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Ann Thorac Surg 2000;70:320-326
© 2000 The Society of Thoracic Surgeons

Current review

Cardiac xenotransplantation: clinical experience and future direction

David H. Adams, MDa, Raymond H. Chen, MD, PhDa, Alexander Kadner, MDa

a Division of Cardiac Surgery, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA

Address reprint requests to Dr Adams, Cardiac Surgery, Brigham and Women’s Hospital, 15 Francis St, Boston, MA 02115
e-mail: dadams{at}partners.org


   Abstract
Top
 Abstract
Introduction
 Immunological barriers
 Past clinical experience
 Xenotransplantation today
 Remaining obstacles
 Future clinical trials
 References
 
The shortage of human organs has focused research on finding an animal source of replacement organs. The immunological barriers to xenotransplantation are now more clearly defined, allowing retrospective interpretation of past clinical experience in humans. Due to physiological compatibilities as well as ethical and infectious considerations, pigs have now emerged as the most likely source of future xenografts. The introduction of transgenic pigs expressing human complement regulatory proteins and new immunosuppressive regimens have shown early promise in the laboratory, although further advancements are needed to advance to clinical trials. Additional clarification of infectious risks and patient strategies are remaining obstacles to application in the clinical arena.


   Introduction
Top
 Abstract
 Introduction
Immunological barriers
 Past clinical experience
 Xenotransplantation today
 Remaining obstacles
 Future clinical trials
 References
 
Shortage in the availability of suitable human donors limits the application of heart replacement in patients with severely impaired cardiac function. It is estimated that tens of thousands of patients per year would benefit from heart transplantation, yet less than 3,500 cardiac transplants worldwide are performed annually [1]. As soon as the feasibility of heart replacement was demonstrated in the laboratory, the limitation of human donors led surgeons to explore the use of animal donors in patients dying of acute heart dysfunction. Recent experimental advances have raised the feasibility of successful pig xenotransplantation into man. This article will review currently understood immunologic barriers in cardiac xenotransplantation. Previous clinical attempts at cardiac xenotransplantation will be discussed in light of these barriers. Finally, current strategies will be reviewed and remaining obstacles defined as pig to human cardiac xenotransplantation moves toward the clinical arena.


   Immunological barriers
Top
 Abstract
 Introduction
 Immunological barriers
Past clinical experience
 Xenotransplantation today
 Remaining obstacles
 Future clinical trials
 References
 
The immunological barriers increase substantially as one moves down the phylogenic tree from humans in search for suitable organs. Consequently, hearts from lower mammals are destroyed within minutes after transplantation into humans [2]. Upon implantation, hearts become grossly congested and cyanotic. Microscopic examination shows interstitial hemorrhage, intravascular thrombosis, perivascular edema, polymononuclear cellular adherence, endothelial cell activation, and myocyte vacuolization [3]. The mechanism behind the hyperacute rejection of lower animal hearts is the expression of the {alpha} (1,3) galactose disaccharide (Gal) carbohydrate on their vascular endothelium [4]. This Gal sugar moiety, similar to that determining ABO blood types, is expressed by all mammals except humans and higher primates, thus humans have circulating natural antibodies against this antigen [5]. Once anti-Gal natural antibodies bind to a xenograft, they activate the complement cascade and trigger endothelial cell dysfunction, platelet aggregation, and vascular thrombosis [6–9].

The hyperacute rejection of xenografts is further aggravated by the physiological incompatibility between species. For instance, the complement cascade is normally closely regulated by complement regulatory proteins which are species-restricted such that porcine complement regulatory proteins fail to down-regulate primate complements [10–12]. The absence of regulatory mechanisms contributes to the explosive destruction of xenografts during hyperacute rejection [13].

Donor organs from primates do not express Gal on their endothelial surface and therefore do not undergo hyperacute rejection in human recipients. Nonetheless, primate-to-primate xenografts invariably undergo rejection days to weeks after implantation. The mechanism of failure is less well defined than that of hyperacute rejection. Theories for delayed xenograft failure include anti-donor humoral-mediated rejection [14], inappropriate endothelial cell activation [15, 16], cell-mediated graft destruction [17], or incompatible thrombin and thrombomodulin regulation [18, 19].


   Past clinical experience
Top
 Abstract
 Introduction
 Immunological barriers
 Past clinical experience
Xenotransplantation today
 Remaining obstacles
 Future clinical trials
 References
 
A total of eight experiences with clinical cardiac xenotransplantation in man have been previously reported in the literature. In each instance, lack of a suitable human donor led to an attempted xenotransplant. Given the fact that these cases occurred during a 28-year period in multiple centers, it is not surprising that available clinical and pathological details vary considerably. Below, we will summarize the available information regarding each case, and comment on the outcome in light of what is now known regarding immunological barriers.

