Current cellular innate immune hurdles in pig-to-primate xenotransplantation

Current Opinion in Organ Transplantation

Volumn 13, Issue 2, 2008, Pages 171-177

  Schneider, Mårten K J ^a   Seebach, Jörg D ^b,c  

^a UNIVERSITY HOSPITAL ZURICH   (Switzerland)

^b UNIVERSITY HOSPITAL   (Switzerland)

^c GENEVA UNIVERSITY HOSPITALS   (Switzerland)

Author keywords

Endothelial cells; Innate immune system; Monocytes macrophages; Natural killer cells; Neutrophils; Xenograft rejection

Indexed keywords

EOTAXIN; GALACTOSYLGALACTOSE; GALECTIN 3; GAMMA INTERFERON; INTERLEUKIN 6; INTERLEUKIN 8; MONOCYTE CHEMOTACTIC PROTEIN 1; NATURAL KILLER CELL RECEPTOR; RANTES; THROMBOCYTE ACTIVATING FACTOR;

ANIMAL EXPERIMENT; ANIMAL MODEL; ANTIBODY DEPENDENT CELLULAR CYTOTOXICITY; CELL ADHESION; CELL INTERACTION; CELL MIGRATION; ENDOTHELIUM CELL; GRAFT REJECTION; HUMORAL IMMUNITY; INNATE IMMUNITY; MACROPHAGE; MONOCYTE; NATURAL KILLER CELL; NATURAL KILLER CELL MEDIATED CYTOTOXICITY; NEUTROPHIL; NONHUMAN; PRIMATE; REVIEW; SWINE; XENOTRANSPLANTATION;

ANIMALS; DISACCHARIDES; ENDOTHELIAL CELLS; ENDOTHELIUM; HUMANS; IMMUNITY, NATURAL; KILLER CELLS, NATURAL; LEUKOCYTES; MODELS, ANIMAL; PRIMATES; SWINE; TRANSPLANTATION IMMUNOLOGY; TRANSPLANTATION, HETEROLOGOUS;

EID: 40649116483     PISSN: 10872418     EISSN: 15317013     Source Type: Journal    
DOI: 10.1097/MOT.0b013e3282f88a30     Document Type: Review

References (88)

