490 PART I The Immune System in Health and Disease CLINICAL FOCUS cells may be blunted if human DAF is pre- sent on the targeted cell to dampen the Is There a clinical future complement reaction. The lack of human for Xenotransplantation DAF is remedied by producing transgenic pigs that express this protein. Addition of human complement regulators to the pig represents a universal solution, in that any nless organ (and those of most mammals other than cell that might become a in the humans and the highest nonhuman pri- transplant will resist complement lysi donations increase drastically, most of mates)of a disaccharide antigen( galacto An additional concern is that pig en the 72,000 U.S. patients on the waiting 1.3-a-galactose)that is not present on dogenous retroviruses will be introduced list for a transplant will not receive one. human cells. The presence of this antigen into humans as a result of xenotransplan- The majority(47,000)need a kidney, but on many microorganisms means that tation and cause disease. Opponents of last year only 12, 500 kidneys were trans- nearly everyone has been exposed to it xenotransplantation raise the specter of planted A solution to this shortfall is to and has formed antibodies against it. the another Hiv-type epidemic resulting from utilize animal organs. Some argue that preexisting antibodies react with pig cells, human infection by a new animal retro- xenografts bring the risk of introducing which are then lysed rapidly by comple- virus. Recently, a Boston-based company pathogenic retroviruses into the human ment. The absence of human regulators announced development of pigs free population; others object based on ethi- of complement activity on the pig cells, in- endogenous pig retroviruses, reducing cal grounds relating to animal rights. cluding human decay-accelerating factor the possibility of this bleak outcome Nevertheless, the use of pigs to supply ( DAF)and human membrane-cofactor Will we see the use of pig kidneys in organs for humans is under serious con- protein(MCP), intensifies the comple- humans in the near future? The increasing sideration. Pigs breed rapidly, have large ment lysis cycle. (See Chapter 13 for de- demand for organs is driving the com- litters, can be housed in pathogen-free scriptions of DAF and MCP) mercial development of colonies of pigs environments and share considerable How can this major obstacle be cir- suitable to become organ donors. While anatomic and physiologic similarity with cumvented? Being tested are strategies kidneys are the most sought-after organ at humans. In fact, pigs have served as for absorbing the antibodies from the present, other organs and cells from the donors of cardiac valves for humans for circulation on solid supports, and using specially bred and engineered animals will years. Primates are more closely related soluble gal-gal disaccharides to block find use if they are proven to be safe and to humans than pigs are, but the avail- antibody reactions. a more elegant solu- effective. A statement from the American ability of large primates as transplant tion involves genetically engineering pigs Society of Transplantation and the Ameri- donors is, and will continue to be, ex to knock out the gene for the enzyme can Society of Transplant Surgeons er remely limited that synthesizes galactosyl-1, 3-ae-galactose. dorses the use of xenotransplants if cer Balancing the advantages of pig do- Solving the immediate rejection reaction tain conditions are met(Xenotransplanta nors are serious difficulites. For example, by interfering with the specific reaction tion 7: 235). These include the demonstra- if a pig kidney were implanted into a hu- against this antigen may not prevent all tion of feasibility in a nonhuman primate man by techniques standard for human antibody-mediated rejection. Certainly other model, proven benefit to the patient, and transplants, it would likely fail in a rapid antigenic differences to which human re- lack of infectious-disease risk. Barriers re- and dramatic fashion due to hyperacute cipients have antibodies will be present main to the clinical use of xenotrans- rejection. This antibody-mediated rejec- in some if not all donor/recipient pairs. plants, but serious efforts are in motion to tion is due to the presence on the pig cells However, any antibody attack on the pig overcome them progress has been made in long-term survival. The use of im- munosuppressive drugs, which are described below, greatly General In immunosuppressive increases the short-term survival of the transplant, but chronic Therapy rejection is not prevented in most cases. Data for rejection of kidney transplants since 1975 indicates an increase from 40% Allogeneic transplantation requires some degree of immu to over 80% in one-year survival of grafts. However, in the nosuppression if the transplant is to survive. Most of the same period long-term survival has risen only slightly; as in immunosuppressive treatments that have been developed 1975, about 50% of transplanted kidneys are still functioning have the disadvantage of being nonspecific; that is, they at 10 years after transplant. Chronic rejection reactions are dif- result in generalized immunosuppression of responses to all ficult to manage with immunosuppressive drugs and may antigens, not just those of the allograft, which places the necessitate another transplantation. recipient at increased risk of infection. In addition, manyprogress