Case reports
Hardy (1964)
Hardy and colleagues performed the first cardiac xenotransplant in 1964 in a 64-year-old man in severe cardiogenic shock for several days secondary to ischemic cardiomyopathy [20]. A chimpanzee heart was placed into the patient in an orthotopic position. The xenograft generated a systolic blood pressure of 90–100 mmHg with a cardiac output of 4.2 l/min. After 2 hours, the graft failed and postmortem microscopic examination "confirmed the approximate 90% occlusion of the coronary vessels." Mode of graft failure was attributed to "its relative small size, and to the advanced state of metabolic deterioration of the recipient ... ".

Comment: This case not only represented the first cardiac xenotransplant, but the first attempt at cardiac replacement of any kind in man. Even in the current era, allotransplantation in a recipient in this preoperative condition would likely fail. The recipient was not immunosuppressed and ABO- and HLA-typing were not performed. Pathologic data suggests acute vascular rejection may have occurred.

Cooley (1968)
In 1968, Cooley transplanted a sheep heart orthotopically into a 48-year-old man dying with terminal ischemic cardiomyopathy [21]. Immunosuppressive therapy, if any, was not reported. The xenograft failed within 10 minutes after establishing circulation. Cooley noted, "the heart took on the appearance of an uterus" [22].

Comment: This case demonstrates the phenomenon of hyperacute rejection, which occurs following transplantation of lower mammal organs into humans.

Ross (1968)
In 1968, Ross placed a pig cardiac xenograft heterotopically in a patient unweanable from cardiopulmonary bypass [22]. Within 4 minutes, "it (the heart) went absolutely rigid and started oozing edema fluid."

Comment: This represents another example of hyperacute rejection in the lower mammal to man combination.

Marion (1969)
In 1969, Marion transplanted a chimpanzee heart (? technique) into a young woman on a cardiac assist device following failed mitral valve replacement. The heart failed "rapidly." There is no report of immunosuppression or postmortem findings. Failure of the graft was attributed to pulmonary hypertension of the recipient [23].

Comment: Limited information is available in this case. It is possible that right heart failure was mechanical and not immunologic in this patient.

Barnard (1977)
In 1977, two heterotopic cardiac xenotransplants were performed by Barnard, using a baboon and a chimpanzee donor [24]. Case 1: The first patient was a 25-year-old woman who could not be weaned from cardiopulmonary bypass after reoperative aortic valve replacement. A heart from a 30-kg baboon was transplanted heterotopically. Immunosuppression was apparently not used. After 5 hours, the native heart fibrillated and the heterotopic xenograft could not sustain adequate systemic perfusion on its own. Light microscopy was unremarkable and the failure was presumed to be due to inadequate size of the donor heart. Case 2: Later that year, Barnard performed a second heterotopic heart transplant of a chimpanzee heart into a 60-year-old man who would not wean from cardiopulmonary bypass following aortic valve replacement. The graft functioned well early on and the patient was taken to the intensive care unit in stable condition. Despite "high dose" immunosuppression, the function of the transplanted heart deteriorated over 4 days, as did native heart function. Postmortem examination revealed severe rejection of the donor heart and infarction of the native heart.

Comment: Perhaps the most significant contribution from this experience was the demonstration that heterotopically placed xenografts could support the circulation from hours to days. Barnard later suggested "evidence that the patient’s own heart’s function will recover rapidly" might be one indication for heterotopic xenotransplantation, linking the "bridge" concept to animal cardiac grafts. The first heart apparently was too small to support the circulation without some contribution from the native heart, although histological analysis later performed by Rose and colleagues showed "foci of severe interstitial edema and focal hemorrhages (indicating) early hyperacute rejection" [25]. The outcome of the second case again illustrated the necessity for more sophisticated immunologic matching and therapy. The presence of hyperacute rejection in this case was shown by signs of "widespread evidence of capillary destruction and interstitial hemorrhage" [25].

Bailey (1984)
The most carefully scrutinized attempt at clinical cardiac xenotransplantation occurred 7 years later, when Bailey performed an orthotopic baboon transplant into a female neonate with hypoplastic left heart syndrome [26]. Unlike previous experiences, careful pretransplant immunologic testing was performed and the donor was selected from a pool of six baboons on this basis. An ABO-mismatch could not be avoided (the patient’s blood type was O, a rare blood type in baboons). HLA typing and serum crossmatching did not differentiate a preferable donor. The baboon causing the weakest patient response in mixed lymphocyte cultures was selected. This patient was also the first xenotransplant recipient to receive cyclosporine immunosuppression. After orthotopic transplantation, the baby did extremely well during the early postoperative period with stable cardiac function. Graft dysfunction was first documented on postoperative day eleven. Over the ensuing days, myocardial injury gradually progressed and the graft failed on postoperative day 20. Detailed microscopic examination was performed, revealing microvascular thrombosis with regions of muscular coagulation necrosis, and only traces of cell-mediated injury. Immunohistochemical analysis revealed patchy but modest amounts of IgG, IgM, IgA, and C3. It was hypothesized that humoral injury secondary to ABO-antibody or anti-baboon antibodies resulted in devastating microvascular injury.

