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• W2082073343 abstract "The most common causes of disability and death are diseases of the heart, lungs, liver, kidneys, and pancreas, many of which are potentially treated by organ transplantation. The effect of organ dysfunction and failure will likely grow over time, and patients will increasingly expect “safer” transplants, in particular in cases of “preemptive transplantation.” New technologies are being developed in part because of the limited availability of organs, and include transplantation with stem cells, tissue engineering, cloning, and xenotransplantation, which some researchers believe promise ready solutions. Although exciting, none of these approaches alone is likely to address the need for organ replacement. We propose that a melding of these new technologies adapted to the distinct challenges and imperatives of the various organs may address this daunting challenge. The most common causes of disability and death are diseases of the heart, lungs, liver, kidneys, and pancreas, many of which are potentially treated by organ transplantation. The effect of organ dysfunction and failure will likely grow over time, and patients will increasingly expect “safer” transplants, in particular in cases of “preemptive transplantation.” New technologies are being developed in part because of the limited availability of organs, and include transplantation with stem cells, tissue engineering, cloning, and xenotransplantation, which some researchers believe promise ready solutions. Although exciting, none of these approaches alone is likely to address the need for organ replacement. We propose that a melding of these new technologies adapted to the distinct challenges and imperatives of the various organs may address this daunting challenge. For nearly 100 years, physicians and scientists have envisioned that diseased and failing organs may be replaced by healthy ones via organ transplantation.1Carrel A Transplantation in mass of the kidneys.J Exp Med. 1908; 10: 98-140Crossref PubMed Scopus (63) Google Scholar, 2Ullman E Tissue and organ transplantation.Ann Surg. 1914; 60: 195-219Crossref PubMed Google Scholar, 3Guthrie CC Blood-Vessel Surgery and Its Applications. Longmans, Green & Co, New York, NY1912Google Scholar However, application of organ transplantation had to await the development of effective means for suppressing immunity against the transplant. Immunosuppressive drugs were developed in the late 1950s and were used immediately to launch the field of clinical organ transplantation.4Calne RY The rejection of renal homografts: inhibition in dogs by 6-mercaptopurine.Lancet. 1960; 1: 417-418Abstract PubMed Scopus (178) Google Scholar, 5Merrill JP Murray JE Takacs FJ Hager EB Wilson RE Dammin GJ Successful transplantation of kidney from a human cadaver.JAMA. 1963; 185: 347-353Crossref PubMed Scopus (61) Google Scholar Because of improved methods of immunosuppression, 77% of cardiac transplants, 81% of kidney transplants, and 72% of liver transplants now function for 3 years,62001 Annual Report of the U.S. Organ Procurement and Transplantation Network and the Scientific Registry for Transplant Recipients: Transplant Data 1991-2000. Department of Health and Human Services, Health Resources and Services Administration, Office of Special Programs, Division of Transplantation, Rockville, Md; United Network for Organ Sharing, Richmond, Va; University Renal Research and Education Association, Ann Arbor, Mich.Available at: www.optn.org/data/annualReport.aspGoogle Scholar for the most part free of rejection, and organ allotransplantation (transplantation between different individuals of the same species) is the preferred treatment of severe failure of the heart, lungs, liver, kidneys, and, in some cases, the pancreas. Despite this success, organ transplantation has never achieved its full potential for the treatment of disease. Relatively few human organs and tissues are available for transplantation. For example, only about 5% of the hearts needed are donated in the United States and Europe7Evans RW Coming to terms with reality: why xenotransplantation is a necessity.in: Platt JL Xenotransplantation. ASM Press, Washington, DC2001: 29-51Google Scholar and even fewer elsewhere. As molecular diagnosis allows prediction of disease and cancer that may be treated with “preemptive transplants,” the need for organs could grow severalfold.8Platt JL Preface: future approaches to replacement of organs.Am J Transplant. 