Lung xenotransplantation: recent progress and current status
Donald G. Harris
Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA
Search for more papers by this authorKevin J. Quinn
Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
Search for more papers by this authorSiamak Dahi
Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
Search for more papers by this authorLars Burdorf
Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
Search for more papers by this authorAgnes M. Azimzadeh
Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
Search for more papers by this authorCorresponding Author
Richard N. Pierson III
Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
Surgical Care Clinical Center, VA Maryland Health Care Center, Baltimore, MD, USA
Address reprint requests to Richard N. Pierson III, MD Division of Cardiac Surgery, University of Maryland Medical Center, 22 S. Greene Street, Baltimore, MD 21201, USA (E-mail: [email protected])Search for more papers by this authorDonald G. Harris
Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, MD, USA
Search for more papers by this authorKevin J. Quinn
Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
Search for more papers by this authorSiamak Dahi
Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
Search for more papers by this authorLars Burdorf
Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
Search for more papers by this authorAgnes M. Azimzadeh
Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
Search for more papers by this authorCorresponding Author
Richard N. Pierson III
Department of Surgery, University of Maryland School of Medicine, Baltimore, MD, USA
Surgical Care Clinical Center, VA Maryland Health Care Center, Baltimore, MD, USA
Address reprint requests to Richard N. Pierson III, MD Division of Cardiac Surgery, University of Maryland Medical Center, 22 S. Greene Street, Baltimore, MD 21201, USA (E-mail: [email protected])Search for more papers by this authorAbstract
Xenotransplantation has undergone important progress in controlling initial hyperacute rejection in many preclinical models, with some cell, tissue, and organ xenografts advancing toward clinical trials. However, acute injury, driven primarily by innate immune and inflammatory responses, continues to limit results in lung xenograft models. The purpose of this article is to review the current status of lung xenotransplantation—including the seemingly unique challenges posed by this organ—and summarize proven and emerging means of overcoming acute lung xenograft injury.
References
- 1Arcasoy SM, Kotloff RM. Lung transplantation. NEJM 1999; 340: 1081–1091.
- 2de Meester J, Smits J, Persijn GG, Haverich A. Listing for lung transplantation: life expectancy and transplant effect, stratified by type of end-stage lung disease, the eurotransplant experience. J Heart Lung Transplant 2001; 20: 518–524.
- 3Christie JD, Edwards LB, Kucheryavaya AY et al. The registry of the International Society for Heart and Lung Transplantation: 29th adult lung and heart-lung transplant report - 2012. J Heart Lung Transplant 2012; 31: 1073–1086.
- 4Eskander A, Waddell TK, Faughnan ME, Chowdhury N, Singer LG. BODE index and quality of life in advanced chronic obstructive pulmonary disease before and after lung transplantation. J Heart Lung Transplant 2011; 30: 1334–1341.
- 5Klein A, Messersmith E, Ratner L et al. Organ donation and utilization in the United States, 1999–2008. Am J Transplant 2010; 10: 973–986.
- 6 Organ Procurement and Transplantation Network. United States Department of Health and Human Services; [accessed on 1 January 2014].
- 7Punch J, Hayes D, Laporte F, McBride V, Seely M. Organ donation and utilization in the United States, 1996–2005. Am J Transplant 2007; 7: 1327–1338.
- 8Valapour M, Paulson K, Smith J et al. OPTN/SRTR 2011 annual data report: lung. Am J Transplant 2013; 13: 149–177.
- 9 United States Department of Health and Human Services. Organ Procurement and Transplantation Network National Data. Available at: http://optn.transplant.hrsa.gov/latestData/step2.asp. [accessed on 7 March 2014].
- 10Cypel M, Yeung JC, Liu M et al. Normothermic ex vivo lung perfusion in clinical lung transplantation. NEJM 2011; 364: 1431–1440.
- 11Cypel M, Keshavjee S. Strategies for safe donor expansion: donor management, donations after cardiac death, ex-vivo lung perfusion. Curr Opin Organ Transplant 2013; 18: 513–517.
- 12Cypel M, Liu M, Rubacha M et al. Functional repair of human donor lungs by IL-10 gene therapy. Sci Transl Med 2009; 1: 4ra9.
