You are in: eMedicine Specialties > Pediatrics: Surgery > Transplantation XenotransplantationArticle Last Updated: Jul 10, 2006AUTHOR AND EDITOR INFORMATIONSection 1 of 8
  Author: William Edward Beschorner, MD, Adjunct Professor, Department of Surgery, Division of Transplantation, University of Nebraska Medical Center; President, Chief Scientific Officer, Ximerex, Inc William E Beschorner is a member of the following medical societies: Transplantation Society and United States and Canadian Academy of Pathology Editors: Richard G Ohye, MD, Director, Pediatric Cardiac Transplantation, Fellowship Program Director, Pediatric Cardiac Surgery, Assistant Professor, Department of Surgery, Section of Cardiac Surgery, University of Michigan Medical Center; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Brian F Gilchrist, MD, Chief, Division of Pediatric Surgery, Tufts-New England Medical Center; Associate Professor, Department of Surgery, Tufts University School of Medicine; Ron Shapiro, MD, Professor of Surgery, University of Pittsburgh; Director, Kidney, Pancreas, and Islet Transplantation, Thomas E Starzl Transplantation Institute, University of Pittsburgh Medical Center; Stuart M Greenstein, MD, Professor of Surgery, Albert Einstein College of Medicine; Consulting Surgeon, Department of Surgery, Division of Transplantation, Montefiore Medical Center Author and Editor Disclosure Synonyms and related keywords: xenotransplantation, diabetes, kidney, heart, lung, liver, transplant, regenerative medicine, immunology, infectious disease, immune tolerance, accommodation. INTRODUCTIONSection 2 of 8
  Organ transplantation has been called a victim of its own success. Although transplanted human organs can replace failed organs and make patients with diabetes insulin free, the severe shortage of human donors means that fewer than 1 in 20 patients who need a transplant receive it. To illustrate the dilemma, consider heart transplants. Heart transplant candidates who are designated on the waiting list as 1A priority (urgent) have a life expectancy of less than a week. If they are fortunate enough to receive a new heart, they typically have than 10 additional years of active life. In 2005, fewer than 2000 heart transplantations were performed in the United States. The Organ Procurement and Transplantation Network/United Network of Organ Sharing (OPTN/UNOS) waiting list has registered more there 3000 heart transplant candidates. However, even this list barely addresses the true need as these it records only candidates of highest priority. The International Heart and Lung Transplant Society has estimated that more than 50,000 Americans many benefit annually from heart transplants if the donors were available. For the primary organs and tissues, 25,953 organ and tissue transplants were performed in the United States in 2005, excluding corneal transplants. At present, 91,350 Americans are on the OPTN/UNOS waiting list. As with heart transplants, the waiting list for organ and tissue transplants underestimates the true need. For hearts, kidneys, livers, and pancreatic islets, an estimated 500,000 transplants could be performed annually in the United States. In other words, 1.3 million transplants could be performed annually in the developed world if the organs were available. Xenotransplantation, or transplanting organs and tissues from a different species, has generated considerable interest as a potential solution to the great unmet need. Also great is interest in stem-cell technology and tissue engineering as potential solutions to the organ shortage. Pigs are considered the optimal source of xenotransplant organs. Many pig organs are similar to their human counterparts in size, anatomy, and physiology. Numerous pigs can be produced quickly under standardized, clean conditions. In addition, pigs can be readily modified, as their genes can be added or removed. Moreover, human cells can be grown in the pig. Contrary to common belief, pig organs have several potential advantages over organs derived from brain-dead human donors. With human organs, little can be done before the donor is declared brain dead. Then, the organs are procured in an emergency manner and immediately transported to the medical center where the transplantation is being performed. The transplantation is also performed with little warning. The transplant organ may come from a suboptimal donor with advanced age, chronic medical conditions, undetected infectious agents, or malignant cells. By contrast, a donor pig can be raised under controlled conditions specifically for use as an organ donor. Potential pathogens can be eliminated from its herd. The donor pig can be extensively analyzed. Organs are then procured from young, robust donors. Procurement and transplantation can be performed on a scheduled, elective basis. Xenografts may provide medical advantages as well. They would be resistant to many human pathogens that are specific for human tissues, such as HIV, hepatitis, and human cytomegalovirus (CMV). Tumors, such as melanoma, have been transferred to the recipient through human allografts. Pigs free of potential pathogens can be produced. Xenografts may be resistant to autoimmune reactions, such as the autoimmune destruction of beta cells with type 1 diabetes. Despite