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Clinical Xenotransplantation

Clinical Xenotransplantation The remarkable half-century transition of whole organ transplantation from experimental intervention to standard clinical practice has resulted in a growing disparity between the number of persons who could potentially benefit from allotransplants and the availability of transplantable human organs.1 This disparity inspired initial attempts to explore alternative therapies for organ failure, among them xenotransplantation, which involves the use of living, nonhuman animal tissues in humans. Prior to the last decade, the US clinical experience with xenotransplantation largely consisted of rare, whole organ transplants. Recipient survival after the xenograft was generally measured in days or weeks. Although animal studies and the early unregulated human trials have not demonstrated whole organ xenograft survival rates high enough to justify proceeding with clinical trials, active preclinical research on whole organ xenografting continues. More promising research also continues regarding the potential role of approaches other than whole organ transplantation in the treatment of human diseases using nonhuman animal cells or tissues. Attempts to ameliorate disease using cellular preparations, often immunoprotected, are currently under way in clinical trials under Food and Drug Administration (FDA) oversight in the United States. This article reviews the current status of xenotransplantation trials and discusses possible infectious risks and immunological barriers associated with xenotransplantation. Definitions The US Public Health Service defines xenotransplantation as any procedure that involves the transplantation, implantation, or infusion into a human recipient of either live cells, tissues, or organs from a nonhuman animal source or human body fluids, cells, tissues, or organs that have had ex vivo contact with live nonhuman animal cells, tissues, or organs.2 A single term that encompasses the living material used in all categories of xenotransplantation, "xenotransplantation product," is now used to refer to the live cells, tissues, or organs (whether human or nonhuman) used in xenotransplantation.2 Clinical Trials and Preclinical Studies Clinical trials and preclinical studies using xenotransplantation products have demonstrated that animal cells and tissues might have the potential to be used successfully for the treatment of various diseases and conditions. Porcine neurologic cells have been implanted in patients with degenerative neurologic disorders, such as Parkinson disease and Huntington disease.3 Patients with fulminant hepatic failure have been supported with blood perfused through devices containing porcine hepatocytes.4 Human epidermal cells cultured ex vivo on a murine cell line have been used to replace missing skin in severely burned patients.5 Recipients of all 3 of these xenotransplantation products have survived for years after receiving them.3-5 Attempts to functionally cure diabetes using injections of porcine pancreatic cells have been explored in clinical trials in Europe and in preclinical animal studies in the United States.6,7 Preclinical studies have explored xenografting of porcine neuronal cells into rodents, raising hopes that porcine neuronal cells might some day be used for axonal regeneration of neurons involved in spinal cord injuries.8 Increasing numbers of human participants in clinical trials of xenotransplantation products are alive months to years after receiving cellular transplantation products that have survived in situ for prolonged periods of time.3-6,9-11 Immunological Barriers The recipient immune response is an important obstacle to the survival of xenotransplantation products. Human serum contains natural antibodies directed against α-galactosyl antigens, which are present on the surface of many mammalian cells, but absent from the cells of humans and other Old World primates. In the presence of complement, these antibodies cause hyperacute rejection of α-galactosyl antigen-bearing tissues, a primary and powerful barrier to survival of xenotransplantation products, especially of vascularized organs.12 Cells from baboons and chimpanzees, phylogenetically the closest primate relatives to Homo sapiens, lack this antigen; thus, using xenotransplantation products from these primates would avoid this common type of hyperacute rejection. However, the use of nonhuman primates as sources of xenotransplantation products raises greater concerns than does the use of animals such as pigs that have been historically bred for industrial purposes. Some scientists have suggested that the phylogenetic proximity between nonhuman primates