- 13Yusen R, Shearon T, Qian Y et al. Lung transplantation in the United States, 1999–2008. Am J Transplant 2010; 10: 1047–1068.
- 14Evans C, Kon Z, Wehman B et al. Bridge to lung transplantation with veno-venous extracorporeal membrane oxygenation for end-stage lung disease: a single center experience. J Heart Lung Transplant 2013; 32: S219.
- 15Rubenfeld GD, Herridge MS. Epidemiology and outcomes of acute lung injury. CHEST J 2007; 131: 554–562.
- 16Sheehy E, Conrad SL, Brigham LE et al. Estimating the number of potential organ donors in the United States. NEJM 2003; 349: 667–674.
- 17Pierson RN, Dorling A, Ayares D et al. Current status of xenotransplantation and prospects for clinical application. Xenotransplantation 2009; 16: 263–280.
- 18Ekser B, Ezzelarab M, Hara H et al. Clinical xenotransplantation: the next medical revolution? Lancet 2012; 379: 672–683.
- 19Cooper D, Keogh A, Brink J 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. J Heart Lung Transplant 2000; 19: 1125–1165.
- 20Pierson RN. Current status of xenotransplantation. JAMA 2009; 301: 967–969.
- 21van Raemdonck D, Neyrinck A, Verleden GM et al. Lung donor selection and management. Proc Am Thorac Soc 2009; 6: 28–38.
- 22Sachs DH, Sykes M, Yamada K. Achieving tolerance in pig-to-primate xenotransplantation: reality or fantasy. Transpl Immunol 2009; 21: 101–105.
- 23Griesemer A, Yamada K, Sykes M. Xenotransplantation: immunological hurdles and progress toward tolerance. Immunol Rev 2014; 258: 241–258.
- 24Mohiuddin M, Singh A, Corcoran P et al. One year heterotopic cardiac xenograft survival in a pig to baboon model. Am J Transplant 2014; 14: 488–489.
- 25McGregor CG, Davies WR, Oi K et al. Cardiac xenotransplantation: recent preclinical progress with 3-month median survival. J Thorac Cardiovasc Surg 2005; 130: 844. e1-844. e9.
- 26Kuwaki K, Tseng Y, Dor FJ et al. Heart transplantation in baboons using α1, 3-galactosyltransferase gene-knockout pigs as donors: initial experience. Nat Med 2004; 11: 29–31.
- 27Nguyen BH, Azimzadeh AM, Zhang T et al. Life-supporting function of genetically modified swine lungs in baboons. J Thorac Cardiovasc Surg 2007; 133: 1354–1363.
- 28Nguyen BH, Azimzadeh AM, Schroeder C et al. Absence of Gal epitope prolongs survival of swine lungs in an ex vivo model of hyperacute rejection. Xenotransplantation 2011; 18: 94–107.
- 29Burdorf L, Stoddard TA, Zhang T et al. Expression of human CD46 modulates inflammation associated with GalTKO lung xenograft injury. Am J Transplant 2014; 14: 1084–1095.
- 30Cooper DK, Ekser B, Burlak C et al. Clinical lung xenotransplantation–what donor genetic modifications may be necessary? Xenotransplantation 2012; 19: 144–158.
- 31Cooper DK, Dorling A, Pierson RN et al. Alpha1,3-galactosyltransferase gene-knockout pigs for xenotransplantation: where do we go from here? Transplantation 2007; 84: 1–7.
- 32Burdorf L, Azimzadeh AM, Pierson RN. Xenogeneic lung transplantation models. In: C Costa, R Manez, eds. Xenotransplantation. New York, NY: Springer, 2012: 169–189.
10.1007/978-1-61779-845-0_11 Google Scholar
- 33Daggett CW, Yeatman M, Lodge AJ et al. Total respiratory support from swine lungs in primate recipients. J Thorac Cardiovasc Surg 1998; 115: 19–27.
- 34Zhu A, Hurst R. Anti-N-glycolylneuraminic acid antibodies identified in healthy human serum. Xenotransplantation 2002; 9: 376–381.
