Spectrum of the early xenograft response: from hyperacute rejection to delayed xenograft injury.

Hyperacute xenograft rejection is a well-defined barrier to clinical pig-to-human xenotransplantation, and intense research in this area has identified potential solutions. In contrast, the next phase of xenograft injury, which can occur days to weeks later, has introduced a new series of immunological and nonimmunological barriers with complex mechanisms. This review addresses mechanisms of the immediate and delayed xenograft response with a focus on the relevant components. The key individual elements include carbohydrate antigens and natural antibodies to these epitopes, the role of the complement and coagulation systems, and the inflammatory cellular xenograft response that is predominantly mediated by the innate immune system. The vascular elements are central targets in this process, and the role of the endothelial cell is discussed. Important recent developments in xenotransplantation include the production of genetically modified pigs (deficient in alphaGal transferase and pigs transgenic for complement regulators) and a progressive understanding of xenograft-induced thrombotic microangiopathy, which threatens the long-term survival of transplanted pig organs and tissue. However, a clear standardized classification of the immunopathological mechanisms involved is essential. Further studies into the delayed xenograft response, using primates, are required before the routine use of pig organs for clinical transplantation.