Comment: Several factors distinguished this attempt at cardiac xenotransplantation. It is the only time a cardiac xenotransplant was performed in an urgent, rather than emergent, setting. The recipient in this case was a neonate, capable of a less-developed immune response. It was the first xenotransplant attempted in the cyclosporine era. It was the only case where sophisticated immunologic testing was performed on prospective baboon donors in an attempt to narrow the disparity gap with the recipient. Clearly, not operating in an emergent setting increased the likelihood of immediate patient survival. Immaturity of the neonate immune response may, in part, explain the delay in rejection observed. In this case and others, cellular rejection is infrequently observed in delayed xenograft rejection, therefore the role cyclosporine played in the outcome is not clear. It is possible that ABO blood-incompatibility between donor and recipient played an immunologic role, although subsequent ABO-incompatible primate-to-primate heart xenotransplant studies suggest other mechanisms may be involved [27]. A devastating anti-xenograft humoral response may also have led to xenograft failure. Perhaps the most significant histologic finding was the predominance of injury involving the microvasculature which probably resulted in ultimate graft failure.

Czaplicki (1992)
In 1992, Czaplicki transplanted a pig heart orthotopically into a 31-year-old man suffering from Marfan’s syndrome with end-stage aortic insufficiency and ascending aortic aneurysm disease [28]. The patient was immunosuppressed with cyclosporine and azathioprine. Both the patient and two potential 90-kg pig donors were treated with several different preparations of embryonal and early fetal thymic tissues and early fetal calf sera. At the time of surgery, the patient was placed on cardiopulmonary bypass and a control pig heart was perfused with the patient’s blood for 20 minutes until it underwent hyperacute rejection. One of the treated donor pig hearts was then connected to the circulation and perfused for 80 minutes without evidence of hyperacute rejection. Finally, the second pig donor heart was harvested and an orthotopic transplantation was performed. The transplanted heart performed well for approximately 4 hours. The patient then developed a low cardiac output syndrome with deteriorating renal function and peripheral perfusion. The patient died 23 hours after graft implantation, and histologic examination "did not show any feature of rejecting the transplanted heart." Cardiac failure was attributed to the disparity between size and function of a sedentary pig’s heart and the patient’s native heart.

Comment: In all likelihood, the cross-circulation of two pig hearts removed sufficient pre-formed natural antibodies to prevent hyperacute rejection of the transplanted third heart. It is impossible to assess what role, if any, the thymic tissue extract and fetal calf sera played in the outcome. Rigorous immunopathological assessment would be required to validate the author’s claim of lack of xenograft rejection. In all likelihood, graft failure resulted from an immunologic rather than a functional cause.


   Xenotransplantation today
Top
 Abstract
 Introduction
 Immunological barriers
 Past clinical experience
 Xenotransplantation today
Remaining obstacles
 Future clinical trials
 References
 
Interest in the field of cardiac xenotransplantation has intensified in recent years as mechanisms of immediate xenograft failure have become better understood. Much of the early work, both in the laboratory and clinical setting, focused on the use of primate organs because primates are man’s closest evolutionary relatives sharing many immunological traits. Despite this potential advantage, primates are unlikely to serve as the primary source of cardiac donors for humans. Primates are not available in large numbers and do not breed easily in captivity. Furthermore, their slow growth rate and limited size severely diminishes overall donor suitability. Limited offspring and long generation time preclude potential efficient genetic manipulation. The potential for retroviral cross-species transmission between primates and humans has now been documented and on its own may preclude further use of primate organs clinically [29]. Finally, the use of primates as organ donors has come under increased ethical scrutiny due to their advanced evolutionary status.

Pigs have now emerged as the most likely source of human replacement organs. They grow to human size in a short period of time and are easy to raise in large numbers. Their long history of domestication and their integral presence in the human diet decreases, but does not eliminate, the likelihood of endogenous virus transmission previously unknown to man. Moreover, clinical medicine has long utilized swine as the source of insulin and heart valves. Millions of pigs are slaughtered yearly for food consumption in the United States alone, and subsequently there is less ethical controversy about the use of pigs as organ donors. Finally, their large litter and short generation time are ideal for genetic manipulation.

In order to combat hyperacute rejection of pig organs, several promising strategies have evolved modifying donor characteristics and recipient response.

Donor strategies
One unique aspect of the efforts underway to generate an animal source of cardiac xenografts is the possibility to genetically modify potential donors in a targeted fashion. Amelioration of species-related physiological dysregulation in terms of control of the early immune response and Gal-antigen alteration are two promising areas of investigation. Under normal circumstances, complement-mediated damage is limited by the activity of several complement regulatory proteins, which act to inhibit different stages of the complement cascade. Porcine endothelial cells are susceptible to dysregulated human complement attacks because porcine complement regulatory proteins cannot efficiently down-regulate human complement pathways. Genetically engineered pigs which express human complement regulatory proteins, such as the decay-accelerating factor (DAF, CD55) [30–32], the membrane cofactor protein (MCP, CD46) [33], and the complement inhibitor (CD59) [34–37], have now been generated. Pig organs expressing these human complement regulatory proteins appear to be protected from hyperacute rejection by down regulating the activated primate complement system.