these advantages, few xenotransplants have been successfully performed in experimental models and none in the clinical arena. Three main reasons are offered. First, the primary obstacle to xenotransplantation is severe rejection involving many antigenic disparities between humans and pigs that elicit several mechanisms of immune rejection. Current opinion is that severe immunosuppression would be required to prevent rejection and this would subject the recipient to a high risk of infection and toxicity. Second, the perceived need for increased immunosuppression leads to concern about infectious agents from the pig, including exogenous viruses, such as circoviruses and hepatitis E, and endogenous viruses, such as porcine endogenous retrovirus (PERV), which may lead to novel infectious diseases in man (xenozoonoses). Third, for some tissues such as liver, the physiologic function of the pig organ is insufficiently close to the human to provide long-term support. A major goal is to achieve prolonged acceptance of pig xenografts with reduced immunosuppression, equivalent to or less than the level of immunosuppression used for human allografts. Because human organs must of necessity be reserved for the sickest patients, a defined level of risk and complications is justifiable if the recipient's life expectancy is threatened. However, if an unlimited supply of donor organs were available to all, and if the morbidity associated with the procedure is minimized, many recipients could be given transplants before the critical stage in their disease. This approach would reduce the burden on the healthcare system. The acceptable level of risk and the complications for this larger group would be less than they for transplant recipients now. If numerous transplants are to be performed annually, attention must also be paid to logistical issues. For example, does the modification of the pig substantially interfere with the size of the litter or other aspects of breeding? If special clean pigs are required, how long would it take to expand the herd to meet the projected need? In view of the potential advantages and the progress made to date, a greater effort than what is currently committed is justified for developing xenotransplantation. Compared with other forms of regenerative medicine, xenotransplantation is closer to clinical reality and more cost-effective. XENOGRAFT REJECTIONSection 3 of 8
The dominant obstacle to successful xenotransplantation is xenograft rejection, which is more vigorous and complex than allograft rejection and more difficult to prevent and reverse. With allotransplants, few antigen disparities are involved, and they principally human leukocyte antigens (HLAs) or histocompatibility antigens. These disparities can be minimized with tissue typing and matching. The major immune response is cellular rejection. In contrast, pig tissues express several antigens that cannot be matched to human recipients, and these elicit multiple reactions, not only through the adaptive immune system but also through the innate immune system. Strategies effective with allografts would not be effective with xenografts. Moreover, the rejection barrier of vascular xenografts, such as hearts, kidneys, livers, and lungs, is greater than that for cellular grafts, such as islets, hepatocytes, and neural tissue. With vascular grafts, injury to the endothelial cells lining the vessels leads to thrombosis, hemorrhage, and prompt loss of the graft because of the vulnerability of the endothelial cells that line the blood vessels, which become activated. Xenograft rejection includes at least 3 processes, namely, hyperacute rejection, acute vascular rejection, and the instant blood-mediated inflammatory reaction (IBMIR). The major antigen, or epitope, on the vascular endothelium that the human immune system attacks is alpha-1,3-galactose (alpha-Gal). Alpha-Gal is expressed on many tissues, especially endothelial cells. Humans and Old-World primates lack this particular oligosaccharide and, therefore, have preformed, natura' antibodies to the alpha-Gal epitope. These antibodies bind to the vascular endothelium and fix complement, leading to lysis and apoptosis of the vascular endothelial cells. Hyperacute rejection may occur within minutes or hours. Pigs express the carbohydrate epitope Gal alpha 1-3 Gal beta 1-4 GlcNAc-R on their cell surfaces. Humans and primates have naturally formed xenoantibodies to this antigen, termed anti-Gal. The interaction of alpha-Gal and anti-Gal antibodies, which are predominantly of the immunoglobulin M and immunoglobulin G subclasses, results in complement-mediated destruction of cells and hyperacute rejection of xenotransplanted organs. Transgenic knock-out pigs, in which the galactosyl transferase responsible for alpha-Gal synthesis is deleted (GalT-KO), have been generated. Pigs homozygous for this deletion do not express alpha-Gal antigens. With these animals, hyperacute rejection is greatly reduced or eliminated. Besides alpha-Gal, primate recipients and donor pigs have other antigenic differences. Hyperacute rejection is generally not observed in pig-to-nonhuman primate transplantations with GalT-KO donor pigs; however, in most studies, inhibition of complement could have blocked the reaction. Cytotoxic