Cardiac xenotransplantation : Recent preclinical progress with 3-month median survival

OBJECTIVES Transplantation is limited by a lack of human organ donors. Organs derived from animals, most likely the pig, represent a potential solution to this problem. For the heart, 90-day median graft survival of life-supporting pig hearts transplanted to nonhuman primates has been considered a reasonable standard for entry into the clinical arena. Overcoming the immune barrier to successful cardiac xenotransplantation is most appropriately first explored with the non-life-supporting heterotopic model. METHODS We performed a series of 7 heterotopic heart transplantations from CD46 transgenic pigs to baboons using a combination of therapeutic agents largely targeted at controlling the synthesis of anti-pig antibodies. Rituximab (anti-CD20) and Thymoglobulin (rabbit antithymocyte globulin [ATG]; SangStat Medical Corp, Fremont, Calif) were used as induction therapy. Baseline immunosuppression consisted of splenectomy, tacrolimus, sirolimus, steroids, and TPC (an anti-Gal antibody therapeutic). Rejection events were not treated. RESULTS By using Kaplan-Meier analysis, median graft survival was 96 days (range, 15-137 days; 95% confidence interval, 38-99 days). Only 2 grafts were lost as a result of rejection, as defined by cessation of graft palpation. There was no evidence of a consumptive coagulopathy, infectious complications were treatable, and no posttransplantation lymphoproliferative disorders occurred. No cellular infiltration was observed. CONCLUSIONS This study reports the longest median survival to date (96 days) of pig hearts transplanted heterotopically into baboons. Duplication of these results in the orthotopic life-supporting position could bring cardiac xenotransplantation to the threshold of clinical application.

[1]  T. Larson,et al.  Overcoming a Positive Crossmatch in Living‐Donor Kidney Transplantation , 2003, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[2]  F. Bach,et al.  Effect of porcine endothelial tissue factor pathway inhibitor on human coagulation factors. , 1997, Transplantation.

[3]  R. Lechler,et al.  Complete Inhibition of Acute Humoral Rejection Using Regulated Expression of Membrane‐tethered Anticoagulants on Xenograft Endothelium , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[4]  D. Sachs,et al.  COAGULATION AND THROMBOTIC DISORDERS ASSOCIATED WITH PIG ORGAN AND HEMATOPOIETIC CELL TRANSPLANTATION IN NONHUMAN PRIMATES , 2000, Transplantation.

[5]  J. Platt,et al.  Transplantation of discordant xenografts: a challenge revisited. , 1996, Immunology today.

[6]  W. Hancock.  Delayed Xenograft Rejection , 1997, World Journal of Surgery.

[7]  M. Goddard,et al.  Three-month survival of HDAFF transgenic pig hearts transplanted into primates. , 1999, Transplantation proceedings.

[8]  R. Colvin,et al.  Disseminated intravascular coagulation in association with the delayed rejection of pig-to-baboon renal xenografts. , 1998, Transplantation.

[9]  H. Dintzis,et al.  Evaluation of different α-galactosyl glycoconjugates for use in xenotransplantation , 2002 .

[10]  H. Dintzis,et al.  Evaluation of different alpha-Galactosyl glycoconjugates for use in xenotransplantation. , 2002, Bioconjugate chemistry.

[11]  J. Platt,et al.  The role of anti-Galalpha1-3Gal antibodies in acute vascular rejection and accommodation of xenografts. , 2000, Transplantation.

[12]  W. Kremers,et al.  Warfarin or Low‐Molecular‐Weight Heparin Therapy does not Prolong Pig‐To‐Primate Cardiac Xenograft Function , 2005, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[13]  R. Evans,et al.  The potential supply of organ donors. An assessment of the efficacy of organ procurement efforts in the United States. , 1992, JAMA.

[14]  R. Lechler,et al.  The cellular rejection of xenografts – recent insights , 2003, Xenotransplantation.

[15]  R. Michler,et al.  Technique for Primate Heterotopic Cardiac Xenotransplantation , 1985, Journal of medical primatology.

[16]  Junzheng Peng,et al.  Effect of tacrolimus (FK506) and sirolimus (rapamycin) mono- and combination therapy in prolongation of renal allograft survival in the monkey. , 1998, Transplantation.