2004; 4: 5-6Crossref Scopus (7) Google Scholar Although irreversible acute rejection of transplants is rare, transplant recipients require lifelong immunosuppression, and this treatment engenders medical complications such as infection, malignancy, and atherosclerosis. In this review, we consider how technology may address these limitations and the barriers to the augmentation and replacement of organ function. A consideration of biological approaches to augmenting and replacing organ function begins with a brief consideration of the barrier posed by the immune system. All foreign transplants incite immune responses (Table 1). Because this reaction is universal and powerful, reaction to foreign cells has been used for the past century as a way of detecting genetic differences between individuals.TABLE 1Immune Responses to Transplantation*MHC = major histocompatibility complex.Type of graftForeign antigenImmune responseTreatment/control neededAutograftNoneNoneNoneCloned cellsMitochondrial proteins (minor antigens)CellularPossibly noneAllograftMHCCellular, humoralImmunosuppressionBlood groupsHumoralDonor selectionMinor antigensCellularImmunosuppressionXenograftGalα1-3GalHumoralTolerance, antigen knock-out, accommodationMHCCellular, humoralImmunosuppressionMinor antigensCellular, humoralImmunosuppression* MHC = major histocompatibility complex. Open table in a new tab When transplantation is performed between individuals of the same species (ie, allografts), proteins encoded by the major histocompatibility complex (MHC) (ie, MHC antigens) stimulate the immune response predominantly. The MHC antigens exert a powerful stimulus, in part because they are extraordinarily polymorphic and thus reliably different in unrelated individuals. However, this reason alone does not suffice because some other proteins (eg, C4, which is made in the liver and in endothelium) are polymorphic, and yet immunity to C4 apparently is not a major barrier to allotransplantation. What makes MHC proteins special is that they can directly stimulate T cells through the antigen receptor; also, for some reason, even fragments of the proteins that cannot stimulate T-cell receptors directly give rise to disproportionately reliable T-cell and B-cell responses. Allogeneic non-MHC proteins can give rise to cellular immune responses and are called minor histocompatibility antigens, among which are proteins encoded by mitochondrial DNA. These antigens may be of particular interest as a hurdle to the application of cloning, as discussed subsequently. Another type of allogeneic antigen is the set of blood group antigens, which includes carbohydrates such as ABO and proteins such as Rh. Blood group antigens can stimulate the production of anti-donor antibodies. Grafts between individuals of different species, xenografts, provoke even more intense responses than allografts.9Cascalho M Platt JL The immunological barrier to xenotransplantation.Immunity. 2001; 14: 437-446Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar We have reviewed the immune responses to xenotransplantation in detail.9Cascalho M Platt JL The immunological barrier to xenotransplantation.Immunity. 2001; 14: 437-446Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar One aspect of the immune response to xenografts that is especially intense is natural or innate immunity, consisting of natural antibodies, complement, and natural killer cells. All immunocompetent individuals have xenoreactive antibodies that recognize a saccharide, Gala1-3Gal, expressed on the cells of lower mammals.10Galili U Interaction of the natural anti-Gal antibody with α-galactosyl epitopes: a major obstacle for xenotransplantation in humans.Immunol Today. 