and humans that diminishes the immune barrier to transplantation may also facilitate transmission of infection.13 Furthermore, the capability to produce and house nonhuman primates in a manner that would make them suitable as sources of xenotransplantation products does not currently exist. The development of this capability, and the use of nonhuman primates for xenotransplantation in general, raises ethical and economic issues that are beyond the scope of this article. For these reasons among others, pigs are currently the preferred source for xenotransplantation products despite the presence of α-galactosyl antigens on their cell surfaces. Attempts to avoid hyperacute rejection have included genetically engineering pigs to reduce their cell surface expression of α-galactosyl antigens or to render their cell surface components capable of inactivating human complement. The removal of natural antibodies from recipients prior to xenotransplantation, which can be accomplished by circulating the intended recipient's blood through devices that contain α-galactosyl residues,12 is another possible approach to avoiding hyperacute rejection. Risk of Infectious Disease Transmission Infectious disease hazards potentially associated with xenotransplantation have generated a great deal of concern.14,15 While xenotransplantation may provide therapeutic benefit if immunologic barriers can be overcome, it also poses potential risk. Xenotransplantation products may infect human recipients with zoonotic and other infectious agents that are not endemic in human populations. Immunosuppressive regimens intended to improve survival of xenotransplantation products may also inhibit immune responses to infection. Scientists and policy makers in the field must deal with the challenge of weighing the uncertain collective risk of xenotransplantation against the potential benefit to both individuals and society. The risk of human recipients of xenotransplantation products being infected with zoonotic infectious agents can be reduced by limiting the lifelong exposures of prospective source animals to infectious agents, as well as by screening both the source animal and the xenotransplantation product itself prior to transplantation.2 Despite these measures, xenotransplantation products may still transmit infectious agents. Infectious agents may not be recognized and eliminated either because they are not known to exist (eg, Nipah virus prior to 1999), diagnostic tools are inadequate to detect them (eg, prions), or they cannot be removed by means currently available (eg, endogenous retroviruses). Endogenous retroviruses exist as proviral DNA integrated into the germline of all mammals adequately studied to date. Some of these endogenous retroviruses, including porcine endogenous retrovirus (PERV), can express virions capable of infecting human cell lines in vitro.16,17 Thus, xenotransplantation products from every species may contain genomic DNA that expresses infectious retrovirus with the potential to create persistent infection in a human recipient. Theoretically, such sequences could be removed by genetic engineering of source animals. However, since PERV is encoded at multiple loci in each genome, such removal would be a daunting, perhaps impossible, undertaking.16,18,19 Recent preclinical scientific investigations have attempted to assess the infectious risk associated with endogenous retroviruses. These studies exemplify the difficulty of quantifying the infectious risks associated with cross-species transplantation. Three variants of PERV are expressed by multiple porcine cell lines, as well as by primary porcine tissue. The capacity of 2 PERV variants to productively infect human cells and cell lines in vitro has been established,16,17 which supports the argument that PERV expressed from porcine xenotransplantation products may be able to infect human recipients. Some investigators, however, suggest that while PERV may infect cells from humans or other species in vivo as well as in vitro, such PERV infections might have limited clinical consequences. Evidence supporting this view comes from a study in which porcine pancreatic islet cells were transplanted into severely immunodeficient mice and abortive, asymptomatic replication of PERV occurred.20 More research in this area is warranted. Approaches that were developed to circumvent the risk of hyperacute rejection may have the unintended consequence of increasing the risk of infection. Since the characteristics of virus envelopes are influenced by the characteristics of the cells in which they replicate, pig cell–derived PERV contains α-galactosyl antigens on its envelope; the presence of these antigens renders PERV vulnerable to inactivation