Another promising strategy on the horizon is the limitation of antigen target for natural antibodies. Since the majority of human natural antibodies target the porcine endothelial sugar Gal, down-regulation of this surface antigen would substantially reduce the susceptibility of pig organs to hyperacute rejection [38]. Alternatively, the synthesis of Gal can be eliminated by creating knockout mouse without the enzyme for Gal synthesis [39]. Ultimately, one might envision the generation of double transgenic pig donors which, after genetic manipulation, express human complement regulatory proteins in the absence of surface Gal antigens.

Recipient strategy
Improved understanding of the mechanisms of hyperacute rejection has also resulted in targeted recipient strategies to facilitate early xenograft survival. Pretransplant reduction in anti-Gal circulating antibody levels has been achieved through extracorporeal immunoadsorption using Gal-affinity columns [40]. Intravenous injection of soluble Gal carbohydrates to bind and neutralize circulating natural antibodies has also been explored [41]. Targeted B-cell immunosuppression with agents like cyclophosphamide or leflunomide have also been relied upon to decrease pretransplant and posttransplant anti-Gal antibody levels [42]. More recently, pretransplant total lymphoid irradiation has been added to prolong pig cardiac xenograft survival in baboon recipients [43]. Others have combined irradiation with porcine bone marrow transplantation in an attempt to induce tolerance to porcine xenografts in primate recipients [44].

Administration of agents capable of sustaining complement inhibition such as soluble complement receptor type 1 have also demonstrated efficacy in preventing early hyperacute rejection [45]. Infusion of anti-complement 5 (C5) monoclonal antibody to block activated complements also shows promise in a perfusion model [46]. Cobra venom factor is a protein substrate that consumes and depletes a critical element in the complement cascade, C3. As such, it has been included as part of the immunosuppressive regimen in xenotransplantation. However, trials in baboons showed the development of anti-cobra venom factor antibodies, which induced anaphylaxis [47].

Although not effective in controlling hyperacute rejection, standard immunosuppressive agents such as cyclosporine, steroids, imuran, and mycophenylate moefitil are typically employed with cyclophosphamide in an attempt to control xenograft rejection. While the employment of multiple immunosuppressive drugs, in conjunction with previously discussed selected strategies, has resulted in improved xenograft survival, primate recipients often poorly tolerate such broad-spectrum immunosuppression. Efforts to minimize generalized immunosuppression with reliance on targeted strategies better tolerated by recipients will continue.


   Remaining obstacles
Top
 Abstract
 Introduction
 Immunological barriers
 Past clinical experience
 Xenotransplantation today
 Remaining obstacles
Future clinical trials
 References
 
Recent advances in our understanding of the mechanisms of immediate xenograft rejection have moved the field to closer clinical trials. Ongoing scientific and ethical issues, however, remain.

Scientific
Hyperacute rejection, mediated by natural antibody-triggered complement activation, is controllable by a combination of immunosuppressive regimens and transgenic technology. Although several day survival of porcine cardiac grafts in primate recipients is now achievable, xenografts invariably fail in days to weeks after implantation. This process, commonly referred to as either "delayed xenograft rejection" or, preferentially, "acute vascular rejection" [48] remains an immunological puzzle. Pathological hallmarks of acute vascular rejection in xenografts include platelet aggregation, fibrin deposition, endothelial cell activation, and mononuclear cellular infiltration [48, 49]. This process may result from a humoral antibody response resulting in nonspecific endothelial cell activation, thrombosis, vascular leakage, specific xenograft endothelial activation, NK cell and macrophage infiltration, or incompatible thrombin and thrombomodulin regulation [16, 19, 50, 51].

There are currently no effective therapies to control acute xenograft vascular rejection. Since antibody may play a significant role in acute vascular rejection, immunoadsorption with either nonselective [52] or Gal-specific columns [53] to remove natural antibodies has shown promise. Competitive inhibition of circulating natural antibodies with soluble Gal carbohydrates also shows efficacy [54]. In addition, multimodality approaches targeting B-cell responses have delayed the onset of acute vascular rejection [42, 43]. Nonetheless, the pathogenesis of acute vascular rejection is unclear, and effective strategies resulting in several month survival of xenografts remain elusive. Furthermore, one can predict that longer surviving xenografts will also undergo both cellular and chronic rejection which will present additional challenges.

Ethical
Remaining ethical barriers to clinical xenotransplantation center around two main issues: animal rights and xenosis, ie, possible infectious transmission via xenografts to recipients, who may in turn expose the general population [55]. As the field moves away from primate donors and towards transgenic pig donors, the animal rights concern has become less controversial [56]. The phylogenetic distance between pigs and humans, and the long history of pig domestication for dietary consumption and medical supplies, makes the use of pigs as organ donors unlikely to generate public disfavor.