1993; 14: 480-482Abstract Full Text PDF PubMed Scopus (580) Google Scholar These antibodies can trigger the activation of complement and the action of natural killer cells, leading to various types of rejection reactions discussed subsequently. In some circumstances, complement and natural killer cells may act directly on xenografts, contributing further to tissue damage. The immune response to xenografts includes immunity to MHC proteins that by some measures may be less11Alter BJ Bach FH Cellular basis of the proliferative response of human T cells to mouse xenoantigens.J Exp Med. 1990; 171: 333-338Crossref PubMed Scopus (98) Google Scholar and by others more12Dorling A Lombardi G Binns R Lechler RI Detection of primary direct and indirect human anti-porcine T cell responses using a porcine dendritic cell population.Eur J Immunol. 1996; 26: 1378-1387Crossref PubMed Scopus (103) Google Scholar intense than the immunity evoked by allogeneic MHC. Regardless, xenografts provoke much stronger responses against non-MHC proteins. One reason is that xenogeneic proteins, compared with the recipient's own proteins, contain many differences in amino acid sequences that give rise to immune responses (practically all xenogeneic proteins incite an immune response, whereas few allogeneic proteins do so). Another reason why immune responses raised by xenografts are so strong is that components of innate immunity that react with xenografts heighten responses by B cells and T cells.13Fearon DT Locksley RM The instructive role of innate immunity in the acquired immune response.Science. 1996; 272: 50-53Crossref PubMed Scopus (1431) Google Scholar, 14Carroll MC The role of complement and complement receptors in induction and regulation of immunity.Annu Rev Immunol. 1998; 16: 545-568Crossref PubMed Scopus (494) Google Scholar Although all allografts and xenografts incite immune responses (Table 1), the effect of the immune response depends considerably on whether the transplant consists of cells or tissues or of an organ (Figure 1). Initially, cell and tissue grafts are susceptible to “primary” or immediate nonfunction caused by natural killer cells, macrophages, and T cells.15Kaufman DB Platt JL Rabe FL Dunn DL Bach FH Sutherland DE Differential roles of Mac-1+ cells, and CD4+ and CD8+ T lymphocytes in primary nonfunction and classic rejection of islet allografts.J Exp Med. 1990; 172: 291-302Crossref PubMed Scopus (182) Google Scholar Allografts and xenografts are also subject to cellular rejection mediated by T cells and targeted especially against MHC antigens. However, cell and tissue grafts are not especially susceptible to injury by antibodies and complement, except when the graft resides within the vascular space. Why cell and tissue grafts are not efficiently attacked by humoral factors is not fully known but may reflect the relatively low concentrations of antibodies and complement found outside vascular spaces (lymphocytes, in contrast, actively migrate through blood vessel walls). In contrast to cell and tissue grafts, organ grafts are susceptible to humoral rejection. Humoral rejection is caused usually by antibodies directed against MHC antigens, blood groups, or, in the case of xenografts, antibodies against Gala1-3Gal10Galili U Interaction of the natural anti-Gal antibody with α-galactosyl epitopes: a major obstacle for xenotransplantation in humans.Immunol Today. 1993; 14: 480-482Abstract Full Text PDF PubMed Scopus (580) Google Scholar that act on blood vessels causing vascular rejection of various types (Figure 1). Hyperacute and acute humoral rejections are uncommon in allogeneic organ transplants because transplantation of such organs is not performed generally in recipients with existing antidonor antibodies (detected by cross-matching) and because immunosuppression controls production of new anti-donor antibodies. In contrast, humoral rejection is common in xenografts because all immunocompetent individuals make xenoreactive antibodies. Figure 1 lists chronic rejection as a form of humoral rejection. In some human subject experimental models, chronic rejection arises in individuals with anti-donor antibodies. However, other causes of chronic rejection are recognized and in humans may be more prevalent.16Halloran PF Melk A Barth C Rethinking chronic allograft nephropathy: the concept of accelerated senescence.J Am Soc Nephrol. 1999; 10: 167-181PubMed Google Scholar, 17Waaga AM Gasser M Laskowski I Tilney NL Mechanisms of chronic rejection.Curr Opin Immunol. 