and lysis by human sera containing antibodies against this antigen. However, a single passage of PERV through human cells results in a viral envelope lacking the antigen present on pig cell–derived virus and has been shown to result in the virus becoming resistant to inactivation by normal human sera.16 These findings support suspicions that modifications intended to facilitate xenograft survival may also compromise lytic complement-mediated clearance of PERV. Efforts to collect more direct information on the infectious risks to humans who receive xenotransplantation products are under way. To date, limited and primarily retrospective studies of 202 humans exposed to pig cells and tissues have demonstrated no clinical or laboratory evidence of PERV infection.9-11,21,22 The analysis of the presence of PERV infection is complicated by microchimerism, the persistent presence of individual cells of graft origin in anatomically dispersed sites in the host even after removal or rejection of the foreign tissues.23,24 In 1 study, persons who underwent transient hemoperfusion through pig spleens showed evidence of persistent microchimerism with porcine cells up to 8 years later.11 Another study identified simian foamy virus and baboon endogenous retrovirus DNA in microchimeric baboon cells in distal anatomic sites of 2 recipients of baboon livers weeks after transplantation.25 Baboon cytomegalovirus was identified in the buffy coat of peripheral blood of 1 of these patients; whether it had infected human host cells or was expressed from microchimeric baboon cells could not be determined.26 Taken together, these observations suggest that even transient exposure to xenotransplantation products may provide enduring exposure to infectious agents carried within them. Since October 1997, when evidence that PERV could infect human cells in vitro emerged, the FDA has required all sponsors of porcine xenotransplantation product trials to develop adequate assays to test such products for infectious virus and to monitor recipients for evidence of PERV infections. Directions for Future Research It may be possible to intervene clinically in ways that diminish the risk of human infection posed by xenotransplantation. An emerging body of investigation demonstrates that the engineering of xenotransplantation products, as well as the duration and nature of the recipient's exposure to a xenotransplantation product, have the potential to influence the risk of recipient exposure to PERV.11,27 The hypothesis that peritransplant use of antiretroviral drugs may increase the selective pressure against persistent PERV infection is undergoing preliminary exploration.28 Phylogenetic analysis demonstrates a close relationship between PERV and feline leukemia virus (FeLV). The ability to protect against FeLV infection with commercial vaccines has led one researcher to hypothesize that protective pretransplantation immunization of human recipients of xenotransplantation products against PERV may also become possible (David Onions, DVM, oral communication, Q-one Biotech, Glasgow, Scotland, October 17, 2000). Recent reports of the identification of pig strains that may exhibit diminished PERV expression and of the successful cloning of pigs suggest other avenues of exploration.29-31 Summary Xenotransplantation products developed from living cells of nonhuman animals are currently being investigated in clinical trials and active preclinical studies. Xenotransplantation offers the potential to ameliorate disease and restore health. The realization of this potential will depend on whether investigators are successful in overcoming immunologic barriers, demonstrating compatible physiologic functioning, and addressing concerns about transfer of adventitial infectious agents. References 1. 1997 Report of the OPTN: Waiting List Activity and Donor Procurement. Richmond, Va: UNOS and Rockville, Md: US Dept of Health and Human Services: 1997. 2. PHS Guideline on Infectious Disease Issues in Xenotransplantation (January 19, 2001). Available at: http://www.fda.gov/cber/gdlns/xenophs0101.htm. Accessibility verified March 29, 2001. 