Concerns regarding the transmission of infectious agents from animals to humans (xenosis), on the other hand, are not so easily dismissed. As in the case of allotransplantation, potential xenograft recipients will require immunosuppression and thus will be susceptible to opportunistic infection, perhaps introduced by the xenograft. The planned development of breeding facilities for potential pig donors which are free of common bacterial and fungal pathogens has focused attention on the danger of novel pathogens, particularly retroviruses. For example, the recent characterization of porcine endogenous retroviruses (PERV) has received wide attention. Although no human disease has ever been associated with PERV, these viruses have been shown to infect human cells in vitro [57, 58]. It remains unclear if PERV can infect human cells in vivo. Heavily immunosuppressed baboons transplanted with porcine endothelial cells do not show PERV infection 2 years after transplantation [59]. In addition, diabetic patients receiving porcine islet transplants between the period 1990–1993 have shown no evidence of PERV infection to date [60]. Continued investigation of potential pathogens like PERV will ultimately lead to testing strategies for screening xenograft donors, which will have a positive effect on clinical safety. Thus far, demonstrated infectious risks do not appear to be sufficient to curtail future clinical trials [61].


   Future clinical trials
Top
 Abstract
 Introduction
 Immunological barriers
 Past clinical experience
 Xenotransplantation today
 Remaining obstacles
 Future clinical trials
References
 
The combination of genetically modified pigs, improved immunosuppressive strategies, and clarified ethical considerations, point toward future attempts at clinical cardiac xenotransplantation. One can predict with certainty clinical trials will be well designed, highly scrutinized, and limited to only a few worldwide centers. The timing of such trials, however, remains controversial. Although several weeks to months survival of porcine xenografts has now been achieved in primates, recipients were heavily immunosuppressed and many succumbed to infections or other complications [42, 62]. The success of transgenic technology needs to be interpreted under such light and caution needs to be exercised before extrapolating such experimental outcomes to the clinical arena. We believe that, to move forward with a clinical trial, the state of technology must first be improved to a point where 90-day porcine cardiac xenograft survival is consistently achieved in the primate model with an immunosuppressive regimen that is clinically tolerable without evidence of primate recipient compromise. It appears that we are years, rather than months, away from realizing this goal.

Once this experimental benchmark is achieved, selected centers will need to adopt guidelines under development by the Food and Drug Administration, the Center for Disease Control, and the international xenotransplant community regarding limitation of infectious risks in recipients and in the general population. Appropriate environmentally controlled pig breeding facilities will need to be built in proximity to involved clinical institutions. Careful donor screening for known and novel pathogens will be required, as will longitudinal screening and banking of serum and biopsies from xenograft recipients [63]. Obviously, special attention to informed consent will be mandatory.

Once these scientific and infectious hurdles are overcome, the design of actual clinical trials will take center stage. The first transgenic porcine-to-human organ application most likely will involve extracorporeal perfusion of liver xenografts for fulminant hepatic failure as a bridge to recovery or liver transplantation. Bridging with nontransgenic livers in the setting of acute hepatic failure showed promising early results [64]. It is harder to predict the order of subsequent organ trials. Renal porcine xenografts can support primate kidney function, but the success associated with renal dialysis suggests that it is unlikely porcine renal xenotransplantation will be attempted until positive experience is achieved with other organs. The first transgenic pig-to-human cardiac xenotransplant is likely to involve the use of porcine cardiac xenografts to bridge patients to allotransplantation or recovery in the setting of cardiomyopathy, acute myocardial infarction, or postcardiotomy shock. We believe that a heterotopic application will be initially employed, given the unpredictability of sustained xenograft function in human recipients, despite available primate data. The ability of a heterotopically placed xenograft to support human life has been previously demonstrated [24]. Furthermore, the benefit of heterotopic placement in human allotransplantation with preservation of the recipient’s own heart was previously established in the precyclosporine era [65], when allograft function was much less predictable. Sudden heterotopic graft demise did not always result in patient death because native heart function was capable of generating life-supporting cardiac output. In the setting of xenotransplantation, this might allow time for replacement of a failed cardiac xenograft with a new one.

The actual selection of appropriate candidates for porcine cardiac xenotransplantation remains controversial, and will require special scrutiny by experienced clinicians in the transplantation community. It is likely candidates will have relative contraindications to conventional mechanical ventricular assistance, such as small body surface area or previous mechanical valve replacement. Ideally, a patient would have a reasonable chance of native heart recovery, although it is more likely selected patients will undergo bridging to allotransplantation.

In summary, cardiac xenotransplantation remains a dream of clinicians and scientists concerned for the care of patients with end-stage heart disease. Improved understanding of the barriers to xenotransplantation and the derived advances in donor and recipient strategies have narrowed the gap between laboratory bench and bedside. Heterotopic bridging to allotransplantation or possible myocardial recovery will likely to be the first step. Detailed analysis of early clinical outcomes will determine whether clinical porcine cardiac xenotransplantation should then proceed to orthotopic placement with hopes for longer survival.


