title: Genetically engineered pigs and target-specific immunomodulation provide significant graft survival and hope for clinical cardiac xenotransplantation.
abstract: OBJECTIVE
  Cardiac transplantation and available mechanical alternatives are the only possible solutions for end-stage cardiac disease. Unfortunately, because of the limited supply of human organs, xenotransplantation may be the ideal method to overcome this shortage. We have recently seen significant prolongation of heterotopic cardiac xenograft survival from 3 to 12 months and beyond.
  
  
  METHODS
  Hearts from genetically engineered piglets that were alpha 1-3 galactosidase transferase knockout and expressed the human complement regulatory gene, CD46 (groups A-C), and the human thrombomodulin gene (group D) were heterotropically transplanted in baboons treated with antithymocyte globulin, cobra venom factor, anti-CD20 antibody, and costimulation blockade (anti-CD154 antibody [clone 5C8]) in group A, anti-CD40 antibody (clone 3A8; 20 mg/kg) in group B, clone 2C10R4 (25 mg/kg) in group C, or clone 2C10R4 (50 mg/kg) in group D, along with conventional nonspecific immunosuppressive agents.
  
  
  RESULTS
  Group A grafts (n = 8) survived for an average of 70 days, with the longest survival of 236 days. Some animals in this group (n = 3) developed microvascular thrombosis due to platelet activation and consumption, which resulted in spontaneous hemorrhage. The median survival time was 21 days in group B (n = 3), 80 days in group C (n = 6), and more than 200 days in group D (n = 5). Three grafts in group D are still contracting well, with the longest ongoing graft survival surpassing the 1-year mark.
  
  
  CONCLUSIONS
  Genetically engineered pig hearts (GTKOhTg.hCD46.hTBM) with modified targeted immunosuppression (anti-CD40 monoclonal antibody) achieved long-term cardiac xenograft survival. This potentially paves the way for clinical xenotransplantation if similar survival can be reproduced in an orthotopic transplantation model.
authors.affiliation: Cardiothoracic Surgery Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md. Electronic address: mohiuddinm@mail.nih.gov.
authors.forename: Muhammad M
authors.initials: MM
authors.lastname: Mohiuddin
authors.affiliation: Cardiothoracic Surgery Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
authors.forename: Avneesh K
authors.initials: AK
authors.lastname: Singh
authors.affiliation: Cardiothoracic Surgery Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
authors.forename: Philip C
authors.initials: PC
authors.lastname: Corcoran
authors.affiliation: Laboratory Animal Sciences Program, Leidos Biomedical Research, Inc, Frederick National Laboratory, Frederick, Md.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Hoyt
authors.affiliation: Division of Veterinary Resources, National Institutes of Health, Bethesda, Md.
authors.forename: Marvin L
authors.initials: ML
authors.lastname: Thomas
authors.affiliation: Revivicor, Inc, Blacksburg, Va.
authors.forename: David
authors.initials: D
authors.lastname: Ayares
authors.affiliation: Cardiothoracic Surgery Research Program, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Md.
authors.forename: Keith A
authors.initials: KA
authors.lastname: Horvath
mesh_terms: D000818:Animals; D030801:Animals, Genetically Modified; D000831:Animals, Newborn; D004359:Drug Therapy, Combination; D005700:Galactosyltransferases / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects; D016027:Heart Transplantation / Q000009:adverse effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D051916:Membrane Cofactor Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D009200:Myocardial Contraction; D010215:Papio; D013552:Swine; D018180:Thrombomodulin / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D013997:Time Factors; D014183:Transplantation, Heterologous; D016277:Ventricular Function, Left; D017725:Ventricular Pressure
chemical_list: C497857:CD46 protein, human; D007166:Immunosuppressive Agents; D051916:Membrane Cofactor Protein; C546931:THBD protein, human; D018180:Thrombomodulin; D005700:Galactosyltransferases; C530267:alpha-1,3-galactosyltransferase 1, porcine