1. Yang YG, Sykes M. Xenotransplantation: current status and a perspective on the future. Nat Rev Immunol 2007; 7:519-531.
2. Cooper DK, Gollackner B, Sachs DH. Will the pig solve the transplantation backlog? Annu Rev Med 2002; 53:133-147.
3. Sprangers B, Waer M, Billiau AD. Xenograft rejection and the innate immune system. Curr Opin Organ Trans 2007; 12:142-147.
4. Sandrin MS, Milland J, Christiansen D. The impact of the alpha 1,3-galactosyltransferase gene knockout pig on xenotranspantation. Curr Opin Organ Trans 2007; 12:154-157.
5. Li S, Yan Y, Lin Y, et al. Rapidly induced, T-independent xenoantibody production is mediated by marginal zone B cells and requires help from natural killer cells. Blood 2007; 110:3926-3935. This study shows that T-cell independent IgM xenoantibody production by marginal zone B cells requires help from natural killer cells, independent of NK cell-mediated IFN-γ production and cytotoxicity, and CD40L signaling.
6. Yin D, Zeng H, Ma L, et al. Cutting edge: natural killer cells mediate IgG1-dependent hyperacute rejection of xenografts. J Immunol 2004; 172:7235-7238.
7. Rieben R, Seebach JD. Xenograft rejection: IgG(1), complement and natural killer cells team up to activate and destroy the endothelium. Trends Immunol 2005; 26:2-5.
8. Inverardi L, Samaja M, Motterlini R, et al. Early recognition of a discordant xenogeneic organ by human circulating lymphocytes. J Immunol 1992; 149:1416-1423.
9. Inverardi L, Pardi R. Early events in cell-mediated recognition of vascularized xenografts: cooperative interactions between selected lymphocyte subsets and natural antibodies. Immunol Rev 1994; 141:71-93.
10. Khalfoun B, Barrat D, Watier H, et al. Development of an ex vivo model of pig kidney perfused with human lymphocytes. Analysis of xenogeneic cellular reactions. Surgery 2000; 128:447-457.
11. Kaplon RJ, Michler RE, Xu H, et al. Absence of hyperacute rejection in newborn pig-to-baboon cardiac xenografts. Transplantation 1995; 59:1-6.
12. Sablinski T, Gianello PR, Bailin M, et al. Pig to monkey bone marrow and kidney xenotransplantation. Surgery 1997; 121:381-391.
13. Chen D, Cao R, Guo H, et al. Pathogenesis and pathology of delayed xenograft rejection in pig-to-rhesus monkey cardiac transplantation. Transplant Proc 2004; 36:2480-2482.
14. Goddard MJ, Dunning J, Horsley J, et al. Histopathology of cardiac xenograft rejection in the pig-to-baboon model. J Heart Lung Transplant 2002; 21:474-484.
15. Al Mohanna F, Collison K, Parhar R, et al. Activation of naive xenogeneic but not allogeneic endothelial cells by human naive neutrophils: a potential occult barrier to xenotransplantation. Am J Pathol 1997; 151:111-120.
16. Robinson 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.
17. Soderlund J, Wennberg L, Castanos VE, et al. Fetal porcine islet-like cell clusters transplanted to cynomolgus monkeys: an immunohistochemical study. Transplantation 1999; 67:784-791.
18. Fox A, Harrison LC. Innate immunity and graft rejection. Immunol Rev 2000; 173:141-147.
19. Sheikh S, Parhar R, al Mohanna F. Rapid static adhesion of human naive neutrophil to naive xenoendothelium under physiologic flow is independent of Galalpha1,3-gal structures. J Leukoc Biol 2002; 71:932-940.
20. Biancone L, Cantaluppi V, Segoloni G, et al. Role of platelet-activating factor in functional alterations induced by xenoreactive antibodies in porcine endothelial cells. Transplantation 2000; 70:1198-1205.
21. Ehrnfelt C, Serrander L, Holgersson J. Porcine endothelium activated by antialpha-GAL antibody binding mediates increased human neutrophil adhesion under flow. Transplantation 2003; 76:1112-1119.
22. Gilli UO, Schneider MKJ, Loetscher P, Seebach JD. Human polymorphonuclear neutrophils are recruited by porcine chemokines acting on CXC chemokine receptor 2. Transplantation 2005; 79:1324-1331.
23. Millan MT, Geczy C, Stuhlmeier KM, et al. Human monocytes activate porcine endothelial cells, resulting in increased E-selectin, interleukin-8, monocyte chemotactic protein-1, and plasminogen activator inhibitor-type-1 expression. Transplantation 1997; 63:421-429.
24. Peterson MD, Vlasova E, Ciano-Oliveira C, et al. Monocyte-induced endothelial calcium signaling mediates early xenogeneic endothelial activation. Am J Transplant 2005; 5:237-247.
25. Goodman DJ, Von Albertini M, Willson A, et al. Direct activation of porcine endothelial cells by human natural killer cells. Transplantation 1996; 61:763-771.