has been made in long-term survival. The use of im￾munosuppressive drugs, which are described below, greatly increases the short-term survival of the transplant, but chronic rejection is not prevented in most cases. Data for rejection of kidney transplants since 1975 indicates an increase from 40% to over 80% in one-year survival of grafts. However, in the same period long-term survival has risen only slightly; as in 1975, about 50% of transplanted kidneys are still functioning at 10 years after transplant. Chronic rejection reactions are dif￾ficult to manage with immunosuppressive drugs and may necessitate another transplantation. General Immunosuppressive Therapy Allogeneic transplantation requires some degree of immu￾nosuppression if the transplant is to survive. Most of the immunosuppressive treatments that have been developed have the disadvantage of being nonspecific; that is, they result in generalized immunosuppression of responses to all antigens, not just those of the allograft, which places the recipient at increased risk of infection. In addition, many 490 PART IV The Immune System in Health and Disease (and those of most mammals other than humans and the highest nonhuman pri￾mates) of a disaccharide antigen (galacto￾syl-1,3--galactose) that is not present on human cells. The presence of this antigen on many microorganisms means that nearly everyone has been exposed to it and has formed antibodies against it. The preexisting antibodies react with pig cells, which are then lysed rapidly by comple￾ment. The absence of human regulators of complement activity on the pig cells, in￾cluding human decay-accelerating factor (DAF) and human membrane-cofactor protein (MCP), intensifies the comple￾ment lysis cycle. (See Chapter 13 for de￾scriptions of DAF and MCP.) How can this major obstacle be cir￾cumvented? Being tested are strategies for absorbing the antibodies from the circulation on solid supports, and using soluble gal-gal disaccharides to block antibody reactions. A more elegant solu￾tion involves genetically engineering pigs to knock out the gene for the enzyme that synthesizes galactosyl-1,3--galactose. Solving the immediate rejection reaction by interfering with the specific reaction against this antigen may not prevent all antibody-mediated rejection. Certainly other antigenic differences to which human re￾cipients have antibodies will be present in some if not all donor/recipient pairs. However, any antibody attack on the pig cells may be blunted if human DAF is pre￾sent on the targeted cell to dampen the complement reaction. The lack of human DAF is remedied by producing transgenic pigs that express this protein. Addition of human complement regulators to the pig represents a universal solution, in that any cell that might become a target in the transplant will resist complement lysis. An additional concern is that pig en￾dogenous retroviruses will be introduced into humans as a result of xenotransplan￾tation and cause disease. Opponents of xenotransplantation raise the specter of another HIV-type epidemic resulting from human infection by a new animal retro￾virus. Recently, a Boston-based company announced development of pigs free of endogenous pig retroviruses, reducing the possibility of this bleak outcome. Will we see the use of pig kidneys in humans in the near future? The increasing demand for organs is driving the com￾mercial development of colonies of pigs suitable to become organ donors. While kidneys are the most sought-after organ at present, other organs and cells from the specially bred and engineered animals will find use if they are proven to be safe and effective. A statement from the American Society of Transplantation and the Ameri￾can Society of Transplant Surgeons en￾dorses the use of xenotransplants if cer￾tain conditions are met (Xenotransplanta￾tion 7:235). These include the demonstra￾tion of feasibility in a nonhuman primate model, proven benefit to the patient, and lack of infectious-disease risk. Barriers re￾main to the clinical use of xenotrans￾plants, but serious efforts are in motion to overcome them. Unless organ donations increase drastically, most of the 72,000 U.S. patients on the waiting list for a transplant will not receive one. The majority (47,000) need a kidney, but last year only 12,500 kidneys were trans￾planted. A solution to this shortfall is to utilize animal organs. Some argue that xenografts bring the risk of introducing pathogenic retroviruses into the human population; others object based on ethi￾cal grounds relating to animal rights. Nevertheless, the use of pigs to supply organs for humans is under serious con￾sideration. Pigs breed rapidly, have large litters, can be housed in pathogen-free environments, and share considerable anatomic and physiologic similarity with humans. In fact, pigs have served as donors of cardiac valves for humans for years. Primates are more closely related to humans than pigs are, but the avail￾ability of large primates as transplant donors is, and will continue to be, ex￾tremely limited. Balancing the advantages of pig do￾nors are serious difficulites. For example, if a pig kidney were implanted into a hu￾man by techniques standard for human transplants, it would likely fail in a rapid and dramatic fashion due to hyperacute rejection. This antibody-mediated rejec￾tion is due to the presence on the pig cells CLINICAL FOCUS Is There a Clinical Future for Xenotransplantation?