Xenogeneic Transplantation

The use of solid organ transplantation as a clinical therapy is greatly limited by the lack of availability of donor organs. For this reason, the possibility of transplantation of organs from other mammals, such as pigs, into human recipients has kindled great interest.

A major immunologic barrier to xenogeneic transplantation is the presence of natural antibodies that cause hyperacute rejection. More than 95% of primates have natural IgM antibodies that are reactive with carbohydrate determinants expressed by cells of species that are evolutionarily distant, such as the pig. The majority of human anti-pig natural antibodies are directed at one particular carbohydrate determinant formed by the blood transfusion AND THE abo AND Rh blood group antigens 383

action of a pig a-galactosyltransferase enzyme. This enzyme places an a-linked galactose moiety on the same substrate that in human and other primate cells is fucosyl-ated to form the blood group H antigen. Species combinations that give rise to natural antibodies against each other are said to be discordant. Natural antibodies are rarely produced against carbohydrate determinants of closely related, concordant species, such as humans and chimpanzees. Thus, organs from chimpanzees or other higher primates might theoretically be accepted in humans. However, ethical and logistic concerns have limited such procedures. For reasons of anatomic compatibility, pigs are the preferred xenogeneic species for organ donation to humans.

Natural antibodies against xenografts induce hyper-acute rejection by the same mechanisms as those seen in hyperacute allograft rejection. These mechanisms include the generation of endothelial cell procoagulants and platelet-aggregating substances, coupled with the loss of endothelial anticoagulant mechanisms. However, the consequences of activation of human complement on pig cells are typically more severe than the consequences of activation of complement by natural antibodies on human allogeneic cells, possibly because some of the complement regulatory proteins made by pig cells, such as decay-accelerating factor, are not able to interact with human complement proteins and thus cannot limit the extent of complement-induced injury (see Chapter 12). A strategy for reducing hyperacute rejection in xeno-transplantation is to breed transgenic pigs that cannot express enzymes that synthesize pig antigens or express human proteins that inhibit human complement activation. For example, a-galactosyltransferase knockout pigs and transgenic pigs expressing human complement regulatory proteins have been generated, and transplants of organs from these animals into primates are resistant to hyperacute rejection.

Even when hyperacute rejection is prevented, xeno-grafts are often damaged by a form of acute vascular rejection that occurs within 2 to 3 days of transplantation. This form of rejection has been called delayed xenograft rejection, accelerated acute rejection, or acute vascular rejection and is characterized by intravascular thrombosis and necrosis of vessel walls. The mechanisms of delayed xenograft rejection are incompletely understood; recent findings indicate that there may be incompatibilities between primate platelets and porcine endothelial cells that promote thrombosis independent of antibody-mediated damage.

Xenografts can also be rejected by T cell-mediated immune responses to xenoantigens. The mechanisms of cell-mediated rejection of xenografts are believed to be similar to those that we have described for allograft rejection, and T cell responses to xenoantigens can be as strong as or even stronger than responses to alloantigens.

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