2000; 12: 517-521Crossref PubMed Scopus (66) Google Scholar Prevention and treatment of rejection are biological challenges that, even when successful, may impose complications on the treated individual. Immunosuppressive drugs usually prevent cellular rejection and help prevent development of antibodies against donor proteins (T-cell-dependent B-cell responses). However, conventional regimens of immunosuppressive drugs do not prevent production of anti-carbohydrate antibodies such as those directed against blood group antigens or against Gala1-3Gal. Because of this problem, researchers in the field of xenotransplantation have been keen to genetically engineer pigs to express human complement regulatory proteins that would limit complement-mediated injury18Cozzi E White DJ The generation of transgenic pigs as potential organ donors for humans.Nat Med. 1995; 1: 964-966Crossref PubMed Scopus (514) Google Scholar, 19McCurry KR Kooyman DL Alvarado CG et al.Human complement regulatory proteins protect swine-to-primate cardiac xenografts from humoral injury.Nat Med. 1995; 1: 423-427Crossref PubMed Scopus (487) Google Scholar and to disrupt the a1,3-glycosyltransferase gene to prevent synthesis of Gala1-3Gal in cloned pigs.20Lai L Kolber-Simonds D Park KW et al.Production of α-1,3-galactosyltransferase knockout pigs by nuclear transfer cloning.Science. 2002; 295: 1089-1092Crossref PubMed Scopus (1141) Google Scholar, 21Dai Y Vaught TD Boone J et al.Targeted disruption of the alpha1,3-galactosyltransferase gene in cloned pigs.Nat Biotechnol. 2002; 20: 251-255Crossref PubMed Scopus (622) Google Scholar Although both approaches have promise, especially when combined, genetic engineering may not suffice to achieve acceptance of xenografts comparable to the acceptance of allografts in the presence of conventional means of immunosuppression.22Platt JL Knocking out xenograft rejection.Nat Biotechnol. 2002; 20: 231-232Crossref PubMed Scopus (16) Google Scholar One way to prevent rejection of allografts and xenografts is induction of immunologic tolerance. Characterized by specific immune nonresponsiveness to the donor but full responsiveness to other donors and to infectious organisms, tolerance should allow a transplant to survive without immunosuppression. Many investigators are striving to devise safe and effective ways to induce tolerance for transplantation and autoimmune disease by such approaches as the engraftment of autologous or foreign bone marrow stem cells (in conjunction with treatments that destroy mature lymphocytes) and the administration of proteins that block co-stimulation of T lymphocytes. The subject of immunologic tolerance to allografts and xenografts has been reviewed recently.23Zheng XX Sanchez-Fueyo A Domenig C Strom TB The balance of deletion and regulation in allograft tolerance.Immunol Rev. 2003; 196: 75-84Crossref PubMed Scopus (94) Google Scholar, 24Walsh PT Strom TB Turka LA Routes to transplant tolerance versus rejection: the role of cytokines.Immunity. 2004; 20: 121-131Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar, 25Wekerle T Sykes M Induction of tolerance.Surgery. 2004; 135: 359-364Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar Currently, it is useful to consider that induction of tolerance is always a challenge and that the approaches vary depending on whether tolerance is to be induced to an isolated protein or carbohydrate, an MHC antigen, or many different antigens. Tolerance can be induced to individual proteins such as factor VIII.26Di Michele DM Immune tolerance: a synopsis of the international experience.Haemophilia. 1998; 4: 568-573Crossref PubMed Scopus (68) Google Scholar Inducing tolerance to isolated proteins generally involves administration of cytotoxic agents that preferentially destroy lymphocytes that respond by proliferation to those proteins. Inducing tolerance to allogeneic MHC antigens as expressed on foreign cells is a greater challenge because it may require temporary eradication or inhibition of all memory T cells. Eradicating memory T cells potentially leaves the treated individual with enduring lacunas in immune responsiveness27Mackall CL Fleisher TA Brown MR et al.Age, thymopoiesis, and CD4+ T-lymphocyte regeneration after intensive chemotherapy.N Engl J Med. 1995; 332: 143-149Crossref PubMed Scopus (948) Google Scholar and may not prevent the de novo generation of immunity by newly developing T cells.28Thomas JM Hubbard WJ Sooudi SK Thomas FT STEALTH matters: a novel paradigm of durable primate allograft tolerance.Immunol Rev. 2001; 183: 223-233Crossref PubMed Google Scholar Because the graft must remain in place for a long period while new T cells are produced, some approaches to tolerance induction involve administration of stem cells, particularly hematopoietic stem cells, that can provide an enduring way of eradicating reactive T cells and B cells.29Cosimi AB Sachs DH Mixed chimerism and transplantation tolerance.Transplantation. 