3. Fink JS, Schumacher JM, Ellias SL. et al. Porcine xenografts in Parkinson's disease and Huntington's disease patients: preliminary results. Cell Transplant.2000;9:273-278.Google Scholar 4. Chari RS, Collins BH, Magee JC. et al. Brief report: treatment of hepatic failure with ex vivo pig-liver perfusion followed by liver transplantation. N Engl J Med.1994;331:234-237.Google Scholar 5. Dapolito G, Auchincloss Jr H. Report of the Food and Drug Administration Subcommittee on Xenotransplantation: meeting of 13 January 2000, Center for Biologics Evaluation and Research. Xenotransplantation.2000;7:75-79.Google Scholar 6. Groth CG, Korsgren O, Tibell A. et al. Transplantation of porcine fetal pancreas to diabetic patients. Lancet.1994;344:1402-1404.Google Scholar 7. Zhang Z, Bedard E, Luo Y. et al. Animal models in xenotransplantation. Expert Opin Investig Drugs.2000;9:2051-2068.Google Scholar 8. Imaizumi T, Lankford KL, Burton WV, Fodor WL, Kocsis JD. Xenotransplantation of pig olfactory ensheathing cells promotes axonal regeneration in rat spinal cord. Nat Biotechnol.2000;18:949-953.Google Scholar 9. Heneine W, Tibell A, Switzer WM. et al. No evidence of infection with the porcine endogenous retrovirus in human recipients of porcine islet cell xenografts. Lancet.1998;352:695-699.Google Scholar 10. Patience C, Patton GS, Takeuchi Y. et al. No evidence of pig DNA or retroviral infection in patients with short-term extracorporeal connection to pig kidneys. Lancet.1998;352:699-701.Google Scholar 11. Paradis K, Langford G, Long Z. et al. Search for cross species transmission of porcine endogenous retrovirus in patients treated with living pig tissue. Science.1999;285:1236-1241.Google Scholar 12. Soin B, Vial CM, Freind PJ. Xenotransplantation. Br J Surg.2000;87:138-148.Google Scholar 13. Allan JS. The risk of using baboons as transplant donors. Ann N Y Acad Sci.1998;862:87-99.Google Scholar 14. Chapman LE, Folks TM, Salomon DR. et al. Xenotransplantation and xenogeneic infections. N Engl J Med.1995;333:1498-1501.Google Scholar 15. Bach FH, Fishman JA, Daniels N. et al. Uncertainty in xenotransplantation: individual benefit versus collective risk. Nat Med.1998;4:141-144.Google Scholar 16. Patience C, Takeuchi Y, Weiss RA. Infection of human cells by an endogenous retrovirus of pigs. Nat Med.1997;3:282-286.Google Scholar 17. Wilson CA, Wong S, Muller J. et al. Type C retrovirus released from porcine primary peripheral blood mononuclear cells infects human cells. J Virol.1998;72:3082-3087.Google Scholar 18. Akiyoshi DE, Denaro M, Zhu H. et al. Identification of a full-length cDNA for an endogenous retrovirus of miniature swine. J Virol.1998;72:4503-4507.Google Scholar 19. Le Tissier P, Stoye JP, Takeuchi Y, Patience C, Weiss RA. Two sets of human-tropic pig retroviruses. Nature.1997;389:681-682.Google Scholar 20. Van der Laan LJW, Lockey C, Griffeth BC. et al. Infection by porcine endogenous retrovirus after islet xenotransplantation in SCID mice. Nature.2000;407:90-94.Google Scholar 21. Schumacher JM, Ellias SA, Palmer EP. et al. Transplantation of embryonic porcine mesencephalic tissue in patients with PD. Neurology.2000;54:1042-1050.Google Scholar 22. Pitkin Z, Mullon C. Evidence of absence of porcine endogenous retrovirus (PERV) infection in patients treated with a bioartificial liver support system. Artif Organs.1999;23:829-833.Google Scholar 23. McDaniel HB, Yang M, Sidner RA, Jindal RM, Sahota A. Prospective study of microchimerism in transplant recipients. Clin Transplant.1999;13:187-192.Google Scholar 24. Nelson JL. Microchimerism and the pathogenesis of systemic sclerosis. Curr Opin Rheumatol.1998;10:564-571.Google Scholar 25. Allen JS, Broussard SR, Michaels MG. et al. Amplification of simian retroviral sequences from human recipients of baboon liver transplants. AIDS Res Hum Retroviruses.1998;14:821-824.Google Scholar 26. Michaels MG, Jenkins FJ, St George K. et al. Detection of infectious baboon cytomegalovirus after baboon to human liver xenotransplantation. J Virol.2001;75:2825-2828.Google Scholar 27. Nyberg SL, Hibbs JR, Hardin JA, Germer JJ, Persing DH. Transfer of porcine endogenous retrovirus across hollow fiber membranes: significance to a bioartificial liver. Transplantation.1999;67:1251-1255.Google Scholar 28. Qari SH, Magre S, Garcia-Lerma JG. et al. Susceptibility of the porcine endogenous retrovirus to reverse transcriptase and protease inhibitors. J Virol.2001;75:1048-1053.Google Scholar 29. Oldmixon B, Wood J, Ericsson T, White-Scharf M, Patience C. Absence of human-tropic endogenous retroviruses in inbred miniature swine. Presented at: 12th International Workshop of Retroviral Pathogenesis; October 30, 2000; Annapolis, Md. 30. Polejaeva IA, Chen S-H, Vaught TD. et al. Cloned pigs produced by nuclear transfer from adult somatic cells. Nature.2000;407:86-90.Google Scholar 31. Onishi A, Iwamoto M, Akita T. et al. Pig cloning by microinjection of fetal fibroblast nuclei. Science.2000;289:1188-1190.Google Scholar http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

Clinical Xenotransplantation

Chapman, Louisa E.; Bloom, Eda T.
JAMA , Volume 285 (18) – May 9, 2001
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References (31)

Publisher
American Medical Association
Copyright
Copyright © 2001 American Medical Association. All Rights Reserved.