antibodies to non-galactose antigens are observed before transplantation. With lungs xenografts, hyperacute rejection is delayed but still observed with GalT-KO pigs. The contribution of antibodies against non-galactose antigens toward hyperacute rejection has not been excluded. Hyperacute rejection can be prevented by removing preformed anti-pig antibodies, by removing antigens, by inhibiting complement, or by accommodating tissue. However, the xenograft is not yet out of danger. Indeed, acute vascular rejection presents an even greater challenge than hyperacute rejection. Endothelial cells are injured by means of several mechanisms, including cytotoxic T cells, innate immunity, and complement-dependent cytotoxicity from induced antibodies. Acute xenograft rejection represents a reaction against both alpha-Gal and non-galactose antigens. Acute rejection with GalT-KO pigs is associated with disordered coagulopathy. The pathology has been described as thrombotic microangiopathy. However, the primary event still appears to be endothelial-cell injury. GalT-KO transgenic pigs have not provided an overall survival advantage over wild-type pigs regarding acute rejection (Chen, 2005). In addition to natural antibodies to alpha-Gal, vascular endothelial cells can be injured by means of several mechanisms, including cytotoxic T cells, natural killer (NK) cells, and antibodies produced de novo after transplantation. The immunosuppression required to block all of these reactions substantially exceeds that required for the prevention of allograft rejection. Cellular xenografts, such as porcine hepatocytes, neural tissue, islets, and islet-cell clusters differ from vascular grafts. Cells of the endocrine pancreas express little or no alpha-Gal, and are less susceptible to hyperacute rejection. IBMIR, an innate immune response that depends on release of tissue factor and binding of complement, may destroy islet-cell mass by means of thrombosis. Acute rejection is principally cellular rejection and induced antibody-mediated rejection. Prolonged engraftment of porcine islets in cynomolgus monkeys was achieved by using wild-type pigs rather than GalT-KO pigs in combination with T-cell suppression. Prolonged insulin-free survival was achieved in diabetic, cynomolgus macaques with transplanted pig islets. The donor pigs were not genetically modified. Rejection was prevented with antibodies to CD25 and CD154, FTY720 (or tacrolimus), everolimus, and leflunomide. Of note, it was not necessary to eliminate antibodies to alpha-Gal or to use pigs modified to eliminate the alpha-Gal antigen. By using islet-cell clusters from 1- to 2-day-old pigs and immunosuppression, prolonged insulin-free survival was achieved in diabetic rhesus macaques. In addition, preformed antibodies to alpha-Gal did not prevent engraftment and function. The induction immunosuppression included antibodies to CD25 and CD154. Maintenance immunosuppression included the use of belatacept and sirolimus or mycophenolate. Prolonged function of vascularized pig xenografts in nonhuman primates is possible if rejection is prevented. Heterotopic pig-heart xenografts have survived for up to 6 months in baboons. The donor pigs were transgenic, expressing the CD46 human complement inhibitor. The baboons received anti-CD20 (Rituximab), antithymocyte globulin (rabbit) (Thymoglobulin) for induction, splenectomy, removal of anti-Gal antibodies, and tacrolimus, sirolimus, and steroids. Genetically engineered pigs expressing CD59, decay accelerating factor (DAF), and membrane cofactor protein (MCP) have been produced, and the expression of these proteins affords some protection against hyperacute rejection. These complement regulatory proteins do mitigate the effects of hyperacute rejection in experimental models. However, these experiences illustrate how the strategy used with allografts (ie, tissue matching and selective immunosuppression) will succeed with xenografts only if the immune system is compromised to an unacceptable level. Therefore, the challenge of xenotransplantation is to prevent xenograft rejection without severely suppressing the recipient's immune competence. Two processes that promote engraftment without the need for immunosuppression include specific immune tolerance and tissue accommodation. A comprehensive approach that resolves multiple antigen disparities and immune responses without severely compromising the recipient's ability to fight infection is needed. Immune tolerance to self is maintained centrally by means of clonal deletion of self-reactive lymphocytes in the thymus, and peripherally by suppressor or regulatory cells that block self-reactive lymphocytes that escape thymic censure. Specific immune tolerance is difficult to achieve in adult recipients. One approach is to induce mixed hemopoietic chimerism, eg, with pig bone marrow transplanted into primates. This can succeed only if the recipient is subjected to a period of severe immunodeficiency. Furthermore, tolerance induced in this way is limited to antigens expressed on hematopoietic cells. In an ideal world, the regulatory cells would lead to specific inhibition of both adaptive and innate immunity, protecting the xenograft but leaving the recipient sufficiently immunocompetent to defend against