- 35Westall GP, Levvey BJ, Salvaris E et al. Sustained function of genetically modified porcine lungs in an ex vivo model of pulmonary xenotransplantation. J Heart Lung Transplant 2013; 32: 1123–1130.
- 36Daggett CW, Yeatman M, Lodge AJ et al. Swine lungs expressing human complement–regulatory proteins are protected against acute pulmonary dysfunction in a human plasma perfusion model. J Thorac Cardiovasc Surg 1997; 113: 390–398.
- 37Macchiarini P, Mazmanian G, Oriol R et al. Ex vivo lung model of pig-to-human hyperacute xenograft rejection. J Thorac Cardiovasc Surg 1997; 114: 315–325.
- 38Demetriou AA, Brown RS Jr, Busuttil RW et al. Prospective, randomized, multicenter, controlled trial of a bioartificial liver in treating acute liver failure. Ann Surg 2004; 239: 660.
- 39Sgroi A, Bühler LH, Morel P, Sykes M, Noel L. International human xenotransplantation inventory. Transplantation 2010; 90: 597–603.
- 40Elliott RB, Escobar L, Tan PL et al. Live encapsulated porcine islets from a type 1 diabetic patient 9.5 yr after xenotransplantation. Xenotransplantation 2007; 14: 157–161.
- 41Yamada K, Yazawa K, Shimizu A et al. Marked prolongation of porcine renal xenograft survival in baboons through the use of α1, 3-galactosyltransferase gene-knockout donors and the cotransplantation of vascularized thymic tissue. Nat Med 2004; 11: 32–34.
- 42Mohiuddin M, Corcoran P, Singh A et al. B-Cell depletion extends the survival of GTKO. hCD46Tg pig heart xenografts in baboons for up to 8 months. Am J Transplant 2012; 12: 763–771.
- 43Brenner P, Schmoeckel M, Wimmer C et al. Mean xenograft survival of 14.6 days in a small group of hDAF-transgenic pig hearts transplanted orthotopically into baboons. Transplant Proc 2005; 37: 472–476.
- 44Vial C, Ostlie D, Bhatti F et al. Life supporting function for over one month of a transgenic porcine heart in a baboon. J Heart Lung Transplant 2000; 19: 224–229.
- 45Byrne GW, McGregor CG. Cardiac xenotransplantation: progress and challenges. Curr Opin Organ Transplant 2012; 17: 148–154.
- 46Reichart B, Guethoff S, Mayr T et al. Discordant cardiac xenotransplantation: broadening the horizons. Eur J Cardiothorac Surg 2014; 45: 1–5.
- 47Cantu E, Balsara K, Li B et al. Prolonged function of macrophage, von Willebrand factor-deficient porcine pulmonary xenografts. Am J Transplant 2007; 7: 66–75.
- 48Cantu E, Parker W, Platt JL, Duane Davis R. Pulmonary xenotransplantation: rapidly progressing into the unknown. Am J Transplant 2004; 4: 25–35.
- 49Ekser B, Rigotti P, Gridelli B, Cooper DK. Xenotransplantation of solid organs in the pig-to-primate model. Transpl Immunol 2009; 21: 87–92.
- 50Gonzalez-Stawinski GV, Daggett CW, Lau CL et al. Non-anti-Galα1-3Gal antibody mechanisms are sufficient to cause hyperacute lung dysfunction in pulmonary xenotransplantation. J Am Coll Surg 2002; 194: 765–773.
- 51den Hengst WA, Gielis JF, Lin JY et al. Lung ischemia-reperfusion injury: a molecular and clinical view on a complex pathophysiological process. Am J Physiol-Heart Circ Physiol 2010; 299: H1283–H1299.
- 52de Perrot M, Liu M, Waddell TK, Keshavjee S. Ischemia–reperfusion–induced lung injury. Am J Respir Crit Care Med 2003; 167: 490–511.
- 53Wohlauer MV, Sauaia A, Moore EE et al. Acute kidney injury and posttrauma multiple organ failure: the canary in the coal mine. J Trauma Acute Care Surg 2012; 72: 373–380.
