Xenotransplantation--state of the art--update 1999.

Organ transplantation is limited by the number of cadaveric human donor organs that become available. Xenotransplantation - the transplantation of organs and tissues between animal species - would supply an unlimited number of organs and offer many other advantages. The pig has been identified as the most suitable donor animal. Pig organs, when transplanted into humans or nonhuman primates, are, however, rejected hyperacutely within minutes by antibody-mediated complement activation. Human anti-pig antibodies have been identified as being directed against galactose alpha 1-3galactose (alpha Gal) epitopes on pig vascular endothelium. Methods have been successfully developed to prevent hyperacute rejection. These include (i) depletion or inhibition of recipient antibodies or complement and (ii) development of transgenic pigs that express a human complement-regulatory protein (e.g. hDAF). The persistence or return of anti-pig antibody, however, even following the use of hDAF pig organs, eventually leads to what has been variously termed "acute vascular rejection" or "delayed xenograft rejection", which is again believed to be largely antibody-dependent. Nevertheless, experimental pig-to-primate organ xenotransplantation now results in transplant function for days and weeks rather than minutes. Little is yet known of the nature of the acute cellular rejection response that is anticipated to follow, and of any subsequent chronic rejection that may develop. Tolerance to both the alpha Gal epitope and to swine leukocyte antigens (SLA) is being explored using gene therapy techniques and by the induction of hematopoietic cell chimerism. The development of genetically engineered pigs that do not express the alpha Gal epitope is also being pursued. Considerable progress has been made in recent years, but experimental results do not yet warrant the initiation of a clinical trial of organ xenotransplantation. However, trials are already underway of pig cell transplants in patients with diabetes and neurodegenerative conditions, such as Parkinson's disease.

[1]  R. Bollinger,et al.  The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants. , 1998, The Journal of clinical investigation.

[2]  D. White,et al.  The generation of transgenic pigs as potential organ donors for humans , 1995, Nature Medicine.

[3]  C. Ferran,et al.  Delayed xenograft rejection. , 1996, World journal of surgery.

[4]  D. Sachs,et al.  Pharmacologic immunosuppressive therapy and extracorporeal immunoadsorption in the suppression of anti‐αGal antibody in the baboon , 1998, Xenotransplantation.

[5]  R. Oriol,et al.  CARBOHYDRATE ANTIGENS OF PIG TISSUES REACTING WITH HUMAN NATURAL ANTIBODIES AS POTENTIAL TARGETS FOR HYPERACUTE VASCULAR REJECTION IN PIG‐TO‐MAN ORGAN XENOTRANSPLANTATION1 , 1993, Transplantation.

[6]  O. Korsgren,et al.  LARGE‐SCALE PRODUCTION OF FETAL PORCINE PANCREATIC ISLETLIKE CELL CLUSTERS: An Experimental Tool for Studies of Islet Cell Differentiation and Xenotransplantation , 1988, Transplantation.

[7]  D. Sachs,et al.  Discordant organ xenotransplantation in primates: world experience and current status. , 1998, Transplantation.

[8]  M. Sandrin,et al.  Overcoming the Anti-Galα(1–3)Gal Reaction To Avoid Hyperacute Rejection: Molecular Genetic Approaches , 1997 .

[9]  D. Cooper,et al.  Screening of baboons as potential liver donors for humans , 1995, Transplantation proceedings.

[10]  G. L. Ong,et al.  The Specificity of Alternative Complement Pathway‐Mediated Lysis of Erythrocytes: A Survey of Complement and Target Cells from 25 Species , 1993, Scandinavian journal of immunology.

[11]  B. Reichart,et al.  Prolongation of cardiac xenograft (vervet monkey to baboon) function by a combination of total lymphoid irradiation and immunosuppressive drug therapy. , 1987, Transplantation proceedings.

[12]  T. Sablinski,et al.  Xenotransplantation from pig to cynomolgus monkey: the potential for overcoming xenograft rejection through induction of chimerism. , 1994, Transplantation proceedings.

[13]  D. Sachs,et al.  Mixed chimerism and permanent specific transplantation tolerance induced by a nonlethal preparative regimen , 1989, The Journal of experimental medicine.

[14]  R. Michler,et al.  Cardiac xenograft survival in baboons treated with cyclosporine in combination with conventional immunosuppression. , 1987, Transplantation proceedings.

[15]  A. Robins,et al.  The alpha-1,3-galactosyltransferase knockout mouse. Implications for xenotransplantation. , 1996, Transplantation.

[16]  B. Gridelli,et al.  Immunopathology of liver allografts and xenografts in nonhuman primates. , 1993, Transplantation proceedings.