ISSN
0098-7484
eISSN
1538-3598
DOI
10.1001/jama.285.18.2304
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Abstract

The remarkable half-century transition of whole organ transplantation from experimental intervention to standard clinical practice has resulted in a growing disparity between the number of persons who could potentially benefit from allotransplants and the availability of transplantable human organs.1 This disparity inspired initial attempts to explore alternative therapies for organ failure, among them xenotransplantation, which involves the use of living, nonhuman animal tissues in humans. Prior to the last decade, the US clinical experience with xenotransplantation largely consisted of rare, whole organ transplants. Recipient survival after the xenograft was generally measured in days or weeks. Although animal studies and the early unregulated human trials have not demonstrated whole organ xenograft survival rates high enough to justify proceeding with clinical trials, active preclinical research on whole organ xenografting continues. More promising research also continues regarding the potential role of approaches other than whole organ transplantation in the treatment of human diseases using nonhuman animal cells or tissues. Attempts to ameliorate disease using cellular preparations, often immunoprotected, are currently under way in clinical trials under Food and Drug Administration (FDA) oversight in the United States. This article reviews the current status of xenotransplantation trials and discusses possible infectious risks and immunological barriers associated with xenotransplantation. Definitions The US Public Health Service defines xenotransplantation as any procedure that involves the transplantation, implantation, or infusion into a human recipient of either live cells, tissues, or organs from a nonhuman animal source or human body fluids, cells, tissues, or organs that have had ex vivo contact with live nonhuman animal cells, tissues, or organs.2 A single term that encompasses the living material used in all categories of xenotransplantation, "xenotransplantation product," is now used to refer to the live cells, tissues, or organs (whether human or nonhuman) used in xenotransplantation.2 Clinical Trials and Preclinical Studies Clinical trials and preclinical studies using xenotransplantation products have demonstrated that animal cells and tissues might have the potential to be used successfully for the treatment of various diseases and conditions. Porcine neurologic cells have been implanted in patients with degenerative neurologic disorders, such as Parkinson disease and Huntington disease.3 Patients with fulminant hepatic failure have been supported with blood perfused through devices containing porcine hepatocytes.4 Human epidermal cells cultured ex vivo on a murine cell line have been used to replace missing skin in severely burned patients.5 Recipients of all 3 of these xenotransplantation products have survived for years after receiving them.3-5 Attempts to functionally cure diabetes using injections of porcine pancreatic cells have been explored in clinical trials in Europe and in preclinical animal studies in the United States.6,7 Preclinical studies have explored xenografting of porcine neuronal cells into rodents, raising hopes that porcine neuronal cells might some day be used for axonal regeneration of neurons involved in spinal cord injuries.8 Increasing numbers of human participants in clinical trials of xenotransplantation products are alive months to years after receiving cellular transplantation products that have survived in situ for prolonged periods of time.3-6,9-11 Immunological Barriers The recipient immune response is an important obstacle to the survival of xenotransplantation products. Human serum contains natural antibodies directed against α-galactosyl antigens, which are present on the surface of many mammalian cells, but absent from the cells of humans and other Old World primates. In the presence of complement, these antibodies cause hyperacute rejection of α-galactosyl antigen-bearing tissues, a primary and powerful barrier to survival of xenotransplantation products, especially of vascularized organs.12 Cells from baboons and chimpanzees, phylogenetically the closest primate relatives to Homo sapiens, lack this antigen; thus, using xenotransplantation products from these primates would avoid this common type of hyperacute rejection. However, the use of nonhuman primates as sources of xenotransplantation products raises greater concerns than does the use of animals such as pigs that have been historically bred for industrial purposes. Some scientists