- 54Gaieski DF, Edwards JM, Kallan MJ, Carr BG. Benchmarking the incidence and mortality of severe sepsis in the United States*. Crit Care Med 2013; 41: 1167–1174.
- 55Vincent J, de Mendonça A, Cantraine F et al. Use of the SOFA score to assess the incidence of organ dysfunction/failure in intensive care units: results of a multicenter, prospective study. Crit Care Med 1998; 26: 1793–1800.
- 56Moore FA, Moore E, Read R. Postinjury multiple organ failure: role of extrathoracic injury and sepsis in adult respiratory distress syndrome. New Horiz 1993; 1: 538.
- 57Dudek SM, Garcia JG. Cytoskeletal regulation of pulmonary vascular permeability. J Appl Physiol 2001; 91: 1487–1500.
- 58Ranieri VM, Suter PM, Tortorella C et al. Effect of mechanical ventilation on inflammatory mediators in patients with acute respiratory distress syndrome. JAMA 1999; 282: 54–61.
- 59Roy S, Sadowitz B, Andrews P et al. Early stabilizing alveolar ventilation prevents acute respiratory distress syndrome: a novel timing-based ventilatory intervention to avert lung injury. J Trauma Acute Care Surg 2012; 73: 391–400.
- 60Slutsky AS, Tremblay LN. Multiple system organ failure: is mechanical ventilation a contributing factor? Am J Respir Crit Care Med 1998; 157: 1721–1725.
- 61Downey GP, Worthen G, Henson P, Hyde D. Neutrophil sequestration and migration in localized pulmonary inflammation. Am Rev Respir Dis 1993; 147: 168–176.
- 62Wagner JG, Roth RA. Neutrophil migration mechanisms, with an emphasis on the pulmonary vasculature. Pharmacol Rev 2000; 52: 349–374.
- 63Ploppa A, Schmidt V, Hientz A et al. Mechanisms of leukocyte distribution during sepsis: an experimental study on the interdependence of cell activation, shear stress and endothelial injury. Crit Care 2010; 14: R201.
- 64Kuebler WM, Kuhnle G, Groh J, Goetz AE. Leukocyte kinetics in pulmonary microcirculation: intravital fluorescence microscopic study. J Appl Physiol 1994; 76: 65–71.
- 65Cutaia M, Rounds S. Hypoxic pulmonary vasoconstriction. Physiologic significance, mechanism, and clinical relevance. CHEST J 1990; 97: 706–718.
- 66Weir E, Archer S. The mechanism of acute hypoxic pulmonary vasoconstriction: the tale of two channels. FASEB J 1995; 9: 183–189.
- 67Shen R, Tai H. Immunoaffinity purification and characterization of thromboxane synthase from porcine lung. J Biol Chem 1986; 261: 11592–11599.
- 68Zamora CA, Baron DA, Heffner JE. Thromboxane contributes to pulmonary hypertension in ischemia-reperfusion lung injury. J Appl Physiol 1993; 74: 224–229.
- 69Klausner JM, Paterson IS, Goldman G et al. Thromboxane A2 mediates increased pulmonary microvascular permeability following limb ischemia. Circ Res 1989; 64: 1178–1189.
- 70Collins BJ, Blum MG, Parker RE et al. Thromboxane mediates pulmonary hypertension and lung inflammation during hyperacute lung rejection. J Appl Physiol 2001; 90: 2257–2268.
- 71Nguyen BH, Zwets E, Schroeder C et al. Beyond antibody-mediated rejection: hyperacute lung rejection as a paradigm for dysregulated inflammation. Curr Drug Targets Cardiovasc Haematol Disord 2005; 5: 255–269.
- 72Schroeder C, Allan J, Nguyen B et al. Hyperacute rejection is attenuated in GalT knockout swine lungs perfused ex vivo with human blood. Transplant Proc 2005; 37: 512–513.
- 73Pierson RN. Antibody-mediated xenograft injury: mechanisms and protective strategies. Transpl Immunol 2009; 21: 65–69.