   Acknowledgments
 
Doctor Chen is an American College of Surgeons Research Scholar 1998–2000 and recipient of NIH Individual National Research Service Award (NRSA) 1F32HL0996601. We thank Lisa Diamond, PhD, and John Logan, PhD (Nextran, Inc), for their continued counsel and scientific collaboration.


   References
Top
 Abstract
 Introduction
 Immunological barriers
 Past clinical experience
 Xenotransplantation today
 Remaining obstacles
 Future clinical trials
 References
 

  1. Hosenpud J.D., Bennett L.E., Keck B.M., Fiol B., Boucek M.M., Novick R.J. The Registry of the International Society for Heart and Lung Transplantation. J Heart Lung Transplant 1998;17:656-668.[Medline]
  2. Larsen R.D., Rivera-Marrero C.A., Ernst L.K., Cummings R.D., Lowe J.B. Frameshift and nonsense mutations in a human genomic sequence homologous to a murine UDP-Gal:beta-D-Gal(1,4)-D-GlcNAc alpha(1,3)-galactosyltransferase cDNA. J Biol Chem 1990;265:7055-7061.[Abstract/Free Full Text]
  3. Platt J.L., Fischel R.J., Matas A.J., Reif S.A., Bolman R.M., Bach F.H. Immunopathology of hyperacute xenograft rejection in a swine-to-primate model. Transplantation 1991;52:214-220.[Medline]
  4. Sandrin M., Vaughan H., Dabkowski P., McKenzie I.F. Anti-pig IgM antibodies in human serum reacts predominantly with Gal (alpha 1,3) epitopes. Proc Natl Acad Sci USA 1993;90:11391-11395.[Abstract/Free Full Text]
  5. Galili U., Clark M.R., Shohet S.B., Buehler J., Macher B.A. Evolutionary relationship between the natural anti-Gal antibody and the Gal alpha 1–3Gal epitope in primates. Proc Natl Acad Sci USA 1987;84:1369-1373.[Abstract/Free Full Text]
  6. Leventhal J.R., Dalmasso A.P., Cromwell J.W., et al. Prolongation of cardiac xenograft survival by depletion of complement. Transplantation 1993;55:857-866.[Medline]
  7. Leventhal J.R., John R., Fryer J.P., et al. Removal of baboon and human antiporcine IgG and IgM natural antibodies by immunoadsorption. Results of in vitro and in vivo studies. Transplantation 1995;59:294-300.[Medline]
  8. Saadi S., Platt J.L. Transient perturbation of endothelial integrity induced by natural antibodies and complement. J Exp Med 1995;181:21-31.[Abstract/Free Full Text]
  9. Platt J.L., Dalmasso A.P., Vercellotti G.M., Lindman B.J., Turman M.A., Bach F.H. Endothelial cell proteoglycans in xenotransplantation. Transplant Proc 1990;22:1066.[Medline]
  10. Hansch G.M., Hammer C.H., Vanguri P., Shin M.L. Homologous species restriction in lysis of erythrocytes by terminal complement proteins. Proc Natl Acad Sci USA 1981;78:5118-5121.[Abstract/Free Full Text]
  11. Rollins S.A., Zhao J., Ninomiya H., Sims P.J. Inhibition of homologous complement by CD59 is mediated by a species-selective recognition conferred through binding to C8 within C5b-8 or C9 within C5b-9. J Immunol 1991;146:2345-2351.[Abstract]
  12. Shin M.L., Hansch G., Hu V.W., Nicholson-Weller A. Membrane factors responsible for homologous species restriction of complement-mediated lysis. J Immunol 1986;136:1777-1782.[Abstract]
  13. Lachmann P.J. The control of homologous lysis. Immunol Today 1991;12:312-315.[Medline]
  14. Cotterell A.H., Collins B.H., Parker W., Harland R.C., Platt J.L. The humoral immune response in humans following cross-perfusion of porcine organs. Transplantation 1995;60:861-868.[Medline]
  15. Fries J.W., Williams A.J., Atkins R.C., Newman W., Lipscomb M.F., Collins T. Expression of VCAM-1 and E-selectin in an in vivo model of endothelial activation. Am J Pathol 1993;143:725-737.[Abstract]
  16. Lawson J.H., Platt J.L. Molecular barriers to xenotransplantation. Transplantation 1996;62:303-310.[Medline]
  17. Inverardi L., Samaja M., Motterlini R., Mangili F., Bender J.R., Pardi R. Early recognition of a discordant xenogeneic organ by human circulating lymphocytes. J Immunol 1992;149:1416-1423.[Abstract]
  18. Lawson J.H., Daniels L.J., Platt J.L. The evaluation of thrombomodulin activity in porcine to human xenotransplantation. Transplant Proc 1997;29:884-885.[Medline]
  19. Bach F.H., Winkler H., Ferran C., Hancock W.W., Robson S.C. Delayed xenograft rejection. Immunol Today 1996;17:379-384.[Medline]
