Clinical xenotransplantion--how close are we?

CONTEXT: Xenotransplantation with pig organs offers a medium-term solution to the shortage of organs available for clinical transplantation. The immunological barriers to xenotransplantation have been, and remain, formidable. In the early 1990s, the identification of Galalpha1,3Gal (Gal) as the main target for human xenoreactive (anti-pig) antibodies and the development of pigs transgenic for a human complement regulatory protein, decay-accelerating factor (hDAF), were major advances. The presence of hDAF on the vascular endothelium of pig organs provided some protection against complement-mediated hyperacute rejection. This protection, however, was short-lived, and, until recently, the longest median time for organ survival that had been achieved (with combinations of biological and pharmacological immunosuppressants) in a series of pig-to-primate organ transplants was under a month. STARTING POINT: Christopher McGregor and colleagues recently reported to the International Society of Heart and Lung Transplantation (J Heart Lung Transplant 2003; 22: S89) that, by combining the use of organs which express hDAF with the administration of a soluble Gal glycoconjugate and other immunosuppressive agents, the survival of pig hearts in baboons can be extended to a median of 76 days. McGregor's work suggests that immunological barriers to xenotransplantation are not insurmountable. WHERE NEXT? The recent generation of pigs that do not express Gal epitopes (alpha1,3-galactosyltransferase gene-knockout pigs) might remove the need both for the expression of hDAF and the administration of a soluble Gal glycoconjugate. The absence of a natural antibody response will allow investigation of the cellular immune response and of any molecular incompatibilities between pig and primate that may be detrimental to graft survival. Furthermore, the absence of a humoral response may open the way for the induction of immunological tolerance (or unresponsiveness in the absence of exogenous immunosuppression) to a transplanted pig organ.