Source Of Xenografts

Many species have been used as sources of tissues and organs for xenotransplantation. Xenografts from sources phylogenetically closer to the recipient would be expected to provoke less immunity and be more physiologically compatible with the recipient. Consistent with that idea, experimental cardiac xenografts from monkeys to baboons have survived greater than a year, and renal xeno-grafts from chimpanzees in humans have survived and functioned up to 9 months (Table 1). However, some biological barriers to xenotransplantation derive from expression of one or very few genes in the donor or recipient. These barriers do not relate directly to overall genetic difference.

The genetic barrier of greatest current interest and importance is the expression of a1,3-galactosyltransferase, a glycosyltransferase that catalyzes synthesis of Gala1-3Gal (Table 3). Gala1-3Gal is a saccharide expressed by lower mammals and New World monkeys but not by humans or Old World monkeys. Humans and Old World monkeys have natural antibodies specific for this saccharide that trigger severe reactions when organs containing Gala1-3Gal are transplanted. Indeed, many of the efforts in

Table 1 Some clinical attempts at xenotransplantation

Year

Donor

Organ

Maximum survival

1906

Pig, goat

Kidney

2 Days

1964

Chimpanzee

Kidney

9 Months

1964

Baboon

Kidney

60 Days

1984

Baboon

Kidney

20 Days

1992

Baboon

Liver

70 Days

genetic engineering and immunosuppression for xeno-transplantation are directed respectively at eradicating expression of the sugar or suppressing immunity directed against it.

Today most efforts in xenotransplantation focus on the pig as a potential source of tissues and organs. The most important reason for favoring the pig is that pigs are available in large numbers. (It is estimated that more than 1 million would be needed for transplants worldwide each year.) Another reason for favoring pigs as a source of xenografts is that pigs can be bred and genetically manipulated, as described later in this article. Still another reason for favoring the pig is that the organs are large enough to fulfill the needs of full-sized humans, and some strains of pigs, such as the mini-pig, may at maturity approximate human size. Finally, the microorganisms harbored by pigs that are potentially infectious for humans are well known, and measures for screening for these organisms are well established.[5] In contrast, some viruses of non-human primates are poorly known and potentially lethal for humans.

Although the experience is limited, the best current evidence suggests that the heart, lung, and kidneys of the pig would function sufficiently to sustain the life of a human. Whether the liver would function sufficiently is a matter of controversy because of the metabolic complexity of that organ and because of the possibility that complex cascades, such as complementing coagulation, could be incompatible between pig and human.

using pigs as a source of xenografts in humans is the possibility that infectious agents might transfer from the graft to the recipient. As indicated above, most infectious agents potentially transmitted from pigs to humans are known, and the means exist to eliminate those agents from potential sources of xenografts. One exception, however, may be the porcine endogenous retrovirus (PERV), which exists in the porcine genome. PERV has been transmitted from porcine cells to the cells of humans and nonhuman primates under a variety of experimental circumstances. Although the subject of much investigation, to date no evidence has emerged that PERV can be transmitted to human cells in vivo as a result of xenotransplantation.1-6-1 This subject will be an active area of investigation until a decisive answer is achieved.

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