now available. It is hoped that a combination of these genetic modifications will offer protection against the development of thrombotic microangiopathy. Most progress has been made with pig islet transplantation in immunosuppressed, diabetic nonhuman primates, where normoglycemia has been maintained for periods in excess of 1 year without the need for exogenous insulin.

The physiologic, safety, and regulatory aspects of xenotransplantation are briefly reviewed. As the potential benefits of xenotransplantation are so considerable, extending to many conditions for which transplantation is not currently undertaken, it is well worth persisting in attempts to overcome the immunologic barriers that remain.