26. Sheikh S, Parhar R, Kwaasi A, et al. Alpha-gal-independent dual recognition and activation of xenogeneic endothelial cells and human naive natural killer cells. Transplantation 2000; 70:917-928.
27. Von Albertini M, Ferran C, Brostjan C, et al. Membrane-associated lymphotoxin on natural killer cells activates endothelial cells via an NF-kappaB-dependent pathway. Transplantation 1998; 66:1211-1219.
28. Malyguine AM, Saadi S, Platt JL, Dawson JR. Human natural killer cells induce morphologic changes in porcine endothelial cell monolayers. Transplantation 1996; 61:161-164.
29. Choi I, Kim SD, Cho B, et al. Xenogeneic interaction between human CD40L and porcine CD40 activates porcine endothelial cells through NF-kappaB signaling. Mol Immunol 2008; 45:575-580. Xenogeneic interactions between human CD40L and porcine CD40 induce chemokine, MHC, and adhesion molecule expression in pEC through NF-κB signaling.
30. Ehrnfelt C, Kumagai-Braesch M, Uzunel M, Holgersson J. Adult porcine islets produce MCP-1 and recruit human monocytes in vitro. Xenotransplantation 2004; 11:184-194.
31. Yang J, Cho B, Choi I, et al. Molecular characterization of miniature porcine RANTES and its chemotactic effect on human mononuclear cells. Transplantation 2006; 82:1229-1233.
32. Simon AR, Warrens AN, Sykes M. Efficacy of adhesive interactions in pig-to-human xenotransplantation. Immunol Today 1999; 20:323-330.
33. Schneider MK, Forte P, Seebach JD. Adhesive interactions between human natural killer cells and porcine endothelial cells. Scand J Immunol 2001; 54:70-75.
34. Nasu K, Whyte A, Green SJ, et al. Alpha-galactosyl-mediated activation of porcine endothelial cells: studies on CD31 and VE-cadherin in adhesion and signaling. Transplantation 1999; 68:861-867.
35. Weber C, Fraemohs L, Dejana E. The role of junctional adhesion molecules in vascular inflammation. Nat Rev Immunol 2007; 7:467-477.
36. Hauzenberger E, Hauzenberger D, Hultenby K, Holgersson J. Porcine endothelium supports transendothelial migration of human leukocyte subpopulations: antiporcine vascular cell adhesion molecule antibodies as species-specific blockers of transendothelial monocyte and natural killer cell migration. Transplantation 2000; 69:1837-1849.
37. Schneider MK, Ghielmetti M, Rhyner DM, Seebach JD. Xenogeneic leukocyte transmigration partly depends on interactions between human CD99 and beta2-integrins with porcine endothelium. Swiss Med Wkly 2007; 137:32S. (Abstract).
38. Schenkel AR, Mamdouh Z, Muller WA. Locomotion of monocytes on endothelium is a critical step during extravasation. Nat Immunol 2004; 5:393-400.
39. Ostermann G, Weber KS, Zernecke A, et al. JAM-1 is a ligand of the beta(2) integrin LFA-1 involved in transendothelial migration of leukocytes. Nat Immunol 2002; 3:151-158.
40. Al Mohanna F, Saleh S, Parhar R, et al. Human neutrophil gene expression profiling following xenogeneic encounter with porcine aortic endothelial cells: the occult role of neutrophils in xenograft rejection revealed. J Leukoc Biol 2005; 78:51-61.
41. Cardozo LA, Rouw DB, Ambrose LR, et al. The neutrophil: the unnoticed threat in xenotransplantation? Transplantation 2004; 78:1721-1728.
42. Ide K, Ohdan H, Kobayashi T, et al. Antibody- and complement-independent phagocytotic and cytolytic activities of human macrophages toward porcine cells. Xenotransplantation 2005; 12:181-188.
43. Subramanian S, Parthasarathy R, Sen S, et al. Species- and cell type-specific interactions between CD47 and human SIRPalpha. Blood 2006; 107:2548-2556.
44. Ide K, Wang H, Tahara H, et al. Role for CD47-SIRPalpha signaling in xenograft rejection by macrophages. Proc Natl Acad Sci U S A 2007; 104:5062-5066. The authors demonstrate that porcine CD47 does not induce SIRPa tyrosine phosphorylation in human macrophages. In contrast, transfection of porcine cells with human CD47 significantly reduced their susceptibility to human macrophage phagocytosis.
45. ••], phagocytosis by mouse macrophages was reduced by expression of mouse CD47 on porcine cells.
46. Xu XC, Goodman J, Sasaki H, et al. Activation of natural killer cells and macrophages by porcine endothelial cells augments specific T-cell xenoresponse. Am J Transplant 2002; 2:314-322.
47. Watier H, Guillaumin JM, Vallee I, et al. Human natural killer cell-mediated direct and IgG-dependent cytotoxicity against xenogeneic porcine endothelial cells. Transpl Immunol 1996; 4:293-299.
