Pig-to-baboon heterotopic heart transplantation - Exploratory preliminary experience with pigs transgenic for human thrombomodulin and comparison of three costimulation blockade-based regimens

Xenotransplantation

Volumn 22, Issue 3, 2015, Pages 211-220

  Iwase, Hayato ^a   Ekser, Burcin ^a,b,h   Satyananda, Vikas ^a   Bhama, Jay ^c   Hara, Hidetaka ^a   Ezzelarab, Mohamed ^a   Klein, Edwin ^d   Wagner, Robert ^d   Long, Cassandra ^a   Thacker, Jnanesh ^c   Li, Jiang ^a   Zhou, Hao ^a,e   Jiang, Maolin ^a,e   Nagaraju, Santosh ^a   Zhou, Huidong ^a,e   Veroux, Massimiliano ^b   Bajona, Pietro ^a   Wijkstrom, Martin ^a   Wang, Yi ^e   Phelps, Carol ^f   Klymiuk, Nikolai ^g   Wolf, Eckhard ^g   Ayares, David ^f   Cooper, David K C ^a   more..

^a UNIVERSITY OF PITTSBURGH MEDICAL CENTER   (United States)

^b UNIVERSITY OF CATANIA   (Italy)

^c UNIVERSITY OF PITTSBURGH SCHOOL OF MEDICINE   (United States)

^d UNIVERSITY OF PITTSBURGH   (United States)

^e THE SECOND AFFILIATED HOSPITAL OF UNIVERSITY OF SOUTH CHINA   (China)

^f REVIVICOR INC   (United States)

^g UNIVERSITY OF MUNICH   (Germany)

^h INDIANA UNIVERSITY SCHOOL OF MEDICINE   (United States)

Author keywords

baboon; complement regulatory proteins; costimulation blockade; heart; pig; thrombomodulin; thrombotic microangiopathy; xenotransplantation; 1,3 galactosyltransferase gene knockout

Indexed keywords

ABATACEPT; ALPHA 1,3 GALACTOSYLTRANSFERASE; BELATACEPT; CD40 LIGAND MONOCLONAL ANTIBODY; D DIMER; DECAY ACCELERATING FACTOR; FIBRINOGEN; THROMBOMODULIN; THYMOCYTE ANTIBODY; IMMUNOSUPPRESSIVE AGENT;

ACUTE GRAFT REJECTION; ALPHA 1,3 GALACTOSYLTRANSFERASE GENE; ANIMAL TISSUE; ANTIGEN EXPRESSION; ARTICLE; ASCITES; AUTOPSY; BABOON; CELLULAR IMMUNITY; CLINICAL EFFECTIVENESS; CONTROLLED STUDY; DRUG RESPONSE; FOLLOW UP; GENE; GENE FUNCTION; GENE IDENTIFICATION; GRAFT SURVIVAL; HEART TRANSPLANTATION; HISTOPATHOLOGY; HUMAN; HUMAN TISSUE; IMMUNE RESPONSE; INFECTIOUS COMPLICATION; LYMPHOCYTE COUNT; MALE; MICROSCOPY; MONOTHERAPY; MUSCLE ATROPHY; NONHUMAN; POSTOPERATIVE PERIOD; PRIORITY JOURNAL; PROTEIN DETERMINATION; PROTEIN EXPRESSION; PROTEIN FUNCTION; SCAR FORMATION; SURGICAL INFECTION; SURVIVAL TIME; T LYMPHOCYTE; THROMBOCYTE COUNT; THROMBOCYTOPENIA; THROMBOTIC THROMBOCYTOPENIC PURPURA; TRANSGENIC PIG; XENOTRANSPLANTATION; ANIMAL; COMPARATIVE STUDY; DRUG EFFECTS; GENETICS; GRAFT REJECTION; HEART; IMMUNOLOGY; METABOLISM; PIG; PROCEDURES; TRANSGENIC ANIMAL; XENOGRAFT;

ANIMALS; ANIMALS, GENETICALLY MODIFIED; GRAFT REJECTION; GRAFT SURVIVAL; HEART; HEART TRANSPLANTATION; HUMANS; IMMUNOSUPPRESSIVE AGENTS; PAPIO; SWINE; THROMBOMODULIN; TRANSPLANTATION, HETEROLOGOUS;

EID: 84930761656     PISSN: 0908665X     EISSN: 13993089     Source Type: Journal    
DOI: 10.1111/xen.12167     Document Type: Article

References (49)