pathogens. Previous work with pigs that were chimeric with human lymphocytes demonstrated that the chimeric lymphocytes specifically inhibited the human versus a pig mixed lymphocyte reaction. Accommodation is the term applied to the phenomenon whereby cells, principally vascular endothelial cells, adapt to resist injury by means of complement. It is typically seen in allograft recipients with antigraft antibodies, as with an AB mismatch. If rejection can be prevented for 2 weeks or longer, as with plasmapheresis, the graft becomes resistant to injury even in the presence of antigraft antibodies. Several protective proteins, such as heme oxygenase-1, protein inhibitor of apoptosis, and A20, are induced. These protect the cells from apoptosis. The protection is antigen nonspecific, providing protection to several antibodies. Other new technologies are being actively explored to reduce the immunosuppression required for prolonged xenograft function. The need for immunosuppression might be reduced by reducing the overall antigenicity of the xenograft. Fetal pig tissues have a reduced density of antigens. These tissues could be transplanted into the recipient, where it later matures. Another method is to induce specific immunotolerance to the pig tissue by reconstituting the immune system by using a porcine thymus in the recipient. Another approach is to block co-stimulation of the mature T-effector cells by inhibiting the second signal with monoclonal antibody, such as anti-CD154. Co-stimulator blockade causes the T-effector cells to undergo apoptosis. Combined with donor-specific transfusions, prolonged acceptance of allografts has been achieved; however, anti-CD154 antibodies appear to be associated with thromboembolic complications. All efforts to induce immune tolerance in the xenograft recipient are limited by the need to induce severe immunodeficiency, at least during induction, and this need renders this clinical strategy unfeasible. A novel approach to prevent xenograft rejection is to generate regulatory cells by engrafting bone marrow from the recipient into the fetal pig destined to be the organ donor. These cells can then be harvested and used to condition the recipient before transplantation. Preliminary evidence suggests that regulatory cells are produced in such models and that the organs retrieved from the fetally injected piglets show accommodation. Such an approach, if successfully transferred to the clinic, could spare the patient the risks associated with therapeutic immunosuppression. Preclinical studies showed that prolonged engraftment can be achieved with pig hearts transplanted into sheep by using modest immunosuppression and by using pig hearts transplanted into sensitized sheep that have preformed antipig antibodies. With a similar approach, clusters of pig islet cells were successfully transplanted into diabetic macaques. XENOGRAFT FUNCTIONSection 4 of 8
The ability of a pig xenograft to replace the function of a failed human organ depends on several physiologic factors. In general, organs that are simple in function are the best candidates for xenotransplantation. Hearts pump blood through the lungs and system. Lungs provide gas exchange of oxygen and carbon dioxide. Pancreatic islets provide a insulin, glucagon, and somatostatin. If rejection can be prevented, these organ xenografts will likely provide long-term support for the human recipients. Pig and human kidneys are similar with respect to renal blood flow, glomerular filtration rate, and creatinine clearance. Porcine erythropoietin is about 80% homologous with human erythropoietin. Pig hearts orthotopically transplanted into nonhuman primates provide adequate circulation until the graft is rejected. Porcine insulin differs from human insulin by just a single amino acid, and it provides excellent control of glucose metabolism. However, the connecting C-peptide of humans and pigs, differs at 11 of 31 amino acids, a difference which may affect microvascular blood flow and the development of chronic vascular pathology. On the contrary, complex organs, such as the pig liver, might be inadequate for long-term support of humans. Among other functions, hepatocytes produce many proteins. Porcine albumin has less than 65% homology with human albumin. Several complement and coagulation factors, such as coagulation factor 6, are species specific. The species-specific proteins produced by the pig liver do not function long term in the human recipient. One innovation under development would produce hybrid pig livers in which native pig hepatocytes are replaced with human hepatocytes. Lines of transgenic pigs have been produced with suicide genes under the control of hepatocyte specific promoters. These promotors would allow for the selective and conditional removal of the native pig hepatocytes. If the challenges of immune rejection and function can be overcome, the antigenic disparity of xenografts may provide advantages for the recipient by avoiding the primary pathology that injured the native organ. Pig xenografts may resist infection with native viruses from the patient. Human CMV infections often infect human allografts and cause disease, including enhanced rejection and accelerated chronic rejection, major problems with allografts. CMV is a species-specific virus. In a study of pig-to-baboon heart transplantation, baboon and porcine CMV were evaluated in the transplanted and native tissues. Although low levels of infection were detected in the xenogeneic tissues (ie, baboon CMV in the pig heart), CMV infection was observed in only the corresponding tissues. Xenografts may also provide resistance to autoimmune disease. For example, porcine islets are partially resistant to the autoimmune reaction to islets in NOD mice. Antibodies to human glutamic acid decarboxylase (GAD) in patients at risk for type 1 diabetes are more predictive of clinical progression to insulin dependence than antibodies to porcine GAD. XENOZOONOSISSection 5 of 8