have suggested that the phylogenetic proximity between nonhuman primates and humans that diminishes the immune barrier to transplantation may also facilitate transmission of infection.13 Furthermore, the capability to produce and house nonhuman primates in a manner that would make them suitable as sources of xenotransplantation products does not currently exist. The development of this capability, and the use of nonhuman primates for xenotransplantation in general, raises ethical and economic issues that are beyond the scope of this article. For these reasons among others, pigs are currently the preferred source for xenotransplantation products despite the presence of α-galactosyl antigens on their cell surfaces. Attempts to avoid hyperacute rejection have included genetically engineering pigs to reduce their cell surface expression of α-galactosyl antigens or to render their cell surface components capable of inactivating human complement. The removal of natural antibodies from recipients prior to xenotransplantation, which can be accomplished by circulating the intended recipient's blood through devices that contain α-galactosyl residues,12 is another possible approach to avoiding hyperacute rejection. Risk of Infectious Disease Transmission Infectious disease hazards potentially associated with xenotransplantation have generated a great deal of concern.14,15 While xenotransplantation may provide therapeutic benefit if immunologic barriers can be overcome, it also poses potential risk. Xenotransplantation products may infect human recipients with zoonotic and other infectious agents that are not endemic in human populations. Immunosuppressive regimens intended to improve survival of xenotransplantation products may also inhibit immune responses to infection. Scientists and policy makers in the field must deal with the challenge of weighing the uncertain collective risk of xenotransplantation against the potential benefit to both individuals and society. The risk of human recipients of xenotransplantation products being infected with zoonotic infectious agents can be reduced by limiting the lifelong exposures of prospective source animals to infectious agents, as well as by screening both the source animal and the xenotransplantation product itself prior to transplantation.2 Despite these measures, xenotransplantation products may still transmit infectious agents. Infectious agents may not be recognized and eliminated either because they are not known to exist (eg, Nipah virus prior to 1999), diagnostic tools are inadequate to detect them (eg, prions), or they cannot be removed by means currently available (eg, endogenous retroviruses). Endogenous retroviruses exist as proviral DNA integrated into the germline of all mammals adequately studied to date. Some of these endogenous retroviruses, including porcine endogenous retrovirus (PERV), can express virions capable of infecting human cell lines in vitro.16,17 Thus, xenotransplantation products from every species may contain genomic DNA that expresses infectious retrovirus with the potential to create persistent infection in a human recipient. Theoretically, such sequences could be removed by genetic engineering of source animals. However, since PERV is encoded at multiple loci in each genome, such removal would be a daunting, perhaps impossible, undertaking.16,18,19 Recent preclinical scientific investigations have attempted to assess the infectious risk associated with endogenous retroviruses. These studies exemplify the difficulty of quantifying the infectious risks associated with cross-species transplantation. Three variants of PERV are expressed by multiple porcine cell lines, as well as by primary porcine tissue. The capacity of 2 PERV variants to productively infect human cells and cell lines in vitro has been established,16,17 which supports the argument that PERV expressed from porcine xenotransplantation products may be able to infect human recipients. Some investigators, however, suggest that while PERV may infect cells from humans or other species in vivo as well as in vitro, such PERV infections might have limited clinical consequences. Evidence supporting this view comes from a study in which porcine pancreatic islet cells were transplanted into severely immunodeficient mice and abortive, asymptomatic replication of PERV occurred.20 More research in this area is warranted. Approaches that were developed to circumvent the risk of hyperacute rejection may have the unintended consequence of increasing the risk of infection. Since the characteristics of virus envelopes are influenced by the characteristics of the cells in which they replicate, pig cell–derived