Xenotransplantation from pigs getting closer

Jul 20 2007

Experiments using pigs genetically engineered for compatibility with the human immune system have raised hopes that cross-species transplantation could soon become an option for patients with diabetes and other currently incurable diseases.

However, many scientific hurdles remain before the ultimate goal of inducing long-term tolerance of animal tissues and organs in human recipients, according to a special paper in the July 15 issue of the journal Transplantation, published by Lippincott Williams & Wilkins, a part of Wolters Kluwer Health.

"The potential benefits of successful xenotransplantation to large numbers of patients with very differing clinical conditions remain immense, fully warranting the current efforts being made to work towards its clinical introduction," concludes the article. The lead author is Dr. David Cooper of Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center.

Dr. Cooper and colleagues review progress to date with a strain of pigs genetically engineered in the hope of addressing chronic shortages of organs and tissues for transplantation. The animals lack the gene responsible for "alpha-1,3-galactosyltransferase" (GT)—an enzyme normally present in the pig vascular system. Humans have natural, preformed antibodies to GT, resulting in immediate (acute) rejection of any pig-to-human transplant.

The fact that these genetically engineered "GT-knockout" pigs lack GT removes one obstacle to cross-species transplantation, or xenotransplantation, between pigs and humans. Apart from the possible transplantation of organs such as the kidney or heart, pigs are also viewed as a potentially invaluable source of islet cells—the insulin-producing cells of the pancreas—for use in transplantation as a treatment for type 1 diabetes.

Preliminary studies have reported encouraging results with transplantation of organs from GT-KO pigs into nonhuman primates. Hearts transplanted from GT-KO pigs into baboons have survived for several months, without the need for intensive drug treatment to suppress the recipient animal's immune system.

However, many obstacles remain to be overcome before exploratory studies of xenotransplantation from GT-KO pigs to humans can begin. The transplanted hearts do not show the pattern of acute, overwhelming rejection typical of cross-species transplantation. However, there is evidence of another type of rejection, characterized by blood clots developing in the small blood vessels.

This suggests a possible "coagulation dysregulation" between pigs and primates. New approaches will be needed to address the problem: either improved approaches to immunosuppressant drug therapy or further genetic manipulation of the donor animals. Studies may also explore techniques of inducing immune tolerance between the animal donor and human recipient before the transplantation procedure is done—an approach that is not generally possible in human-to-human transplantation.

The development of GT-KO pigs has been a significant advance toward making xenotransplantation a reality. However, "these organ-source pigs have not proved the 'quantum leap' that had been hoped, and there are clearly other immunologic problems that require resolution before a clinical trial can be initiated," according to Dr. Cooper and colleagues. More research is needed to identify the nature of the human antibodies to GT, and perhaps to further modify the GT-KO pigs to overcome the observed blood clotting problems.

"Advances in these areas might allow the initiation of clinical trials of xenotransplantation, at least for cell or islet transplantation or for the use of a pig organ to 'bridge' a patient until a human organ is obtained," Dr. Cooper and coauthors write. They conclude, "The potential benefits of successful xenotransplantation to large numbers of patients with very differing clinical conditions remain immense, fully warranting the current efforts being made to work towards its clinical introduction."

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