The most discussed risk of porcine xenotransplantation is the potential to pass infectious agents from the donor pig to the patient. The discussion led to a moratorium against xenotransplantation in Europe and to US Food and Drug Administration (FDA) guidelines outlining extensive measures for monitoring xenograft recipients. Although some caution is appropriate with any new technology, the extensive media exposure has given pig xenotransplantation an undeserved reputation as a high-risk procedure. In fact, pig herds can be produced that are free of pathogens; such pigs may pose less risk of infection than human allografts do. Most of the concern of xenozoonosis comes from the perceived need for high levels of immunosuppression to prevent xenograft rejection. With severe immunodeficiency, the recipient is most susceptible to acquiring an agent from the donor pig. The problem would be compounded if xenotransplantation were done on a widespread basis. As technology reduces the need for severe immunosuppression and as accumulating experience demonstrates the relative safety of porcine xenotransplantation, the concern about xenozoonosis will likely fade. Viral zoonotic agents can be divided into endogenous and exogenous viruses. Endogenous viruses are encoded within the genome and therefore cannot be eliminated from the herd by using conventional technology. In 1997, co-culture of human and porcine cells led to porcine endogenous retroviruses appearing n the human cells. Speculation about porcine endogenous retroviruses (PERV) progressed to concern that PERV could become a public health hazard. However, despite considerable research, no pathology related to PERV has been observed. Indeed, though a major portion of the world's population consumes or prepares pork, no known PERV-related disease has ever been described. Although recent research has demonstrated that PERV is capable of in vitro infection of human cells, no clinically defined PERV infection has been conclusively documented in humans. In a retrospective study of patients transplanted or transfused with viable pig tissue, no evidence of infection was observed. A few subjects had detectable PERV RNA, but it was consistent with RNA from circulating pig cells. In humanized mouse models infused with porcine cells, a few mice were described in which the human cells were initially thought to contain PERV. However, subsequent researchers attributed this apparent infection to murine leukemia virus. The risk of PERV becoming a public health hazard is infinitesimal. PERV would need to undergo a series of improbable transformations to make it both a pathogen and contagious. Many herds of pigs have been described in which PERV is not passed to human cells in co-culture. Some strains of pigs have limited copies of PERV in their genome. The risk is further reduced by the extensive monitoring of patients and cohorts required and by the sensitivity of PERV to antiviral agents. The potential medical value of xenotransplants far outweigh the minimal potential risk of PERV and should not be a barrier to xenotransplantation. On the other hand, some ubiquitous exogenous viruses pose a real danger to xenograft recipients, but they have received relatively little attention. Examples of viruses that could potentially be passed from swine to humans include swine influenza virus, Nipah virus, Menangle virus, hepatitis E virus, encephalomyocarditis virus, and Japanese encephalitis virus. Some viruses may have a low potential to infect the recipient tissues, but they could adversely affect the graft. Porcine lymphotropic herpes viruses may lead to posttransplantional lymphoproliferative syndrome in recipients receiving porcine lymphocytes. Porcine CMV and porcine encephalomyocarditis virus may adversely affect vascular xenografts, such as hearts. Some porcine exogenous viruses adversely affect the health of the donor herd, leading to other adverse effects. Porcine circoviruses cause wasting in piglets after weaning. The piglets are immunodeficient, making them susceptible to additional infections. Porcine parvovirus is associated with late-term abortions. Different strains of porcine coronaviruses lead to chronic diarrhea, respiratory disease, and encephalitis. Exogenous viruses can be eliminated from the pig donor herd by means of intense careful husbandry and persistent monitoring of the herd. In producing a clean herd, some have proposed starting with hysterotomy-delivered, colostrum-deprived piglets. This beginning eliminates the bacterial and fungal pathogens but does not eliminate pathogens, such as