[17]  A. Sun,et al.  Normalization of diabetes in spontaneously diabetic cynomologus monkeys by xenografts of microencapsulated porcine islets without immunosuppression. , 1996, The Journal of clinical investigation.

[18]  O. Korsgren,et al.  THE MAIN INFILTRATING CELL IN XENOGRAFT REJECTION IS A CD4+ MACROPHAGE AND NOT A T LYMPHOCYTE , 1995, Transplantation.

[19]  C. Ferran,et al.  A20 inhibits NF-kappaB activation in endothelial cells without sensitizing to tumor necrosis factor-mediated apoptosis. , 1998, Blood.

[20]  J. Griffiss,et al.  Interaction between human natural anti-alpha-galactosyl immunoglobulin G and bacteria of the human flora , 1988, Infection and immunity.

[21]  H. Auchincloss,et al.  Mechanism of Cellular Xenograft Rejection , 1991 .

[22]  D. Fearon,et al.  Effect of repetitive doses of soluble human complement receptor type 1 on survival of discordant cardiac xenografts. , 1993, Transplantation Proceedings.

[23]  M. Satake,et al.  Immunological Characteristics of Islet Cell Xenotransplantation in Humans and Rodents , 1994, Immunological reviews.

[24]  A. Dalmasso,et al.  Antibody removal by column immunoabsorption prevents tissue injury in an ex vivo model of pig-to-human xenograft hyperacute rejection. , 1995, The Journal of surgical research.

[25]  H. Auchincloss,et al.  CD4+ T cells, without CD8+ or B lymphocytes, can reject xenogeneic skin grafts , 1994 .

[26]  R. Waldherr,et al.  Prolongation of discordant renal xenograft survival by depletion of complement. Comparative effects of systemically administered cobra venom factor and soluble complement receptor type 1 in a guinea‐pig to rat model , 1994, Transplant international : official journal of the European Society for Organ Transplantation.

[27]  B. Reichart,et al.  Virological implications of the use of primates in xenotransplantation. , 1987, Transplantation proceedings.

[28]  G. Abouna.  Extracorporeal Xenogeneic Liver Perfusion for the Treatment of Hepatic Failure , 1997 .

[29]  A. Sun,et al.  Xenografts of rat islets into diabetic mice. An evaluation of new smaller capsules. , 1992, Transplantation.

[30]  R. Oriol,et al.  PROTECTION OF PIG KIDNEY (PK15) CELLS FROM THE CYTOTOXIC EFFECT OF ANTI‐PIG ANTIBODIES BY α‐GALACTOSYL OLIGOSACCHARIDES1 , 1994, Transplantation.

[31]  W. Hancock.  Immunopathology of Discordant Xenograft Rejection , 1997 .

[32]  D. Sachs,et al.  Xenogeneic Tolerance Through Hematopoietic Cell and Thymic Transplantation , 1997 .

[33]  J. Pober,et al.  Porcine aortic endothelial cells activate human T cells: direct presentation of MHC antigens and costimulation by ligands for human CD2 and CD28. , 1994, Immunity.

[34]  J. Wallwork,et al.  Effect of Transgenic Expression of Human Decay—Accelerating Factor on the Inhibition of Hyperacute Rejection of Pig Organs , 1997 .

[35]  R. Ceredig,et al.  Role of CD4+ T-Lymphocytes in Rejection by Mice of Fetal Pig Proislet Xenografts , 1989, Diabetes.

[36]  R. Pierson,et al.  Xenogeneic proliferation and lymphokine production are dependent on CD4+ helper T cells and self antigen-presenting cells in the mouse , 1990, The Journal of experimental medicine.

[37]  Ole Isacson,et al.  Histological evidence of fetal pig neural cell survival after transplantation into a patient with Parkinson's disease , 1997, Nature Medicine.

[38]  M. Goddard,et al.  Orthotopic heart transplantation in a transgenic pig-to-primate model. , 1998, Transplantation.

[39]  S. Kosanke,et al.  Comparative histopathology of hepatic allografts and xenografts in the nonhuman primate , 1998, Xenotransplantation.

[40]  R. Michler,et al.  Role of natural killer cells, macrophages, and accessory molecule interactions in the rejection of pig-to-primate xenografts beyond the hyperacute period. , 1998, Human immunology.

[41]  J. Platt,et al.  Genetic therapies for xenotransplantation. , 1998, Journal of the American College of Surgeons.

[42]  R. Michler,et al.  Anti-GaL IgG antibodies in sera of newborn humans and baboons and its significance in pig xenotransplantation. , 1997, Transplantation.