  20. Hardy J.D., Chavez C.M. The first heart transplant in man. Transplant Proc 1969;1:717-725.[Medline]
  21. Cooley D.A., Hallman G.L., Bloodwell R.D., Nora J.J., Leachman R.D. Human heart transplantation. Experience with twelve cases. Am J Cardiol 1968;22:804-810.[Medline]
  22. Shapiro H. The pathological findings in patients who have died. Experience with human heart transplantation: Proceedings of the Cape Town Symposium, 13–16 July 1968. New York: Butterworths, 1969:227–9.
  23. Marion P. Les transplantations cardiaques et les transplantations hepatiques [Heart transplantation and liver transplantation]. Lyon Med 1969;222:606–7.
  24. Barnard C.N., Wolpowitz A., Losman J.G. Heterotopic cardiac transplantation with a xenograft for assistance of the left heart in cardiogenic shock after cardiopulmonary bypass. S Afr Med J 1977;52:1035-1038.[Medline]
  25. Rose A.G., Cooper D.K.C., Human P.A., Reichenspurner H., Reichart B. Histopathology of hyperacute rejection of the heart. J Heart Lung Transplant 1991;10:223-234.[Medline]
  26. Bailey L.L., Nehlsen-Cannarella S.L., Concepcion W., Jolley W.B. Baboon-to-human cardiac xenotransplantation in a neonate. JAMA 1985;254:3321-3329.[Abstract/Free Full Text]
  27. Cooper D.K., Human P.A., Rose A.G., 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. J Thorac Cardiovasc Surg 1989;97:447-455.[Abstract]
  28. Czaplicki J., Blonska B., Religa Z. The lack of hyperacute xenogeneic heart transplant rejection in a human. J Heart Lung Transplant 1992;11:393-397.[Medline]
  29. Gao F., Bailes E., Robertson D.L., et al. Origin of HIV-1 in the chimpanzee Pan troglodytes troglodytes. Nature 1999;397:436-441.[Medline]
  30. Byrne G.W., McCurry K.R., Kagan D., et al. Protection of xenogeneic cardiac endothelium from human complement by expression of CD59 or DAF in transgenic mice. Transplantation 1995;60:1149-1156.[Medline]
  31. Davitz M.A. Decay-accelerating factor (DAF). Acta Med Scand 1987;715(Suppl):111.
  32. Schmoeckel M., Nollert G., Shahmohammadi M., et al. Prevention of hyperacute rejection by human decay accelerating factor in xenogeneic perfused working hearts. Transplantation 1996;62:729-734.[Medline]
  33. Liszewski M.K., Post T.W., Atkinson J.P. Membrane cofactor protein (MCP or CD46). Annu Rev Immunol 1991;9:431-455.[Medline]
  34. Miyagawa S., Shirakura R., Matsumiya G., et al. Possibility of prevention of hyperacute rejection by DAF and CD59 in xenotransplantation. Transplant Proc 1994;26:1235-1238.[Medline]
  35. Brooimans R.A., van Wieringen P.A., van Es L.A., Daha M.R. Relative roles of decay-accelerating factor, membrane cofactor protein, and CD59 in the protection of human endothelial cells against complement-mediated lysis. Eur J Immunol 1992;22:3135-3140.[Medline]
  36. Miki T., Goller A., Rao A., et al. Tacrolimus enhances the immunosuppressive effect of cyclophosphamide but not that of leflunomide or mycophenolate mofetil in a model of discordant liver xenotransplantation. Transplant Proc 1998;30:1091-1092.[Medline]
  37. Byrne G.W., McCurry K.R., Martin M.J., McClellan S.M., Platt J.L., Logan J.S. Transgenic pigs expressing human CD59 and decay-accelerating factor produce an intrinsic barrier to complement-mediated damage. Transplantation 1997;63:149-155.[Medline]
  38. Sharma A., Okabe J., Birch P., et al. Reduction in the level of Gal(alpha1,3)Gal in transgenic mice and pigs by the expression of an alpha(1,2)fucosyltransferase. Proc Natl Acad Sci USA 1996;93:7190-7195.[Abstract/Free Full Text]
  39. Van Denderen B.J., Salvaris E., Romanella M., et al. Combination of decay-accelerating factor expression and alpha 1,3-galactosyltransferase knockout affords added protection from human complement-mediated injury. Transplantation 1997;64:882-888.[Medline]
  40. Lambrigts D., Van Calster P., Xu Y., et al. Pharmacologic immunosuppressive therapy and extracorporeal immunoadsorption in the suppression of anti-{alpha}Gal antibody in the baboon. Xenotransplantation 1998;5:274-283.[Medline]
  41. Cooper D.K., Koren E., Oriol R. Oligosaccharides and discordant xenotransplantation. Immunol Rev 1994;141:31-58.[Medline]
  42. Schmoeckel M., Bhatti F.N., Zaidi A., et al. Orthotopic heart transplantation in a transgenic pig-to-primate model. Transplantation 1998;65:1570-1577.[Medline]
