Hurdles To Xenotransplantation

The main hurdle to xenotransplantation is the immune reaction of the recipient against the graft (see Ref. 2 for a review). Much of the immune response is directed against Gala1-3Gal. Another problem with the pig is that the proteins of that species are so different from the proteins of humans that they too provoke strong immune reactions, thus increasing the challenge of developing an effective approach to immunosuppression. Still another hurdle to

Table 2 Technologies for organ replacement

Technology

Potential applications

Allotransplantation

Heart, lung, liver, kidney, pancreas

Implantable devices

Heart, pancreas

Cell transplantation

Heart, liver, pancreas

Stem cells

Heart, liver, pancreas

Tissue engineering

Liver

Organogenesis

Kidney, lung

Transplantation

Heart, lung, liver, kidney, pancreas

Table 3 Phylogeny of expression of Galal 3Gal

Functional

AntiGala1-3Gal

Species

a1,3GT

Gala1-3Gal

antibodies

Mouse

+

+

Pig

+

+

-

New World

+

+

-

monkey

Baboon

-

-

+

Human

-

-

+

Recent efforts have focused on eliminating a1,-3-ga-lactosyltransferase by gene targeting. Gene targeting in pigs was recently made feasible by advances in reproductive cloning. At the time of this writing, several groups have targeted one allele and one group has generated pigs fully deficient in a1,3-galactosyltransferase. Though these advances have stimulated excitement, preliminary work in several laboratories suggests that targeting this gene will not fully eradicate immune reactions against pig cells.

Genetic engineering may be applied in other ways in xenotransplantation. One potential application is to eliminate endogenous viruses, such as PERV, should these viruses be found to cause human pathology. Another potential application of genetic engineering is to eliminate or replace porcine genes that pose a physiologic hurdle to the success of transplantation or toxicity to the recipient. For example, porcine coagulation factors may be incompatible with human control proteins, and hence genes for human coagulation factors might replace the genes for these factors in pigs. Still another application might be to introduce genes whose expression could provide therapeutic benefit for the recipient of a transplant. For example, human genes might be expressed in a pig, potentially under specific regulation. The genes would then be expressed in the human individual who receives a transplant from the pig. In this way, a genetically engineered pig cell might be used as a vehicle for expressing genes of therapeutic interest, such as enzymes, growth factors, antitumor agents, etc.

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