1. Kolber-Simonds D, Lai L, Watt SR, et al., Production of alpha-1,3-galactosyltransferase null pigs by means of nuclear transfer with fibroblasts bearing loss of heterozygosity mutations. Proc Natl Acad Sci USA 2004; 101: 7335-7340.
2. Phelps CJ, Koike C, Vaught TD, et al., Production of alpha 1,3-galactosyltransferase-deficient pigs. Science 2003; 299: 411-414.
3. Kuwaki K, Tseng YL, Dor FJ, et al., Heart transplantation in baboons using alpha1,3-galactosyltransferase gene-knockout pigs as donors: initial experience. Nat Med 2005; 11: 29-31.
4. Tseng YL, Kuwaki K, Dor FJ, et al., alpha1,3-Galactosyltransferase gene-knockout pig heart transplantation in baboons with survival approaching 6 months. Transplantation 2005; 80: 1493-1500.
5. Ezzelarab M, Garcia B, Azimzadeh A, et al., The innate immune response and activation of coagulation in alpha1,3-galactosyltransferase gene-knockout xenograft recipients. Transplantation 2009; 87: 805-812.
6. Houser SL, Kuwaki K, Knosalla C, et al., Thrombotic microangiopathy and graft arteriopathy in pig hearts following transplantation into baboons. Xenotransplantation 2004; 11: 416-425.
7. Shimizu A, Hisashi Y, Kuwaki K, et al., Thrombotic microangiopathy associated with humoral rejection of cardiac xenografts from alpha1,3-galactosyltransferase gene-knockout pigs in baboons. Am J Pathol 2008; 172: 1471-1481.
8. Mohiuddin MM, Corcoran PC, Singh AK, 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.
9. Lawson JH, Daniels LJ, Platt JL,. The evaluation of thrombomodulin activity in porcine to human xenotransplantation. Transplant Proc 1997; 29: 884-885.
10. Siegel JB, Grey ST, Lesnikoski BA, et al., Xenogeneic endothelial cells activate human prothrombin. Transplantation 1997; 64: 888-896.
11. Kopp CW, Grey ST, Siegel JB, et al., Expression of human thrombomodulin cofactor activity in porcine endothelial cells. Transplantation 1998; 66: 244-251.
12. Mohiuddin MM, Singh AK, Corcoran PC, et al., One-year heterotopic cardiac xenograft survival in a pig to baboon model. Am J Transplant 2014; 14: 488-489.
13. Mohiuddin M, Singh AK, Corcoran PC, et al., Genetically engineered pigs and target-specific immunomodulation provide significant graft survival and hope for clinical cardiac xenotransplantation. JTCS 2014; 148: 1106-1113.
14. Cozzi E, White DJ,. The generation of transgenic pigs as potential organ donors for humans. Nat Med 1995; 1: 964-966.
15. Petersen B, Ramackers W, Tiede A, et al., Pigs transgenic for human thrombomodulin have elevated production of activated protein C. Xenotransplantation 2009; 16: 486-495.
16. Miwa Y, Yamamoto K, Onishi A, et al., Potential value of human thrombomodulin and DAF expression for coagulation control in pig-to-human xenotransplantation. Xenotransplantation 2010; 17: 26-37.
17. Wuensch A, Baehr A, Bongoni AK, et al., Regulatory sequences of the porcine THBD gene facilitate endothelial-specific expression of bioactive human thrombomodulin in single- and multitransgenic pigs. Transplantation 2014; 97: 138-147.
18. Yazaki S, Iwamoto M, Onishi A, et al., Production of cloned pigs expressing human thrombomodulin in endothelial cells. Xenotransplantation 2012; 19: 82-91.
19. Ezzelarab MB, Ekser B, Echeverri G, et al., Costimulation blockade in pig artery patch xenotransplantation-a simple model to monitor the adaptive immune response in nonhuman primates. Xenotransplantation 2012; 19: 221-232.
20. Kawai T, Andrews D, Colvin RB, Sachs DH, Cosimi AB,. Thromboembolic complications after treatment with monoclonal antibody against CD40 ligand. Nat Med 2000; 6: 114.
21. Knosalla C, Gollackner B, Cooper DK,. Anti-CD154 monoclonal antibody and thromboembolism revisited. Transplantation 2002; 74: 416-417.
22. Ayares D, Phelps C, Vaught TD, et al., Multi-transgenic pigs for vascularized pig organ xenografts. Xenotransplantation 2011; 18: 269 (abstract #119).
23. Klymiuk N, Wuensch A, Kurome M, et al., GalT-KO/CD46/hTM triple-transgenic donor animals for pig-to-baboon heart transplantation. Xenotransplantation 2011; 18: 271 (Abstract #126).
24. Loveland 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.
25. Cooper DKC, Ye Y, Niekrasz M,. Heart transplantation in primates. In:, Cramer DVPL, Makowka L, eds. Handbook of Animal Models in Transplantation Research. Boca Raton: CRC Press, 1994: 173-200.