circovirus, Arterivirus, and parvoviruses, which pass the placental barrier. Pig lymphotropic herpesvirus (PLHV) and encephalomyocarditis virus may also escape this procedure. The production of a herd of donor pigs that is viral pathogen-free requires considerable time and effort. The pigs must be housed in a filtered environment and protected from pathogens from human caretakers, food, insects, rodents, and other sources. The pigs must be screened for the agents and for serologic evidence of agents. All infected and exposed animals must be removed. Although the effort to produce a biomedical-grade herd of pathogen-free donor pigs is a prerequisite for xenotransplantation, it reflects a major opportunity that does not exist for human allografts. The elimination of exogenous pathogens from the donor pig herd combined with a reduced need for immunosuppression could make xenotransplantation safer than allotransplantation regarding infectious diseases. CLINICAL XENOTRANSPLANTATIONSection 6 of 8
The use of animals as organ and tissue donors is not a new idea. When our medical technology and our understanding of immunology and physiology were primitive, animals were the preferred source. Jean Babtiste Deny performed the first blood transfusion into a patient in 1667 using blood taken from a sheep. In 1906, Jaboulay performed the first vascular xenotransplantations, transplanting kidneys from a pig and a dog into patients with renal insufficiency. In 1963, Hitchcock transplanted a kidney from a baboon into 65-yaer-old woman. It functioned for 4 days. Reemtsma and Starzl (1964) achieved a measure of clinical success transplanting kidneys from nonhuman primates into human recipients. Over the next 25 years, focus turned to transplanting organs and tissues from human donors. In the early 1990s, porcine islets prepared from fetal pigs were transplanted into patients with diabetes and modest immunosuppression. Porcine C-peptide was monitored in the urine until the grafts eventually rejected. In 1992 and1993, 2 orthotopic xenotransplants were performed by placing baboon livers into patients with liver failure related to infection with hepatitis B virus. Multidrug therapy was administered to prevent cellular and antibody-mediated rejection. The patients survived 70 and 26 days. The grafts provided at least partial function. Although the grafts were not rejected, one patient developed a terminal aspergillosis related to immunosuppression. Baboon marrow was transplanted into a patient with AIDS with the knowledge that the baboon CD4+ lymphocytes were resistant to HIV. Although the patient's body rejected the baboon cells, his clinical condition improved, and he continued to do well at the time of publication. Dopaminergic neurons from a fetal pig were transplanted into the brain of a patient with Parkinson disease. The transplant significantly improved the patient's clinical course. Seven months later, the fetal pig neurons were identified. The implantation of pig neural tissue into an immune-privileged environment of the brain reduced the risk of rejection. However, a subsequent controlled trial failed to demonstrate a statistically significant difference compared with the control group. Patients with acute liver failure have been supported for a few hours to days with extracorporeal liver perfusion (ECLP) while a human liver donor is being sought. Blood from the patient is perfused through the pig liver and returned. Results of these procedures indicate that the pig liver is functional on a short-term basis. Patients typically have clinical improvement, with reduced blood levels of ammonia and lactic acid, with conjugation and excretion of bilirubin, and with stabilization of the prothrombin time. Devices that incorporate cells or tissue from animals or incorporate human cells or tissues that were co-cultured with animal cells are considered xenografts. One promising device provides short-term support for patients with acute liver failure. Data from initial clinical trials are promising in that the device may provide time to bridge to human liver transplantation. Some patients had a spontaneous recovery during the support period. After a series of public hearings by the National Institutes of Health (NIH), the Centers for Disease Control and Prevention (CDC), and the FDA, the FDA published guidelines for xenotransplantation to address concerns raised about infectious diseases from donor animals. The latest guidelines were published in 2003. For a clinical trial to be allowed, the investigator must demonstrate evidence of efficacy of the xenotransplants in nonhuman primates. The investigator must also demonstrate compliance with the safety guidelines, including use of a certified source herd, prolonged archiving of tissues and records, and facilities and procedures in accordance with current good manufacturing practices (cGMPs). The first successful clinical trials will most likely involve cellular transplants, such as pancreatic islets, neural cells, or hepatocytes. Because vascular xenografts are sensitive to rejection of the endothelial cells, the threshold is set high. Heart xenografts and kidney xenografts are likely be the first tested. Lung xenografts are presently the most challenging xenografts because of the extensive capillary network and the sensitivity of endothelial cells to hyperacute rejection. FUTURE OF XENOTRANSPLANTATION AND REGENERATIVE MEDICINESection 7 of 8