48. Seebach JD, Waneck GL. Natural killer cells in xenotransplantation. Xenotransplantation 1997; 4:201-211.
49. Matter-Reissmann UB, Forte P, Schneider MK, et al. Xenogeneic human natural killer cytotoxicity against porcine endothelial cells is perforin/granzyme B dependent and not inhibited by Bcl-2 overexpression. Xenotransplantation 2002; 9:325-337.
50. Matter-Reissmann UB, Sonntag KC, Gilli UO, et al. Human Fas-ligand expression on porcine endothelial cells does not protect against xenogeneic natural killer cytotoxicity. Xenotransplantation 2004; 11:43-52.
51. Forte P, Lilienfeld BG, Baumann BC, Seebach JD. Human natural killer cytotoxicity against porcine cells is triggered by natural killerp44 and natural killerG2D. J Immunol 2005; 175:5463-5470.
52. Garcia-Borges CN, Phanavanh B, Saraswati S, et al. Molecular cloning and characterization of a porcine UL16 binding protein (ULBP)-like cDNA. Mol Immunol 2005; 42:665-671.
53. Lilienfeld BG, Garcia-Borges C, Crew MD, Seebach JD. Porcine UL16-binding protein 1 expressed on the surface of endothelial cells triggers human natural killer cytotoxicity through natural killerG2D. J Immunol 2006; 177:2146-2152. The authors demonstrate that porcine ULBP1 is the predominant functional porcine ligand for the human natural killer activating receptor natural killerG2D.
54. Lilienfeld BG, Schildknecht A, Imbach LL, et al. Characterization of porcine UL16-binding protein 1 (pULBP1) endothelial cell surface expression. Xenotransplantation (in press).
55. Seebach JD, Yamada K, McMorrow I, et al. Xenogeneic human antipig cytotoxicity mediated by activated natural killer cells. Xenotransplantation 1996; 3:188-197.
56. Sullivan JA, Oettinger HF, Sachs DH, Edge AS. Analysis of polymorphism in porcine MHC class I genes: alterations in signals recognized by human cytotoxic lymphocytes. J Immunol 1997; 159:2318-2326.
57. Forte P, Pazmany L, Matter-Reissmann UB, et al. HLA-G inhibits rolling adhesion of activated human natural killer cells on porcine endothelial cells. J Immunol 2001; 167:6002-6008.
58. Forte P, Matter-Reissmann UB, Strasser M, et al. Porcine aortic endothelial cells transfected with HLA-G are partially protected from xenogeneic human natural killer cytotoxicity. Hum Immunol 2000; 61:1066-1073.
59. Seebach JD, Comrack C, Germana S, et al. HLA-Cw3 expression on porcine endothelial cells protects against xenogeneic cytotoxicity mediated by a subset of human natural killer cells. J Immunol 1997; 159:3655-3661.
60. Sharland A, Patel A, Lee JH, et al. Genetically modified HLA class I molecules able to inhibit human natural killer cells without provoking alloreactive CD8+ CTLs. J Immunol 2002; 168:3266-3274.
61. Sharland A, Lee JH, Saidman S, Waneck GL. CD8-interaction mutant HLA-Cw3 molecules protect porcine cells from human natural killer cell-mediated antibody-dependent cellular cytotoxicity without stimulating cytotoxic T lymphocytes. Transplantation 2003; 76:1615-1622.
62. Crew MD. Play it in E or G: utilization of HLA-E and -G in xenotransplantation. Xenotransplantation 2007; 14:198-207.
63. Matsunami K, Miyagawa S, Nakai R, et al. Modulation of the leader peptide sequence of the HLA-E gene up-regulates its expression and down-regulates natural killer cell-mediated swine endothelial cell lysis. Transplantation 2002; 73:1582-1589.
64. Sasaki H, Xu XC, Mohanakumar T. HLA-E and HLA-G expression on porcine endothelial cells inhibit xenoreactive human natural killer cells through CD94/natural killerG2-dependent and -independent pathways. J Immunol 1999; 163:6301-6305.
65. Forte P, Baumann BC, Weiss EH, Seebach JD. HLA-E expression on porcine cells: protection from human natural killer cytotoxicity depends on peptide loading. Am J Transplant 2005; 5:2085-2093.
66. Crew MD, Cannon MJ, Phanavanh B, Garcia-Borges CN. An HLA-E single chain trimer inhibits human natural killer cell reactivity towards porcine cells. Mol Immunol 2005; 42:1205-1214.
67. Lilienfeld BG, Crew MD, Forte P, et al. Transgenic expression of HLA-E single chain trimer protects porcine endothelial cells against human natural killer cell-mediated cytotoxicity. Xenotransplantation 2007; 14:126-134. Stable surface expression of HLA-E on pEC was accomplished by using a single-chain trimer. The level of protection of pEC from human NK cytotoxicity correlated with the intensity of HLA-E expression, and was reversed by blocking the HLA-E specific NK inhibitory receptor CD94/NKG2A.