2004; 77: 943-946Crossref PubMed Scopus (90) Google Scholar An alternative way of generating tolerance to transplantation for long periods is to generate “immunoregulatory T cells” that can provide ongoing suppression of immune responses.30Graca L Thompson S Lin CY Adams E Cobbold SP Waldmann H Both CD4(+)CD25(+) and CD4(+)CD25(-) regulatory cells mediate dominant transplantation tolerance.J Immunol. 2002; 168: 5558-5565PubMed Google Scholar How immunoregulatory T cells can be induced reliably and effectively for clinical application is not yet certain. Inducing tolerance to xenografts is an even greater challenge because xenografts carry a great diversity of foreign antigens. In fact, tolerance to xenografts from disparate species has not been achieved and may not be possible in the foreseeable future.31Samstein B Platt JL Xenotransplantation and tolerance.Philos Trans R Soc Lond B Biol Sci. 2001; 356: 749-758Crossref PubMed Scopus (17) Google Scholar, 32Hoerbelt R Madsen JC Feasibility of xeno-transplantation.Surg Clin North Am. 2004; 84: 289-307Abstract Full Text Full Text PDF PubMed Scopus (15) Google Scholar It is pertinent also to mention that, under some conditions, stem cells can induce tolerance.33Bartholomew A Sturgeon C Siatskas M et al.Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo.Exp Hematol. 2002; 30: 42-48Abstract Full Text Full Text PDF PubMed Scopus (1969) Google Scholar, 34Fandrich F Lin X Chai GX et al.Preimplantation-stage stem cells induce long-term allogeneic graft acceptance without supplementary host conditioning.Nat Med. 2002; 8: 171-178Crossref PubMed Scopus (282) Google Scholar We recently reviewed the means by which stem cells may induce tolerance.35Koch CA Platt JL Natural mechanisms for evading graft rejection: the fetus as an allograft.Springer Semin Immunopathol. 2003; 25: 95-117Crossref PubMed Scopus (47) Google Scholar Clearly, the ability of foreign stem cells to induce tolerance may be critical to the ready application of therapies using those cells. The field of transplantation began with the development of vascular anastomosis.2Ullman E Tissue and organ transplantation.Ann Surg. 1914; 60: 195-219Crossref PubMed Google Scholar, 3Guthrie CC Blood-Vessel Surgery and Its Applications. Longmans, Green & Co, New York, NY1912Google Scholar This technique enabled surgeons to implant organs in experimental animals, showing that an organ could function after removal from its natural anatomical attachments.1Carrel A Transplantation in mass of the kidneys.J Exp Med. 1908; 10: 98-140Crossref PubMed Scopus (63) Google Scholar We now know that intact heart, lungs, kidneys, liver, and pancreas function after removal from the body and transplantation into another individual, even when the source of the organ is a genetically disparate species.36Schmoeckel M Bhatti FN Zaidi A et al.Orthotopic heart transplantation in a transgenic pig-to-primate model [published correction appears in Transplantation. 1998;66:943].Transplantation. 1998; 65: 1570-1577Crossref PubMed Scopus (189) Google Scholar, 37Daggett CW Yeatman M Lodge AJ et al.Total respiratory support from swine lungs in primate recipients.J Thorac Cardiovasc Surg. 1998; 115: 19-27Abstract Full Text Full Text PDF PubMed Scopus (65) Google Scholar, 38Sablinski T Latinne D Gianello P et al.Xenotransplantation of pig kidneys to nonhuman primates, I: development of the model.Xenotransplantation. 1995; 2: 264-270Crossref Scopus (68) Google Scholar, 39Ramirez P Chavez R Majado M et al.Life-supporting human complement regulator decay accelerating factor transgenic pig liver xenograft maintains the metabolic function and coagulation in the nonhuman primate for up to 8 days.Transplantation. 