26. Iwase H, Ekser B, Satyananda V, et al., Initial in vivo experience of pig artery patch transplantation in baboons using mutant MHC (CIITA-DN) pigs. Transplant Immunol. 2015: 99-108.
27. Lowe M, Badell IR, Thompson P, et al., A novel monoclonal antibody to CD40 prolongs islet allograft survival. Am J Transplant 2012; 12: 2079-2087, 52.
28. Larsen CP, Pearson TC, Adams AB, et al., Rational development of LEA29Y (belatacept), a high-affinity variant of CTLA4-Ig with potent immunosuppressive properties. Am J Transplant 2005; 5: 443-453.
29. Ekser B, Bianchi J, Ball S, et al., Comparison of hematologic, biochemical, and coagulation parameters in alpha1,3-galactosyltransferase gene-knockout pigs, wild-type pigs, and four primate species. Xenotransplantation 2012; 19: 342-354.
30. Buhler L, Awwad M, Basker M, et al., High-dose porcine hematopoietic cell transplantation combined with CD40 ligand blockade in baboons prevents an induced anti-pig humoral response. Transplantation 2000; 69: 2296-2304.
31. Adams AB, Shirasugi N, Jones TR, et al., Development of a chimeric anti-CD40 monoclonal antibody that synergizes with LEA29Y to prolong islet allograft survival. J Immunol 2005; 174: 542-550.
32. Haanstra KG, Ringers J, Sick EA, et al., Prevention of kidney allograft rejection using anti-CD40 and anti-CD86 in primates. Transplantation 2003; 75: 637-643.
33. Kenyon NS, Chatzipetrou M, Masetti M, et al., Long-term survival and function of intrahepatic islet allografts in rhesus monkeys treated with humanized anti-CD154. Proc Natl Acad Sci USA 1999; 96: 8132-8137.
34. Kirk AD, Harlan DM, Armstrong NN, et al., CTLA4-Ig and anti-CD40 ligand prevent renal allograft rejection in primates. Proc Natl Acad Sci USA 1997; 94: 8789-8794.
35. Pearson TC, Trambley J, Odom K, et al., Anti-CD40 therapy extends renal allograft survival in rhesus macaques. Transplantation 2002; 74: 933-940.
36. Tai HC, Campanile N, Ezzelarab M, Cooper DK, Phelps C,. Measurement of anti-CD154 monoclonal antibody in primate sera by competitive inhibition ELISA. Xenotransplantation 2006; 13: 566-570.
37. Thompson P, Cardona K, Russell M, et al., CD40-specific costimulation blockade enhances neonatal porcine islet survival in nonhuman primates. Am J Transplant 2011; 11: 947-957.
38. Ezzelarab M, Hara H, Busch J, et al., Antibodies directed to pig non-Gal antigens in naive and sensitized baboons. Xenotransplantation 2006; 13: 400-407.
39. Hara H, Ezzelarab M, Rood PP, et al., Allosensitized humans are at no greater risk of humoral rejection of GT-KO pig organs than other humans. Xenotransplantation 2006; 13: 357-365.
40. Hara 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.
41. Ekser B, Klein E, He J, et al., Genetically-engineered pig-to-baboon liver xenotransplantation: histopathology of xenografts and native organs. PLoS ONE 2012; 7: e29720.
42. Chen 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.
43. Ezzelarab M, Ezzelarab C, Wilhite T, et al., Genetically-modified pig mesenchymal stromal cells: xenoantigenicity and effect on human T-cell xenoresponses. Xenotransplantation 2011; 18: 183-195.
44. Wilhite T, Ezzelarab C, Hara H, et al., The effect of Gal expression on pig cells on the human T-cell xenoresponse. Xenotransplantation 2012; 19: 56-63.
45. Ezzelarab C, Ayares D, Cooper DK, Ezzelarab MB,. Human T-cell proliferation in response to thrombin-activated GTKO pig endothelial cells. Xenotransplantation 2012; 19: 311-316.
46. Gorski A, Wasik M, Nowaczyk M, Korczak-Kowalska G,. Immunomodulating activity of heparin. FASEB J 1991; 5: 2287-2291.
47. Heinzelmann M, Bosshart H,. Fondaparinux sodium lacks immunomodulatory effects of heparin. Am J Surg 2004; 187: 111-113.
48. Hochart H, Jenkins PV, Preston RJ, et al., Concentration-dependent roles for heparin in modifying lipopolysaccharide-induced activation of mononuclear cells in whole blood. Thromb Haemost 2008; 99: 570-575.
49. Ranjbaran H, Wang Y, Manes TD, et al., Heparin displaces interferon-gamma-inducible chemokines (IP-10, I-TAC, and Mig) sequestered in the vasculature and inhibits the transendothelial migration and arterial recruitment of T cells. Circulation 2006; 114: 1293-1300.