PERV contains α-galactosyl antigens on its envelope; the presence of these antigens renders PERV vulnerable to inactivation and lysis by human sera containing antibodies against this antigen. However, a single passage of PERV through human cells results in a viral envelope lacking the antigen present on pig cell–derived virus and has been shown to result in the virus becoming resistant to inactivation by normal human sera.16 These findings support suspicions that modifications intended to facilitate xenograft survival may also compromise lytic complement-mediated clearance of PERV. Efforts to collect more direct information on the infectious risks to humans who receive xenotransplantation products are under way. To date, limited and primarily retrospective studies of 202 humans exposed to pig cells and tissues have demonstrated no clinical or laboratory evidence of PERV infection.9-11,21,22 The analysis of the presence of PERV infection is complicated by microchimerism, the persistent presence of individual cells of graft origin in anatomically dispersed sites in the host even after removal or rejection of the foreign tissues.23,24 In 1 study, persons who underwent transient hemoperfusion through pig spleens showed evidence of persistent microchimerism with porcine cells up to 8 years later.11 Another study identified simian foamy virus and baboon endogenous retrovirus DNA in microchimeric baboon cells in distal anatomic sites of 2 recipients of baboon livers weeks after transplantation.25 Baboon cytomegalovirus was identified in the buffy coat of peripheral blood of 1 of these patients; whether it had infected human host cells or was expressed from microchimeric baboon cells could not be determined.26 Taken together, these observations suggest that even transient exposure to xenotransplantation products may provide enduring exposure to infectious agents carried within them. Since October 1997, when evidence that PERV could infect human cells in vitro emerged, the FDA has required all sponsors of porcine xenotransplantation product trials to develop adequate assays to test such products for infectious virus and to monitor recipients for evidence of PERV infections. Directions for Future Research It may be possible to intervene clinically in ways that diminish the risk of human infection posed by xenotransplantation. An emerging body of investigation demonstrates that the engineering of xenotransplantation products, as well as the duration and nature of the recipient's exposure to a xenotransplantation product, have the potential to influence the risk of recipient exposure to PERV.11,27 The hypothesis that peritransplant use of antiretroviral drugs may increase the selective pressure against persistent PERV infection is undergoing preliminary exploration.28 Phylogenetic analysis demonstrates a close relationship between PERV and feline leukemia virus (FeLV). The ability to protect against FeLV infection with commercial vaccines has led one researcher to hypothesize that protective pretransplantation immunization of human recipients of xenotransplantation products against PERV may also become possible (David Onions, DVM, oral communication, Q-one Biotech, Glasgow, Scotland, October 17, 2000). Recent reports of the identification of pig strains that may exhibit diminished PERV expression and of the successful cloning of pigs suggest other avenues of exploration.29-31 Summary Xenotransplantation products developed from living cells of nonhuman animals are currently being investigated in clinical trials and active preclinical studies. Xenotransplantation offers the potential to ameliorate disease and restore health. The realization of this potential will depend on whether investigators are successful in overcoming immunologic barriers, demonstrating compatible physiologic functioning, and addressing concerns about transfer of adventitial infectious agents. References 1. 1997 Report of the OPTN: Waiting List Activity and Donor Procurement. Richmond, Va: UNOS and Rockville, Md: US Dept of Health and Human Services: 1997. 2. PHS Guideline on Infectious Disease Issues in Xenotransplantation (January 19, 2001). Available at: http://www.fda.gov/cber/gdlns/xenophs0101.htm. Accessibility verified March 29, 2001. 