2000; 70: 989-998Crossref PubMed Scopus (134) Google Scholar There are several limitations to cellular transplantation. First, in contrast to what is observed for organs, cells and tissues removed from their natural attachments do not necessarily function after transplantation. For example, beta cells isolated from the pancreas produce relatively little insulin in culture and function poorly after transplantation.40Pipeleers D The biosociology of pancreatic B cells.Diabetologia. 1987; 30: 277-291Crossref PubMed Scopus (148) Google Scholar This problem is solved in part by using pancreatic islets, within which cellular attachments are maintained. However, pancreatic islets are not available in sufficient numbers for all who need them. Hence, some researchers have turned to the potential use of stem cells that, unlike fixed tissue cells, may survive after isolation and can, at least in principle, be coaxed to differentiate into mature cells and tissues.41Lumelsky N Blondel O Laeng P Velasco I Ravin R McKay R Differentiation of embryonic stem cells to insulin-secreting structures similar to pancreatic islets [published correction appears in Science. 2001;293:428].Science. 2001; 292: 1389-1394Crossref PubMed Scopus (1306) Google Scholar We describe the potential uses and limitations of stem cells for this purpose in the “Stem Cells” section. A second limitation of cellular transplantation is obtaining a sufficient mass of viable cells to exert a biological effect. For example, 1 kg of human liver tissue, representing the probable minimal physiological mass, contains approximately 250 × 109 hepatocytes. This large number of cells may be obtained from a donated liver; however, such livers are in short supply and are histoincompatible with the person to be treated. Later, we discuss how this problem may be overcome by use of stem cells. The third limitation to cellular transplantation, especially in using stem cells, involves getting the cells to mature and contribute physiological functions. Stem cells can mature potentially, but maturation requires extrinsic cues delivered by growth factors, extracellular matrix, adjacent cells, and adjacent tissues, which may be unavailable. Even a greater challenge may be the positioning of cells in a way that normal functions can be exerted by those cells that do mature. For example, myoblasts implanted in the heart can mature42Murry CE Wiseman RW Schwartz SM Hauschka SD Skeletal myoblast transplantation for repair of myocardial necrosis.J Clin Invest. 1996; 98: 2512-2523Crossref PubMed Scopus (553) Google Scholar and contribute to myocardial contractility,43Taylor DA Atkins BZ Hungspreugs P et al.Regenerating functional myocardium: improved performance after skeletal myoblast transplantation [published correction appears in Nat Med. 1998;4:1200].Nat Med. 1998; 4: 929-933Crossref PubMed Scopus (996) Google Scholar but it is unlikely that function of randomly positioned myocytes will approach that of normal myocardium. This limitation may be addressed by growing cells on an artificial matrix, that is, by tissue engineering.44Fukuda K Development of regenerative cardiomyocytes from mesenchymal stem cells for cardiovascular tissue engineering.Artif Organs. 2001; 25: 187-193Crossref PubMed Scopus (242) Google Scholar, 45Bianco P Robey PG Stem cells in tissue engineering.Nature. 2001; 414: 118-121Crossref PubMed Scopus (836) Google Scholar, 46Griffith LG Naughton G Tissue engineering—current challenges and expanding opportunities.Science. 2002; 295: 1009-1014Crossref PubMed Scopus (1941) Google Scholar However, tissue engineering is applied more readily to repairing focal defects and cannot be used to generate whole organs. Nearly every day we hear about a new technology or a new application for an existing technology that could be used for augmenting or replacing organ function. Naturally, those who develop new technologies know the most about them and believe strongly in them. Journals are more likely to publish positive than negative results. Consequently, scientists and the public may see a distorted or incomplete view of the limitations of these technologies. In the next section, we have tried to provide a balanced perspective on some technologies