Clinicians in the field of regenerative medicine is looking for an alternate technology to supplement allotransplantation in the cure of organ and tissue failure. Xenotransplantation is the first such technology to be pursued. It is arguably 100 years old this year and has preceded allotransplantation by almost a half century. Mechanical devices, tissue engineering, and stem-cell technology have joined xenotransplantation. Each technology has competitive advantages and weaknesses. Although each continues in its development and shows promise, none has yet proved to be clinically effective in providing long-term life support for the millions of patients in need. The primary drawback to xenotransplantation has always been vigorous rejection. The difficulties in preventing rejection may explain the commonly held view of pigs as a second-rate alternative source of transplant organs and tissues. Until rejection can be prevented with minimal immunosuppression, the transplantation of viable pig tissues will not be done on a large scale. As the need for immunosuppression decreases, so will concern about zoonotic infections, such as that due to PERV. In recent years, the challenge of rejection is quietly being resolved with innovative methods for inducing tolerance and accommodation to the pig tissues. The potential for long-term functional xenografts without chronic immunosuppression is a realistic vision today. For some organs, such as livers, the physiology of the unmodified pig xenograft does not provide long-term life support. For other tissues, including hearts, kidneys, lungs, and pancreatic islets, the physiology of pig tissue should provide long-term support. If the rejection challenge were resolved, a strong case could be made that pig xenografts provide major advantages in regenerative medicine over mechanical devices, tissue engineering, tissues derived from stem cells, and even over human allografts. The obvious advantage of xenografts over mechanical devices and tissue engineering is that xenograft development begins with fully developed tissues and organs. Long-term interaction between the host and artificial materials is not a concern, and there is no concern that the batteries will run down as xenografts derive their energy from the host. There is no need for innovation to provide adequate circulation to a 3-dimensional structure. Depending on the demands of the host, the circulation may also change appropriately. That parts may wear out with time and fail is not a concern. Viable tissues can be regenerated, repaired, and remodeled depending on the host's needs. Viable tissues can monitor themselves and defending against foreign pathogens. Pig organs have been in development and in large animal preclinical trials for about 65 million years. The donor organs are grown in pigs rather manufactured by engineers and technicians. Water and corn meal, rather than culture media and growth factors, provide cellular nourishment. Therefore, xenografts can be produced in a more cost-effective manner than with other technologies. This is an important consideration if the goal is to cure all patients in need and not just a few. Stem-cell technology has unfortunately divided opinions based on the ethics of using embryonic stem cells and cloning. However, aside from the ethical issues, the technical barriers to successful stem-cell technology are also substantial. The challenge is to generate a functional transplant from the stem cells in vitro. This ranges from generating human beta cells that produce adequate levels of insulin to generating 3-dimensional tissues, such as kidneys, hearts, and livers, that contain several cell lines. An exciting prospect is that stem-cell science may be applied to enhance xenotransplants. For example, when fetal sheep were injected with human CD34+ bone marrow cells, the livers of the newborn lambs were found to contain human hepatocytes. This trans-speciation of the tissues, coupled with the induction of accommodation and generation of regulatory cells, could conceivably offer a way forward for physiologically disparate xenografts such as livers. Once the issue of rejection is resolved, xenografts would provide major advantages compared with human allografts. Transplantations would be performed electively rather than as emergency procedures. The quality of the graft will be better than it is now, as they will be coming from healthy, young donors raised specifically for transplantation. The risk of passing on an infectious agent or tumor to the recipient would be minimized. Xenografts might also provide protection against recurrence of the primary disease by autoimmunity and against complications of human viruses, such as accelerated vasculopathy related to human CMV. Given recent progress and innovative solutions, as well as the competitive advantages over other technologies, xenotransplantation is a realistic solution to the severe shortage of donor organs and a realistic possible cure for type 1 diabetes. A substantially enhanced effort to bring xenotransplantation into the clinic is justified. REFERENCESSection 8 of 8
Article Last Updated: Jul 10, 2006 |