- 74Pierson RN, Kasper-Konig W, Tew DN et al. Hyperacute lung rejection in a pig-to-human transplant model: the role of anti-pig antibody and complement. Transplantation 1997; 63: 594–603.
- 75Azimzadeh A, Zorn G, Blair K et al. Hyperacute lung rejection in the pig-to-human model. 2. Synergy between soluble and membrane complement inhibition. Xenotransplantation 2003; 10: 120–131.
- 76Galili U. The α-gal epitope (Galα1-3Galβ1-4GlcNAc-R) in xenotransplantation. Biochimie 2001; 83: 557–563.
- 77Joziasse D, Oriol R. Xenotransplantation: the importance of the Galα1, 3Gal epitope in hyperacute vascular rejection. Biochim Biophys Acta 1999; 1455: 403–418.
- 78Harnden I, Kiernan K, Kearns-Jonker M. The anti-non-gal xenoantibody response to galactosyltransferase gene knockout (galtko) pig xenografts. Curr Opin Organ Transplant 2010; 15: 207.
- 79Park J, Park M, Bui H et al. α1, 3-galactosyltransferase deficiency in germ-free miniature pigs increases N-glycolylneuraminic acids as the xenoantigenic determinant in pig-human xenotransplantation. Cell Reprogram 2012; 14: 353–363.
- 80Macchiarini P, Oriol R, Azimzadeh A et al. Evidence of human non-alpha-galactosyl antibodies involved in the hyperacute rejection of pig lungs and their removal by pig organ perfusion. J Thorac Cardiovasc Surg 1998; 116: 831–843.
- 81Cowan PJ, Roussel JC, D'apice AJ. The vascular and coagulation issues in xenotransplantation. Curr Opin Organ Transplant 2009; 14: 161–167.
- 82Chen D, Dorling A. Microcoagulation processes after xenotransplantation. Curr Opin Organ Transplant 2005; 10: 240–245.
- 83Siegel JB, Grey ST, Lesnikoski B et al. Xenogeneic endothelial cells activate human prothrombin. Transplantation 1997; 64: 888–896.
- 84Cowan PJ, d'Apice AJ. The coagulation barrier in xenotransplantation: incompatibilities and strategies to overcome them. Curr Opin Organ Transplant 2008; 13: 178–183.
- 85Roussel J, Moran C, Salvaris E et al. Pig thrombomodulin binds human thrombin but is a poor cofactor for activation of human protein C and TAFI. Am J Transplant 2008; 8: 1101–1112.
- 86Lawson J, Daniels L, Platt J. The evaluation of thrombomodulin activity in porcine to human xenotransplantation. Transplant Proc 1997; 29: 884–885.
- 87Gaca JG, Lesher A, Aksoy O et al. Disseminated intravascular coagulation in association with pig-to-primate pulmonary xenotransplantation1. Transplantation 2002; 73: 1717–1723.
- 88Mazzucato M, de Marco L, Pradella P et al. Porcine von Willebrand factor binding to human platelet GPIb induces transmembrane calcium influx. Thromb Haemost 1996; 75: 655–660.
- 89Li S, Waer M, Billiau AD. Xenotransplantation: role of natural immunity. Transpl Immunol 2009; 21: 70–74.
- 90Ehrnfelt C, Serrander L, Holgersson J. Porcine endothelium activated by anti-α-GAL antibody binding mediates increased human neutrophil adhesion under flow. Transplantation 2003; 76: 1112–1119.
- 91Goodman DJ, von Albertini M, Willson A, Millan MT, Bach FH. Direct activation of porcine endothelial cells by human natural killer cells 1. Transplantation 1996; 61: 763–771.
- 92Sheikh S, Parhar R, Kwaasi A et al. Alpha-gal-independent dual recognition and activation of xenogeneic endothelial cells and human naive natural killer cells1. Transplantation 2000; 70: 917–928.
- 93Sheikh S, Parhar R, Al-Mohanna F. Rapid static adhesion of human naïve neutrophil to naïve xenoendothelium under physiologic flow is independent of Galα1, 3-gal structures. J Leukoc Biol 2002; 71: 932–940.
