Fig. 15.50 Preexisting antibody against donor graft antigens can cause hyperacute graft rejection. Prior to transplantation, some recipients have made antibodies that react with donor ABO or HLA class I antigens. When the donor organ is grafted into such a recipient, these antibodies bind to the vascular endothelium in the graft, initiating the complement and clotting cascades. Blood vessels in the graft become obstructed by clots and leak, causing hemorrhage of blood into the graft. The graft becomes engorged, turns purple from the presence of deoxygenated blood, and dies.
15-33 Antibodies that react with endothelium cause hyperacute graft rejection.
Antibody responses are an important potential cause of graft rejection. Preexisting alloantibodies against blood group antigens and polymorphic MHC antigens can cause rapid rejection of transplanted organs in a complement-dependent reaction that can occur within minutes of transplantation. This type of reaction is known as hyperacute graft rejection. Most grafts that are transplanted routinely in clinical medicine are vascularized organ grafts linked directly to the recipient’s circulation. In some cases the recipient may have preexisting antibodies against donor graft antigens. Antibodies of the ABO type can bind to all tissues, not just red blood cells. In addition, antibodies against other antigens can be produced in response to a previous transplant or a blood transfusion. All such preexisting antibodies can cause rapid rejection of vascularized grafts because they react with antigens on the vascular endothelial cells of the graft and initiate the complement and blood clotting cascades. The vessels of the graft become blocked, or thrombosed, causing its rapid destruction. Such grafts become engorged and purple-colored from hemorrhaged blood, which becomes deoxygenated (Fig. 15.50). This problem can be avoided by ABO-matching as well as cross-matching donor and recipient. Cross-matching involves determining whether the recipient has antibodies that react with the white blood cells of the donor. Antibodies of this type, when found, have hitherto been considered a serious contraindication to transplantation of most solid organs, because in the absence of any treatment they lead to near-certain hyperacute rejection.
For reasons that are incompletely understood, some transplanted organs, particularly the liver, are less susceptible to this type of injury, and can be transplanted despite ABO incompatibilities. In addition, the presence of donor-specific MHC alloantibodies and a positive cross-match are no longer considered an absolute contraindication for transplantation, as treatment with intravenous immunoglobulin has been successful in a proportion of patients in whom antibodies against the donor tissue were already present.
A similar problem prevents routine use of animal organs—xenografts—in transplantation. If xenografts could be used, it would circumvent a limitation in organ replacement therapy: the shortage of donor organs. Pigs have been suggested as a source of organs for xenografting, but most humans have antibodies that react with a ubiquitous cell-surface carbohydrate antigen (α-Gal) of other mammalian species, including pigs. When pig xenografts are placed in humans, these antibodies trigger hyperacute rejection by binding graft endothelial cells and initiating complement and clotting cascades. The problem of hyperacute rejection is exacerbated in xenografts because complement-regulatory proteins such as CD59, DAF (CD55), and MCP (CD46) (see Section 2-16) work less efficiently across a species barrier. A recent step toward xenotransplantation has been the development of transgenic pigs expressing human DAF as well as pigs that lack α-Gal. These approaches might one day reduce or eliminate hyperacute rejection in xenotransplantation.