  43. Xu H., Gundry S.R., Hancock W.W., et al. Prolonged discordant xenograft survival and delayed xenograft rejection in a pig-to-baboon orthotopic cardiac xenograft model. J Thorac Cardiovasc Surg 1998;115:1342-1349.[Abstract/Free Full Text]
  44. Kozlowski T., Shimizu A., Lambrigts D., et al. Porcine kidney and heart transplantation in baboons undergoing a tolerance induction regimen and antibody adsorption. Transplantation 1999;67:18-30.[Medline]
  45. Davis E.A., Pruitt S.K., Greene P.S., et al. Inhibition of complement, evoked antibody, and cellular response prevents rejection of pig-to-primate cardiac xenografts. Transplantation 1996;62:1018-1023.[Medline]
  46. Kroshus T.J., Rollins S.A., Dalmasso A.P., et al. Complement inhibition with an anti-C5 monoclonal antibody prevents acute cardiac tissue injury in an ex vivo model of pig-to-human xenotransplantation. Transplantation 1995;60:1194-1202.[Medline]
  47. Kobayashi T., Taniguchi S., Ye Y., et al. Delayed xenograft rejection in C3-depleted discordant (pig-to-baboon) cardiac xenografts treated with cobra venom factor. Transplant Proc 1996;28:560.[Medline]
  48. Platt J.L., Lin S.S., McGregor C.G. Acute vascular rejection. Xenotransplantation 1998;5:169-175.[Medline]
  49. Blakely M.L., Van der Werf W.J., Berndt M.C., Dalmasso A.P., Bach F.H., Hancock W.W. Activation of intragraft endothelial and mononuclear cells during discordant xenograft rejection. Transplantation 1994;58:1059-1066.[Medline]
  50. Bach F.H., Robson S.C., Ferran C., et al. Xenotransplantation. Transplant Proc 1995;27:77-79.[Medline]
  51. Lin S.S., Platt J.L. Immunologic barriers to xenotransplantation. J Heart Lung Transplant 1996;15:547-555.[Medline]
  52. Lin S.S., Weidner B.C., Byrne G.W., et al. The role of antibodies in acute vascular rejection of pig-to-baboon cardiac transplants. J Clin Invest 1998;101:1745-1756.[Medline]
  53. Taniguchi S., Neethling F.A., Korchagina E.Y., et al. In vivo immunoadsorption of antipig antibodies in baboons using a specific Gal(alpha)1-3Gal column. Transplantation 1996;62:1379-1384.[Medline]
  54. Cairns T., Lee J., Goldberg L., et al. Inhibition of the pig to human xenograft reaction, using soluble Gal alpha 1-3Gal and Gal alpha 1-3Gal beta 1-4GlcNAc. Transplantation 1995;60:1202-1207.[Medline]
  55. Fishman J. Miniature swine as organ donors for man. Xenotransplantation 1994;1:47-57.
  56. Caplan A. ... and this little saved lives!. Dial Transplant 1998;27:618-620.[Medline]
  57. Martin U., Kiessig V., Blusch J.H., et al. Expression of pig endogenous retrovirus by primary porcine endothelial cells and infection of human cells. Lancet 1998;352:692-694.[Medline]
  58. Patience C., Takeuchi Y., Weiss R.A. Infection of human cells by an endogenous retrovirus of pigs. Nat Med 1997;3:282-286.[Medline]
  59. Martin U., Steinhoff G., Kiessig V., et al. Porcine endogenous retrovirus (PERV) was not transmitted from transplanted porcine endothelial cells to baboons in vivo. Transpl Int 1998;11:247-251.[Medline]
  60. Heneine W, Tibell A, Switzer WM, et al. No evidence of infection with porcine endogenous retrovirus in recipients of porcine islet-cell xenografts [published erratum appears in Lancet 1998;352:1478]. Lancet 1998;352:695–9.
  61. In: Fishman J., Sachs D., Shaikh R., eds. . Xenotransplantation. New York: The New York Academy of Sciences, 1998.
  62. Chen R.H., Naficy S., Logan J.S., Diamond L.E., Adams D.H. Hearts from transgenic pigs constructed with CD59/DAF genomic clones demonstrate improved survival in primates. Xenotransplantation 1999;6:122-132.
  63. Fishman J.A. Infection and xenotransplantation. Developing strategies to minimize risk. Ann N Y Acad Sci 1998;862:52-66.[Medline]
  64. Chari R.S., Collins B.H., Magee J.C., et al. Brief report. N Engl J Med 1994;331:234-237.[Free Full Text]
  65. Losman J.G., Levine H., Campbell C.D., et al. Changes in indications for heart transplantation. An additional argument for the preservation of the recipient’s own heart. J Thorac Cardiovasc Surg 1982;84:716-726.[Abstract]




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