- 94Robinson LA, Tu L, Steeber DA et al. The role of adhesion molecules in human leukocyte attachment to porcine vascular endothelium: implications for xenotransplantation. J Immunol 1998; 161: 6931–6938.
- 95Stocker CJ, Sugars KL, Yarwood H et al. Cloning of porcine intercellular adhesion molecule-1 and characterization of its induction on endothelial cells by cytokines. Transplantation 2000; 70: 579–586.
- 96Ezzelarab M, Garcia B, Azimzadeh A et al. The innate immune response and activation of coagulation in α1, 3-galactosyltransferase gene-knockout xenograft recipients. Transplantation 2009; 87: 805–812.
- 97Gaca JG, Palestrant D, Lukes DJ et al. Prevention of acute lung injury in swine: depletion of pulmonary intravascular macrophages using liposomal clodronate. J Surg Res 2003; 112: 19–25.
- 98Cantu E, Gaca JG, Palestrant D et al. Depletion of pulmonary intravascular macrophages prevents hyperacute pulmonary xenograft dysfunction. Transplantation 2006; 81: 1157–1164.
- 99Wiebe K, Oezkur M, Poling J, Haverich A. Potential of an injectable polymer to prevent hyperacute rejection of ex vivo perfused porcine lungs. Transplantation 2006; 82: 681–688.
- 100Phelps CJ, Koike C, Vaught TD et al. Production of α1, 3-galactosyltransferase-deficient pigs. Science 2003; 299: 411–414.
- 101Dai Y, Vaught TD, Boone J et al. Targeted disruption of the α1, 3-galactosyltransferase gene in cloned pigs. Nat Biotechnol 2002; 20: 251–255.
- 102Chen G, Qian H, Starzl T et al. Acute rejection is associated with antibodies to non-Gal antigens in baboons using Gal-knockout pig kidneys. Nat Med 2005; 11: 1295–1298.
- 103Hara H, Long C, Lin YJ et al. In vitro investigation of pig cells for resistance to human antibody-mediated rejection. Transpl Int 2008; 21: 1163–1174.
- 104Bush EL, Barbas AS, Holzknecht ZE et al. Coagulopathy in α-galactosyl transferase knockout pulmonary xenotransplants. Xenotransplantation 2011; 18: 6–13.
- 105Lutz AJ, Li P, Estrada JL et al. Double knockout pigs deficient in N-glycolylneuraminic acid and galactose α-1, 3-galactose reduce the humoral barrier to xenotransplantation. Xenotransplantation 2013; 20: 27–35.
- 106Loveland BE, Milland J, Kyriakou P et al. Characterization of a CD46 transgenic pig and protection of transgenic kidneys against hyperacute rejection in non-immunosuppressed baboons. Xenotransplantation 2004; 11: 171–183.
- 107Wiebe K, Poeling J, Meliss R et al. Improved function of transgenic pig lungs in ex vivo lung perfusion with human blood. Transplant Proc 2001; 33: 773–774.
- 108Schröder C, Pfeiffer S, Wu G et al. Effect of complement fragment 1 esterase inhibition on survival of human decay-accelerating factor pig lungs perfused with human blood. J Heart Lung Transplant 2003; 22: 1365–1375.
- 109Kulick DM, Salerno CT, Dalmasso AP et al. Transgenic swine lungs expressing human CD59 are protected from injury in a pig-to-human model of xenotransplantation. J Thorac Cardiovasc Surg 2000; 119: 690–699.
- 110Yeatman M, Daggett CW, Parker W et al. Complement-mediated pulmonary xenograft injury: studies in swine-to-primate orthotopic single lung transplant models. Transplantation 1998; 65: 1084–1093.
- 111Chen D, Riesbeck K, McVey JH et al. Regulated inhibition of coagulation by porcine endothelial cells expressing P-selectin-tagged hirudin and tissue factor pathway inhibitor fusion proteins. Transplantation 1999; 68: 832–839.
- 112Chen D, Riesbeck K, Kemball-Cook G et al. Inhibition of tissue factor-dependent and-independent coagulation by cell surface expression of novel anticoagulant fusion proteins. Transplantation 1999; 67: 467–474.