[43]  C H Hammer,et al.  Homologous species restriction in lysis of erythrocytes by terminal complement proteins. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[44]  D. Cooper.  Depletion of natural antibodies in non-human primates--a step towards successful discordant xenografting in humans. , 1992, Clinical transplantation.

[45]  A. Norin,et al.  ONE‐YEAR MONKEY HEART XENOGRAFT SURVIVAL IN CYCLOSPORINE‐TREATED BABOONS SUPPRESSION OF THE XENOANTIBODY RESPONSE WITH TOTAL‐LYMPHOID IRRADIATION , 1992, Transplantation.

[46]  J. Najarian,et al.  EXPERIMENTAL RENAL HETEROTRANSPLANTATION: I. In Widely Divergent Species , 1966, Transplantation.

[47]  W. Baldwin,et al.  THE EFFECT OF SOLUBLE COMPLEMENT RECEPTOR TYPE 1 ON HYPERACUTE XENOGRAFT REJECTION , 1991, Transplantation.

[48]  D. Boehm,et al.  Optimalization of immunosuppression after xenogeneic heart transplantation in primates. , 1989, The Journal of heart transplantation.

[49]  E. Korchagina,et al.  In vivo immunoadsorption of antipig antibodies in baboons using a specific Gal(alpha)1-3Gal column. , 1996, Transplantation.

[50]  B. Reichart,et al.  The role of ABO blood group compatibility in heart transplantation between closely related animal species. An experimental study using the vervet monkey to baboon cardiac xenograft model. , 1989, The Journal of thoracic and cardiovascular surgery.

[51]  F. Mangili,et al.  Early recognition of a discordant xenogeneic organ by human circulating lymphocytes. , 1992, Journal of immunology.

[52]  M. Satake,et al.  Limited specificity of xenoantibodies in diabetic patients transplanted with fetal porcine islet cell clusters. Main antibody reactivity against α‐linked galactose‐containing epitopes , 1994 .

[53]  D. Cooper,et al.  Monoclonal antiidiotypic antibodies neutralize cytotoxic effects of anti-alphaGal antibodies. , 1996, Transplantation.

[54]  J. Cunningham,et al.  TLI induces specific B-cell unresponsiveness and long-term monkey heart xenograft survival in cyclosporine-treated baboons. , 1992, Transplantation Proceedings.

[55]  P. Friend,et al.  Life-supporting pig-to-primate renal xenotransplantation using genetically modified donors. , 1998, Transplantation.

[56]  P. Dellapelle,et al.  Human cell-mediated rejection of porcine xenografts in an immunodeficient mouse model. , 1997, Transplantation.

[57]  F. Reinholt,et al.  Transplantation of porcine fetal pancreas to diabetic patients , 1994, The Lancet.

[58]  D. Zopf,et al.  Intravenous infusion of Galalpha1-3Gal oligosaccharides in baboons delays hyperacute rejection of porcine heart xenografts. , 1998, Transplantation.

[59]  S. Kosanke,et al.  Auxiliary liver allografting and xenografting in the nonhuman primate. , 1995, Transplantation.

[60]  D. Cooper.  Ethical aspects of xenotransplantation of current importance , 1996 .

[61]  A. Rose,et al.  Effects of cyclosporine and antibody adsorption on pig cardiac xenograft survival in the baboon. , 1988, The Journal of heart transplantation.

[62]  H. Ohdan,et al.  Tolerization of Anti–Galα1-3Gal Natural Antibody–forming B Cells by Induction of Mixed Chimerism , 1998, The Journal of experimental medicine.

[63]  T. Sablinski,et al.  Removal of anti-porcine natural antibodies from human and nonhuman primate plasma in vitro and in vivo by a Galalpha1-3Galbeta1-4betaGlc-X immunoaffinity column. , 1998, Transplantation.

[64]  R. Colvin,et al.  Mixed Allogeneic Chimerism And Renal Allograft Tolerance In Cynomolgus Monkeys , 1995, Transplantation.

[65]  D. Cooper,et al.  Clinical xenotransplantation: past, present and future. , 1997, Annals of the Royal College of Surgeons of England.

[66]  J. A. Smit,et al.  Experimental Concordant Kidney Xenotransplantation in Primates , 1997 .

[67]  C. Ferran,et al.  Mechanisms of Delayed Xenograft Rejection , 1997 .

[68]  A. Kirk,et al.  The effect of soluble complement receptor type 1 on hyperacute rejection of porcine xenografts. , 1994, Transplantation.