that may be applied for augmenting or replacing organ function. We do this with some trepidation because we realize that technologies improve over time, as does our awareness of the limitations. Still, we believe it important to avoid assuming that our technology, eg, stem cells, will solve every problem. Fully implantable artificial organs have been sought for decades as means for augmenting or replacing organ function. Implantable defibrillators help prevent some cases of sudden cardiac failure and death, and application will broaden with improvements in the ability to predict life-threatening ventricular arrhythmias. The left ventricular assist device can be used successfully in the treatment of left ventricular failure either as a prelude to cardiac transplantation or even as a long-term treatment.47Rose EA Gelijns AC Moskowitz AJ Randomized Evaluation of Mechanical Assistance for the Treatment of Congestive Heart Failure (REMATCH) Study Group et al.Long-term mechanical left ventricular assistance for end-stage heart failure.N Engl J Med. 2001; 345: 1435-1443Crossref PubMed Scopus (3363) Google Scholar Fully implantable artificial hearts are in various stages of development and are used primarily as a “bridge” to transplantation.48Copeland JG Smith RG Arabia FA CardioWest Total Artificial Heart Investigators et al.Cardiac replacement with a total artificial heart as a bridge to transplantation.N Engl J Med. 2004; 351: 859-867Crossref PubMed Scopus (416) Google Scholar Early experience with these devices suggests that use may be complicated by thrombosis or infection; however, there is reason to believe that improvement in engineering will address these problems, at least in part. Despite this encouraging view with respect to the heart, development of fully implantable devices to replace the lungs, kidneys, and liver seems remote. That is not to say that external devices, such as those used for dialysis and membrane oxygenation, cannot be adapted for routine use, but rather that the biological approaches discussed subsequently may provide greater efficiency and acceptability. Because engineering of artificial devices requires special expertise and considerable cost, it seems important to keep a current perspective on the status of biological therapies that often can be brought into clinical practice more quickly. For 100 years, xenotransplantation (transplantation between individuals of different species) has been considered the most obvious way to replace failing organs.2Ullman E Tissue and organ transplantation.Ann Surg. 1914; 60: 195-219Crossref PubMed Google Scholar, 49Jaboulay M De reins au pli du coude par soutures arterielles et veineuses.Lyon Med. 1906; 107: 575-577Google Scholar Xenotransplantation with use of the organs of lower animals such as pigs would clearly address the shortage of human organs, and because the grafts may resist infection by human viruses50Starzl TE Fung J Tzakis A et al.Baboon-to-human liver transplantation.Lancet. 1993; 341: 65-71Abstract PubMed Scopus (360) Google Scholar, 51Mueller YM Davenport C Ildstad ST Xenotransplantation: application of disease resistance.Clin Exp Pharmacol Physiol. 1999; 26: 1009-1012Crossref PubMed Scopus (13) Google Scholar, 52Cascalho M Platt JL Xenotransplantation and other means of organ replacement.Nat Rev Immunol. 2001; 1: 154-160Crossref PubMed Scopus (75) Google Scholar or recurrence of disease that caused organ failure, they may be preferred even to allografts, in some circumstances. In the future, xenotransplantation may provide the means to customize transplants by genetic manipulation of the animals. Beyond this, animals, particularly fetal animals, may provide an environment in which to grow human tissues or organs de novo, hence organogenesis.52Cascalho M Platt JL Xenotransplantation and other means of organ replacement.Nat Rev Immunol. 2001; 1: 154-160Crossref PubMed Scopus (75) Google Scholar Finally, xenotransplants may be used as a temporary measure while customized approaches such as organogenesis or therapeutic cloning are co" @default.
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• W2082073343 title "New Technologies for Organ Replacement and Augmentation" @default.
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• next