- 113Petersen B, Ramackers W, Tiede A et al. Pigs transgenic for human thrombomodulin have elevated production of activated protein C. Xenotransplantation 2009; 16: 486–495.
- 114Salvaris E, Fisicaro N, Moran C, Cowan P. In vitro assessment of the compatibility of thrombomodulin and endothelial protein C receptor in the pig-to-human setting. Xenotransplantation 2013; 20: 345.
- 115Budorf L, Rybak E, Zhang T et al. Human EPCR expression in GalTKO. hCD46 lungs extends survival time and lowers PVR in a xenogenic lung perfusion model. J Heart Lung Transplant 2013; 32: S137.
- 116Kim YT, Lee HJ, Lee SW et al. Pre-treatment of porcine pulmonary xenograft with desmopressin: a novel strategy to attenuate platelet activation and systemic intravascular coagulation in an ex-vivo model of swine-to-human pulmonary xenotransplantation. Xenotransplantation 2008; 15: 27–35.
- 117Lin CC, Cooper DK, Dorling A. Coagulation dysregulation as a barrier to xenotransplantation in the primate. Transpl Immunol 2009; 21: 75–80.
- 118Sanchez PG, Bittle GJ, Burdorf L, Pierson RN, Griffith BP. State of art: clinical ex vivo lung perfusion: rationale, current status, and future directions. J Heart Lung Transplant 2012; 31: 339–348.
- 119Cypel M, Rubacha M, Yeung J et al. Normothermic ex vivo perfusion prevents lung injury compared to extended cold preservation for transplantation. Am J Transplant 2009; 9: 2262–2269.
- 120Beck-Broichsitter M, Gauss J, Packhaeuser CB et al. Pulmonary drug delivery with aerosolizable nanoparticles in an< i> ex vivo lung model. Int J Pharm 2009; 367: 169–178.
- 121Harris D, Benipal P, Gao Z et al. Activated protein C decreases thrombosis on porcine endothelium transgenic for human endothelial protein C receptor-A novel mechanism to decrease porcine xenograft injury. J Surg Res 2014; 186: 579.
10.1016/j.jss.2013.11.516 Google Scholar
- 122Burdorf L, Zhang T, Rybak E et al. 295 blocking GP1b-vWF interaction by anti-GP1b fab reduces activation and sequestration of platelets in a xenogeneic pig lung perfusion model. J Heart Lung Transplant 2011; 30: S103.
- 123Harris D, Benipal P, Cheng X, Azimzadeh A, Pierson RN. Four-dimensional in-vitro modeling of xenogeneic thrombosis under shear flow: a novel technique. Xenotransplantation 2013; 20: 356.
- 124Burdorf L, Zhang T, Rybak E et al. Combined GPIb and GPIIb/IIIa blockade prevents sequestration of platelets in a pig-to-human lung perfusion model. Xenotransplantation 2011; 18: 287.
- 125Burdorf L, Rybak E, Zhang T et al. Combined thromboxane synthase inhibition and H2-receptor blockade prevents PVR elevation during GalTKO.hCD46.hCD55 pig lung perfusion with human blood. J Heart Lung Transplant 2014; 33: S257–S258.
- 126Hering BJ, Wijkstrom M, Graham ML et al. Prolonged diabetes reversal after intraportal xenotransplantation of wild-type porcine islets in immunosuppressed nonhuman primates. Nat Med 2006; 12: 301–303.
- 127Cozzi E, Vial C, Ostlie D et al. Maintenance triple immunosuppression with cyclosporin A, mycophenolate sodium and steroids allows prolonged survival of primate recipients of hDAF porcine renal xenografts. Xenotransplantation 2003; 10: 300–310.
- 128Gaca JG, Lesher A, Aksoy O et al. The role of the porcine von Willebrand factor: baboon platelet interactions in pulmonary xenotransplantation. Transplantation 2002; 74: 1596–1603.
- 129Pöling J, Oezkur M, Kogge K et al. Hyperacute rejection in ex vivo-perfused porcine lungs transgenic for human complement regulatory proteins. Transpl Int 2006; 19: 225–232.