[69]  J. Turtle,et al.  Growth and Hormonal Content of Human Fetal Pancreas Passaged in Athymic Mice , 1986, Diabetes.

[70]  H. Auchincloss,et al.  The strength of cell‐mediated xenograft rejection in the mouse is due to the CD4+ indirect response , 1998, Xenotransplantation.

[71]  D. Sachs,et al.  Human anti-porcine xenogeneic T cell response. Evidence for allelic specificity of mixed leukocyte reaction and for both direct and indirect pathways of recognition. , 1995, Journal of immunology.

[72]  D. Cooper,et al.  The Pig as Potential Organ Donor for Man , 1991 .

[73]  R. Oriol,et al.  Oligosaccharides and Discordant Xenotransplantation , 1994, Immunological reviews.

[74]  R. Lanza,et al.  Xenotransplantation of cells and tissues: application to a range of diseases, from diabetes to Alzheimer's. , 1998, Molecular medicine today.

[75]  D. Cramer,et al.  The use of a pig liver xenograft for temporary support of a patient with fulminant hepatic failure. , 1995, Transplantation.

[76]  J. Allan.  Xenotransplantation at a crossroads: Prevention versus progress , 1996, Nature Medicine.

[77]  T. Kawai,et al.  Xenotransplantation from pig to cynomolgus monkey: approach toward tolerance induction. , 1993, Transplantation proceedings.

[78]  A. Sun,et al.  Prolonged Reversal of Diabetic State in NOD Mice by Xenografts of Microencapsulated Rat Islets , 1991, Diabetes.

[79]  A. Rose,et al.  Delayed xenograft rejection of pig-to-baboon cardiac transplants after cobra venom factor therapy. , 1997, Transplantation.

[80]  E. Setter,et al.  Enzymatic remodelling of the carbohydrate surface of a xenogenic cell substantially reduces human antibody binding and complement-mediated cytolysis , 1995, Nature Medicine.

[81]  P. Lacy,et al.  Renal subcapsular xenotransplantation of purified porcine islets. , 1987, Transplantation.

[82]  U. Galili.  Interaction of the natural anti-Gal antibody with alpha-galactosyl epitopes: a major obstacle for xenotransplantation in humans. , 1993, Immunology today.

[83]  H. Auchincloss,et al.  Human anti‐pig cell‐mediated cytotoxicity in vitro involves non‐T as well as T cell components , 1996 .

[84]  M. Satake,et al.  Specificities of human IgM and IgG anticarbohydrate xenoantibodies found in the sera of diabetic patients grafted with fetal pig islets , 1994 .

[85]  M. Satake,et al.  Kinetics and character of xenoantibody formation in diabetic patients transplanted with fetal porcine islet cell clusters , 1994 .

[86]  D. Sachs,et al.  Inhibition of xenoreactive natural antibody production by retroviral gene therapy. , 1998, Science.

[87]  T. Sundt,et al.  Specific tolerance induction across a xenogeneic barrier: production of mixed rat/mouse lymphohematopoietic chimeras using a nonlethal preparative regimen , 1990, The Journal of experimental medicine.

[88]  D. Sachs,et al.  Anti-Gal(alpha)1-3Gal antibody response to porcine bone marrow in unmodified baboons and baboons conditioned for tolerance induction. , 1998, Transplantation.

[89]  R. Pierson,et al.  Xenogeneic skin graft rejection is especially dependent on CD4+ T cells , 1989, The Journal of experimental medicine.

[90]  R. Gill,et al.  CD4+ T cells are both necessary and sufficient for islet xenograft rejection. , 1994, Transplantation proceedings.

[91]  A. Mellgren,et al.  Tissue Culture of Human Fetal Pancreas: Development and Function of B-Cells In Vitro and Transplantation of Explants to Nude Mice , 1985, Diabetes.

[92]  D H Sachs,et al.  The pig as a potential xenograft donor. , 1994, Veterinary immunology and immunopathology.

[93]  H. Gooszen,et al.  HUMAN COMPLEMENT ACTIVATION VIA THE ALTERNATIVE PATHWAY ON PORCINE ENDOTHELIUM INITIATED BY IgA ANTIBODIES , 1995, Transplantation.

[94]  C. Ferran,et al.  Modification of vascular responses in xenotransplantation: Inflammation and apoptosis , 1997, Nature Medicine.

[95]  S. Shohet,et al.  Man, apes, and Old World monkeys differ from other mammals in the expression of alpha-galactosyl epitopes on nucleated cells. , 1988, The Journal of biological chemistry.

[96]  D. Cooper,et al.  Identification of carbohydrate structures that bind human antiporcine antibodies: implications for discordant xenografting in humans. , 1992, Transplantation proceedings.