[17]  N. Mueller,et al.  Heart transplantation in baboons using α1,3-galactosyltransferase gene-knockout pigs as donors: initial experience , 2005, Nature Medicine.

[18]  R. Pierson,et al.  Report of the Xenotransplantation Advisory Committee of the International Society for Heart and Lung Transplantation: the present status of xenotransplantation and its potential role in the treatment of end-stage cardiac and pulmonary diseases. , 2000, The Journal of heart and lung transplantation : the official publication of the International Society for Heart Transplantation.

[19]  R. Morris,et al.  Anti‐non‐Gal porcine endothelial cell antibodies in acute humoral xenograft rejection of hDAF‐transgenic porcine hearts in cynomolgus monkeys , 2004, Xenotransplantation.

[20]  L. Stevenson,et al.  Management of end-stage heart disease , 1998 .

[21]  J. Platt,et al.  Humoral responses to pig-to-baboon cardiac transplantation: implications for the pathogenesis and treatment of acute vascular rejection and for accommodation. , 1997, Human immunology.

[22]  N. Mueller,et al.  Suppression of Natural and Elicited Antibodies in Pig‐to‐Baboon Heart Transplantation Using a Human Anti‐Human CD154 mAb‐Based Regimen , 2004, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[23]  S. Grey,et al.  Expression of human thrombomodulin cofactor activity in porcine endothelial cells. , 1998, Transplantation.

[24]  C. Bordignon.  Progress Towards the Clinical Application of Somatic Cell Gene Therapy , 1993 .

[25]  J. Platt,et al.  A HUMAN CD46 TRANSGENIC PIG MODEL SYSTEM FOR THE STUDY OF DISCORDANT XENOTRANSPLANTATION , 2001, Transplantation.

[26]  A. B. Stewart,et al.  Renal xenografts from triple-transgenic pigs are not hyperacutely rejected but cause coagulopathy in non-immunosuppressed baboons. , 2000, Transplantation.

[27]  A. Dalmasso,et al.  Alpha-galactosyl epitope-mediated activation of porcine aortic endothelial cells: type II activation. , 1998, Transplantation.

[28]  H. Tazelaar,et al.  Cardiac Xenotransplantation: Progress Toward the Clinic , 2004, Transplantation.

[29]  D. Adams,et al.  Technique for heterotopic pig heart xenotransplantation in primates. , 1999, The Annals of thoracic surgery.

[30]  H. Tazelaar,et al.  Effective antiplatelet therapy does not prolong transgenic pig to baboon cardiac xenograft survival , 2004, Xenotransplantation.

[31]  H. Schuurman,et al.  Incidence of hyperacute rejection in pig-to-primate transplantation using organs from hDAF-transgenic donors , 2002, Transplantation.

[32]  R. Colvin,et al.  Pig kidney transplantation in baboons: anti-Gal(alpha)1-3Gal IgM alone is associated with acute humoral xenograft rejection and disseminated intravascular coagulation. , 2001, Transplantation.

[33]  J. Platt,et al.  Acute vascular rejection , 1998, Transplantation proceedings.

[34]  D. Cooper,et al.  An investigation of the specificity of induced anti‐pig antibodies in baboons , 2003, Xenotransplantation.

[35]  J. Platt,et al.  The evaluation of thrombomodulin activity in porcine to human xenotransplantation. , 1997, Transplantation proceedings.

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

[37]  J. Platt,et al.  Transgenic pigs expressing human CD59 and decay-accelerating factor produce an intrinsic barrier to complement-mediated damage. , 1997, Transplantation.

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

[39]  H. Tazelaar,et al.  Prevention, detection, and management of early bacterial and fungal infections in a preclinical cardiac xenotransplantation model that achieves prolonged survival , 2005, Xenotransplantation.

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

[41]  D. Adams,et al.  Analysis of the control of the anti-gal immune response in a non-human primate by galactose &agr;1-3 galactose trisaccharide-polyethylene glycol conjugate , 2002, Transplantation.

[42]  J. Logan.  Prospects for xenotransplantation. , 2000, Current opinion in immunology.

[43]  R. Oriol,et al.  Identification of alpha-galactosyl and other carbohydrate epitopes that are bound by human anti-pig antibodies: relevance to discordant xenografting in man. , 1993, Transplant immunology.