68. Imbach LL, Lilienfeld BG, Schneider MK, Seebach JD. Strategies to prevent porcine endothelial cell-induced IFNg secretion by human natural killer cells. Xenotransplantation 2007; 14:404. (Abstract).
69. Seebach JD. natural killer cell education, activation and inhibition. Xenotransplantation 2007; 14:396. (Abstract).
70. Galili U. Interaction of the natural anti-Gal antibody with alpha-galactosyl epitopes: a major obstacle for xenotransplantation in humans. Immunol Today 1993; 14:480-482.
71. Schaapherder AF, Daha MR, te Bulte MT, et al. Antibody-dependent cell-mediated cytotoxicity against porcine endothelium induced by a majority of human sera. Transplantation 1994; 57:1376-1382.
72. Cooke SP, Pearson JD, Savage CO. Human IgG xenoreactive antibodies mediate damage to porcine endothelial cells in vitro by both humoral and cellular mechanisms. Transpl Immunol 1997; 5:39-44.
73. Baumann BC, Stussi G, Huggel K, et al. Reactivity of human natural antibodies to endothelial cells from Galalpha(1,3)Gal-deficient pigs. Transplantation 2007; 83:193-201. This study shows individual differences among 120 donors in the levels of human antiporcine nonαGal XNA as well as their relative contribution to XNA/complement-induced lysis and ADCC of pEC.
74. Saethre M, Baumann BC, Fung M, et al. Characterization of natural human antinongal antibodies and their effect on activation of porcine gal-deficient endothelial cells. Transplantation 2007; 84:244-250. The authors studied individual levels of human antiporcine nonaGal XNA, in particular against the anti-Hanganutziu-Deicher xenoantigen, and their relative contribution to pEC activation.
75. Baumann BC, Forte P, Hawley RJ, et al. Lack of galactose-alpha-1,3-galactose expression on porcine endothelial cells prevents complement-induced lysis but not direct xenogeneic natural killer cytotoxicity. J Immunol 2004; 172:6460-6467.
76. Miklos K, Tolnay M, Bazin H, Medgyesi GA. Antibody mediated lysis of hapten-conjugated target cells by macrophages and by complement: the influence of IgG subclass, antibody and hapten density. Mol Immunol 1992; 29:379-384.
77. Fearon DT, Locksley RM. The instructive role of innate immunity in the acquired immune response. Science 1996; 272:50-53.
78. Inverardi L, Clissi B, Stolzer AL, et al. Human natural killer lymphocytes directly recognize evolutionarily conserved oligosaccharide ligands expressed by xenogeneic tissues. Transplantation 1997; 63:1318-1330.
79. Goodman DJ, Millan MT, Ferran C, Bach FH. Mechanisms of delayed xenograft rejection. In: Cooper DKC, Kemp E, Paul WE, et al., editors. Xenotransplantation. Springer; 1997. p. 77.
80. Kwiatkowski P, Artrip JH, Wang SF, et al. Human monocytes bind to two distinct carbohydrate capping structures on porcine endothelium. Transplant Proc 2000; 32:927.
81. Peterson MD, Jin R, Hyduk S, et al. Monocyte adhesion to xenogeneic endothelium during laminar flow is dependent on {alpha}-Gal-mediated monocyte activation. J Immunol 2005; 174:8072-8081.
82. Jin R, Greenwald A, Peterson MD, Waddell TK. Human monocytes recognize porcine endothelium via the interaction of galectin 3 and alpha-GAL. J Immunol 2006; 177:1289-1295.
83. Artrip JH, Kwiatkowski P, Michler RE, et al. Target cell susceptibility to lysis by human natural killer cells is augmented by alpha(1,3)-galactosyltransferase and reduced by alpha(1,2)-fucosyltransferase. J Biol Chem 1999; 274:10717-10722.
84. Miyagawa S, Nakai R, Yamada M, et al. Regulation of natural killer cell-mediated swine endothelial cell lysis through genetic remodeling of a glycoantigen. J Biochem 1999; 126:1067-1073.
85. Costa C, Barber DF, Fodor WL. Human natural killer cell-mediated cytotoxicity triggered by CD86 and Gal alpha 1,3-Gal is inhibited in genetically modified porcine cells. J Immunol 2002; 168:3808-3816.
86. Christiansen D, Mouhtouris E, Milland J, et al. Recognition of a carbohydrate xenoepitope by human natural killerRP1A (CD161). Xenotransplantation 2006; 13:440-446.
87. Baumann BC, Schneider MK, Lilienfeld BG, et al. Endothelial cells derived from pigs lacking Gala(1,3)Gal: no reduction of human leukocyte adhesion and natural killer cytotoxicity. Transplantation 2005; 79:1067-1072.
88. He Z, Ehrnfelt C, Kumagai-Braesch M, et al. Aberrant expression of alpha-Gal on primary human endothelium does not confer susceptibility to natural killer cell cytotoxicity or increased natural killer cell adhesion. Eur J Immunol 2004; 34:1185-1195.