[97]  C. Marboe,et al.  Comparable survival of intra-species and cross-species primate cardiac transplants. , 1987, Transplantation proceedings.

[98]  J. Platt,et al.  Prolongation of cardiac xenograft survival by depletion of complement. , 1993, Transplantation.

[99]  D. Cooper.  Xenoantigens and xenoantibodies , 1998, Xenotransplantation.

[100]  Calne Ry.  Organ transplantation between widely disparate species. , 1970 .

[101]  E. Koren,et al.  Manipulation of the anti‐αGal antibody‐αGal epitope system in experimental discordant xenotransplantation , 1996 .

[102]  U. Galili,et al.  A Unique Natural Human Igg Antibody with Anti-a-galactosyl Specificity , 2022 .

[103]  M. Sandrin,et al.  Anti-pig IgM antibodies in human serum react predominantly with Gal(alpha 1-3)Gal epitopes. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[104]  D. Sachs,et al.  Depletion of anti‐Galα1–3Gal antibody in baboons by specific α‐Gal immunoaffinity columns , 1998 .

[105]  D. Sachs,et al.  Xenogeneic human anti‐pig cytotoxicity mediated by activated natural killer cells , 1996 .

[106]  J. Platt.  Hyperacute Xenograft Rejection , 1995 .

[107]  R. Weiss.  Transgenic pigs and virus adaptation , 1998, Nature.

[108]  H. Reichenspurner,et al.  Histopathology of hyperacute rejection of the heart: experimental and clinical observations in allografts and xenografts. , 1991, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[109]  P Aebischer,et al.  TRANSPLANTATION IN HUMANS OF ENCAPSULATED XENOGENEIC CELLS WITHOUT IMMUNOSUPPRESSION: A PRELIMINARY REPORT , 1994, Transplantation.

[110]  A. Rose,et al.  A histopathologic grading system of hyperacute (humoral, antibody-mediated) cardiac xenograft and allograft rejection. , 1996, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[111]  W. Hancock,et al.  Investigation of the anti‐complement agents, FUT‐175 and K76COOH, in discordant xenotransplantation , 1996 .

[112]  D. Sachs,et al.  Human anti‐pig T‐cell mediated cytotoxicity , 1996 .

[113]  A. Dalmasso,et al.  The synergistic effect of combined antibody and complement depletion on discordant cardiac xenograft survival in nonhuman primates. , 1994, Transplantation.

[114]  G. R. Carson,et al.  Soluble human complement receptor type 1: in vivo inhibitor of complement suppressing post-ischemic myocardial inflammation and necrosis. , 1990, Science.

[115]  R. Oriol,et al.  Evidence that intravenously administered alpha-galactosyl carbohydrates reduce baboon serum cytotoxicity to pig kidney cells (PK15) and transplanted pig hearts. , 1994, Transplantation.

[116]  B. Gridelli,et al.  Xenogeneic orthotopic liver transplantation in nonhuman primates. , 1993, Transplantation proceedings.

[117]  D. Sachs,et al.  Mixed allogeneic chimeras prepared by a non-myeloablative regimen: requirement for chimerism to maintain tolerance. , 1992, Bone marrow transplantation.

[118]  L. Svensson,et al.  Intravenous synthetic αgal saccharides delay hyperacute rejection following pig‐to‐baboon heart transplantation , 1999, Xenotransplantation.

[119]  E. Cozzi,et al.  Production of pigs transgenic for human DAF: A strategy for xenotransplantation , 1995 .

[120]  P. Noguchi,et al.  Xenotransplantation and xenogeneic infections. , 1995, The New England journal of medicine.

[121]  R. Colvin,et al.  Porcine kidney and heart transplantation in baboons undergoing a tolerance induction regimen and antibody adsorption. , 1999, Transplantation.

[122]  P. Aebischer,et al.  Treatment of amyotrophic lateral sclerosis using a gene therapy approach. , 1995, European neurology.

[123]  J. Platt,et al.  Human complement regulatory proteins protect swine-to-primate cardiac xenografts from humoral injury , 1995, Nature Medicine.

[124]  O. Korsgren,et al.  Transplantation of porcine fetal pancreas to a diabetic patient. , 1992, Transplantation proceedings.

[125]  R. Oriol,et al.  Specific intravenous carbohydrate therapy: a new approach to the inhibition of antibody-mediated rejection following ABO-incompatible allografting and discordant xenografting. , 1993, Transplantation proceedings.

[126]  K. Stuhlmeier,et al.  Barriers to xenotransplantation , 1995, Nature Medicine.