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Organ Replacement Technologies: A New Frontier: Xenotransplantation Must Overcome Rejection


Xenotransplantation Must Overcome Rejection

"Why can't we just go to the barnyard and xenotransplant a heart?" asked David J. G. White, PhD,[18] from the University of Western Ontario. When a transplanted pig heart begins pumping human blood, hyperacute rejection caused by human alpha-gal antibodies to pig cells begins immediately. Next comes acute vascular rejection, characterized by thrombosis, hemorrhage, edema, and infiltration of neutrophils and mononuclear cells.

In addition to immunosuppressive therapy, the best solution to xenotransplant rejection may be transgenic pigs, created by injecting relevant human genes into a fertilized pig ovum. Critical gene targets include alpha-gal and species-specific complement regulators, such as human decay accelerating factor (DAF).

Survival of transgenic pig hearts transplanted into baboons is better than survival of unmodified pig hearts, according to Dr. White. Despite immunosuppressant treatment, however, acute vascular rejection limits survival. The culprit may be anti-DAF antibodies, found in 8 of 11 baboons studied. The most promising solution appears to be using the gal-knockout pig as a donor source, combined with complement regulator proteins. "The ability to alter the donor species by genetic engineering provides great opportunities for the future of transplantation," Dr. White concluded.

Lung Xenotransplantation

As pulmonary transplantation has become more effective, the shortage of suitable human donor lungs is even more critical. "For every 3 lung transplants we do in the United States, 2 patients die while on the waiting list," said R. Duane Davis, MD,[19] of Duke University Medical Center in Durham, North Carolina. Dr. Davis is investigating swine lung xenotransplantation, which may be more feasible than xenotransplantation of heart or kidney. Lung grafts survive longer and present less of an immunologic challenge, as evidenced by relatively little IgM and complement deposition. Unfortunately, in pig-to-primate transplantation, lung graft survival is currently measured in only minutes-to-hours. Strategies to decrease rejection may include depletion of xenoreactive antibody and complement and use of transgenic swine.

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