3. Fink JS, Schumacher JM, Ellias SL. et al. Porcine xenografts in Parkinson's disease and Huntington's disease patients: preliminary results. Cell Transplant.2000;9:273-278.Google Scholar 4. Chari RS, Collins BH, Magee JC. et al. Brief report: treatment of hepatic failure with ex vivo pig-liver perfusion followed by liver transplantation. N Engl J Med.1994;331:234-237.Google Scholar 5. Dapolito G, Auchincloss Jr H. Report of the Food and Drug Administration Subcommittee on Xenotransplantation: meeting of 13 January 2000, Center for Biologics Evaluation and Research. Xenotransplantation.2000;7:75-79.Google Scholar 6. Groth CG, Korsgren O, Tibell A. et al. Transplantation of porcine fetal pancreas to diabetic patients. Lancet.1994;344:1402-1404.Google Scholar 7. Zhang Z, Bedard E, Luo Y. et al. Animal models in xenotransplantation. Expert Opin Investig Drugs.2000;9:2051-2068.Google Scholar 8. Imaizumi T, Lankford KL, Burton WV, Fodor WL, Kocsis JD. Xenotransplantation of pig olfactory ensheathing cells promotes axonal regeneration in rat spinal cord. Nat Biotechnol.2000;18:949-953.Google Scholar 9. Heneine W, Tibell A, Switzer WM. et al. No evidence of infection with the porcine endogenous retrovirus in human recipients of porcine islet cell xenografts. Lancet.1998;352:695-699.Google Scholar 10. Patience C, Patton GS, Takeuchi Y. et al. No evidence of pig DNA or retroviral infection in patients with short-term extracorporeal connection to pig kidneys. Lancet.1998;352:699-701.Google Scholar 11. Paradis K, Langford G, Long Z. et al. Search for cross species transmission of porcine endogenous retrovirus in patients treated with living pig tissue. Science.1999;285:1236-1241.Google Scholar 12. Soin B, Vial CM, Freind PJ. Xenotransplantation. Br J Surg.2000;87:138-148.Google Scholar 13. Allan JS. The risk of using baboons as transplant donors. Ann N Y Acad Sci.1998;862:87-99.Google Scholar 14. Chapman LE, Folks TM, Salomon DR. et al. Xenotransplantation and xenogeneic infections. N Engl J Med.1995;333:1498-1501.Google Scholar 15. Bach FH, Fishman JA, Daniels N. et al. Uncertainty in xenotransplantation: individual benefit versus collective risk. Nat Med.1998;4:141-144.Google Scholar 16. Patience C, Takeuchi Y, Weiss RA. Infection of human cells by an endogenous retrovirus of pigs. Nat Med.1997;3:282-286.Google Scholar 17. Wilson CA, Wong S, Muller J. et al. Type C retrovirus released from porcine primary peripheral blood mononuclear cells infects human cells. J Virol.1998;72:3082-3087.Google Scholar 18. Akiyoshi DE, Denaro M, Zhu H. et al. Identification of a full-length cDNA for an endogenous retrovirus of miniature swine. J Virol.1998;72:4503-4507.Google Scholar 19. Le Tissier P, Stoye JP, Takeuchi Y, Patience C, Weiss RA. Two sets of human-tropic pig retroviruses. Nature.1997;389:681-682.Google Scholar 20. Van der Laan LJW, Lockey C, Griffeth BC. et al. Infection by porcine endogenous retrovirus after islet xenotransplantation in SCID mice. Nature.2000;407:90-94.Google Scholar 21. Schumacher JM, Ellias SA, Palmer EP. et al. Transplantation of embryonic porcine mesencephalic tissue in patients with PD. Neurology.2000;54:1042-1050.Google Scholar 22. Pitkin Z, Mullon C. Evidence of absence of porcine endogenous retrovirus (PERV) infection in patients treated with a bioartificial liver support system. Artif Organs.1999;23:829-833.Google Scholar 23. McDaniel HB, Yang M, Sidner RA, Jindal RM, Sahota A. Prospective study of microchimerism in transplant recipients. Clin Transplant.1999;13:187-192.Google Scholar 24. Nelson JL. Microchimerism and the pathogenesis of systemic sclerosis. Curr Opin Rheumatol.1998;10:564-571.Google Scholar 25. Allen JS, Broussard SR, Michaels MG. et al. Amplification of simian retroviral sequences from human recipients of baboon liver transplants. AIDS Res Hum Retroviruses.1998;14:821-824.Google Scholar 26. Michaels MG, Jenkins FJ, St George K. et al. Detection of infectious baboon cytomegalovirus after baboon to human liver xenotransplantation. J Virol.2001;75:2825-2828.Google Scholar 27. Nyberg SL, Hibbs JR, Hardin JA, Germer JJ, Persing DH. Transfer of porcine endogenous retrovirus across hollow fiber membranes: significance to a bioartificial liver. Transplantation.1999;67:1251-1255.Google Scholar 28. Qari SH, Magre S, Garcia-Lerma JG. et al. Susceptibility of the porcine endogenous retrovirus to reverse transcriptase and protease inhibitors. J Virol.2001;75:1048-1053.Google Scholar 29. Oldmixon B, Wood J, Ericsson T, White-Scharf M, Patience C. Absence of human-tropic endogenous retroviruses in inbred miniature swine. Presented at: 12th International Workshop of Retroviral Pathogenesis; October 30, 2000; Annapolis, Md. 30. Polejaeva IA, Chen S-H, Vaught TD. et al. Cloned pigs produced by nuclear transfer from adult somatic cells. Nature.2000;407:86-90.Google Scholar 31. Onishi A, Iwamoto M, Akita T. et al. Pig cloning by microinjection of fetal fibroblast nuclei. Science.2000;289:1188-1190.Google Scholar

Journal

JAMA – American Medical Association

Published: May 9, 2001

There are no references for this article.