DOI QR코드

DOI QR Code

Evaluation of Cytotoxicity for Immunity Rejection of US11, hDAF and FasL Transgene-Transfected Cells

  • Kang, Jung Won (Department of Animal Science & Biotechnology, Chungnam National University) ;
  • Shin, Hyeon Yeong (Department of Animal Science & Biotechnology, Chungnam National University) ;
  • Oqani, Reza K. (Department of Animal Science & Biotechnology, Chungnam National University) ;
  • Lin, Tao (Department of Animal Science & Biotechnology, Chungnam National University) ;
  • Lee, Jae Eun (Department of Animal Science & Biotechnology, Chungnam National University) ;
  • Kim, So Yeon (Department of Animal Science & Biotechnology, Chungnam National University) ;
  • Lee, Joo Bin (Department of Animal Science & Biotechnology, Chungnam National University) ;
  • Jin, Dong Il (Department of Animal Science & Biotechnology, Chungnam National University)
  • Received : 2017.08.29
  • Accepted : 2017.08.31
  • Published : 2017.08.31

Abstract

Xenotransplantation is proposed as a solution to the problem of organ shortage. However, transplantation of xenogeneic organs induces an antigen-antibody reaction in ${\alpha}$-1,3-gal structure that are not present in humans and primates, and thus complement is also activated and organs die within minutes or hours. In this study, we used FasL gene, which is involved in the immune response of NK cell, and US11, which suppresses MHC Class I cell membrane surface expression, to inhibit cell mediated rejection in the interspecific immunity rejection, and also hDAF(CD55) was introduced to confirm the response to C3 complement. These genes were tranfeced into Korean native pig fetal fibroblasts using pCAGGS vector. And cytotoxicity of NK cell and human complement was confirmed in each cell line. The US11 inhibited the cytotoxicity of NK cell and, in addition, the simultaneous expression of US11 and Fas ligand showed excellent suppress to T-lymphocyte cytotoxicity, hDAF showed weak resistance to cytotoxicity of natural killer cell but not in CD8+ CTLs. Cytotoxicity study with human complement showed that hDAF was effective for reducing complement reaction. In this studies have demonstrated that each gene is effective in reducing immune rejection.

Keywords

References

  1. Alexopoulou AN, Couchman JR, Whiteford JR (2008): The CMV early enhancer/chicken beta actin (CAG) promoter can be used to drive transgene expression during the differentiation of murine embryonic stem cells into vascular progenitors. BMC Cell Biology 9:2. https://doi.org/10.1186/1471-2121-9-2
  2. Alwayn IP, Basker M, Buhler L, Cooper DK (1999): The problem of anti-pig antibodies in pig-to-primate xenografting: Current and novel methods of depletion and/or suppression of production of anti-pig antibodies. Xenotransplantion 6:157-168. https://doi.org/10.1034/j.1399-3089.1999.00030.x
  3. Bach FH, Robson SC, Winkler H, Ferran C (1995): Barriers to xenotransplantation. Nat Med 1:869-873. https://doi.org/10.1038/nm0995-869
  4. Bach FH, Winkler H, Ferran C, Hancock WW, Robson SC (1996): Delayed xenograft rejection. Immunol Today 17:379-384. https://doi.org/10.1016/0167-5699(96)10024-4
  5. Barnes PD, Grundy JE (1992): Down-regulation of the class I HLA heterodimer and b2-microglobulin on the surface of cells infected with cytomegalovirus. J Gen Virol 73:2395-2403. https://doi.org/10.1099/0022-1317-73-9-2395
  6. Besold K, Wills M, Plachter B (2009): Immune evasion proteins gpUS2 and gpUS11 of human cytomegalovirus incompletely protect infected cells from CD-8 T cell recognition. Virology 391:5-19. https://doi.org/10.1016/j.virol.2009.06.004
  7. Cooper DK, Gollackner B, Sachs DH (2002): Will the pig solve the transplantation backlog?. Annu Rev Med 53:133-147. https://doi.org/10.1146/annurev.med.53.082901.103900
  8. Cooper DK (2003): Clinical xenotransplantation - how close are we?. Lancet 362:557-559. https://doi.org/10.1016/S0140-6736(03)14118-9
  9. Cooper DK, Human PA, Lexer G, Rose AG, Rees J, Keraan M, Du Toit E (1988): Effects of cyclosporine and antibody adsorption on pigcardiac xenograft survival in the baboon. J Heart Transplant 7:238-246.
  10. DaGe Liu, Takaaki Kobayashi, Akira Onishi, Tadashi Furusawa, Masaki, Iwamoto, Shunichi Suzuki, Yuko Miwa, Takaharu Nagasaka, Shoichi Maruyama, Kenji Kadomatsu, Kazuharu Uchida, Akimasa Nakao (2007): Relation between human decay-accelerating factor (hDAF) expression in pig cells and inhibition of human serum anti-pig cytotoxicity: value of highly expressed hDAF for xenotransplantation. Xenotransplantation 67-73.
  11. Dorling A, Lombardi G, Binns R, Lechler RI (1996): Detection of primary direct and indirect human anti-porcine T cell responses using a porcine dendritic cell population. Eur J Immunol 26:1378-1387. https://doi.org/10.1002/eji.1830260630
  12. Galili U, Shohet SB, Kobrin E, Stults CL, Macher B (1988): Man, apes and Old World monkeys differ from other mammals in the expression of a-galactosyl epitopes on nucleated cells. J Biol Chem 263:17755-17762.
  13. Galili U, Matta KL (1996): Inhibition of anti-gal IgG binding to porcine endothelial cells by synthetic oligosaccharides. Trnasplantation 62:256-262. https://doi.org/10.1097/00007890-199607270-00018
  14. Good AH, Cooper DK, Malcolm AJ, Ippolito RM, Koren E, Neethling FA, Zudhi YY, Lamontagne LR (1992): Identification of carbohydrate structures that bind human antiporcine antibodies: Implications for discordant xenografting in human. Transplant Proc 24:559-562.
  15. Haddad E (1995): Treatment of Chediak-Higashi syndrome by allogenic bone marrow transplantation: report of 10 cases. Blool 11:3328.
  16. Hannon JP, Bossone CA, Wade CE (1990): Normal physiological values for conscious pigs used in biomedical research. Lab Anim Sci 40:293-298.
  17. Inveradi L, Clissi B, Stolzer A, Bender JR, Sandrin MS, Pardi R (1997): Human natural killer lymphocytes directly recognize evolutionarily conserved oligosaccharide ligands expressed by xenogeneic tissues. Transplantation 63:1318-1324. https://doi.org/10.1097/00007890-199705150-00021
  18. John S Logan (2000): Prospects for xenotransplantation. Current Opinion in Immunology 563-568.
  19. Jones TR, Wiertz EJ, Sun L, Fish KN, Nelson JA, Ploegh HL (1996): Human cytomegalovirus US3 impairs transport and maturation of major histocompatibility complex class I heavy chains. Proc Natl Acad Sci USA 93:11327-11333. https://doi.org/10.1073/pnas.93.21.11327
  20. Kobayashi T, Tanigchi S, Neethling FA, Rose AG, Hancock WW, Ye Y, Niekrasz M, Kosanke S, Wright LI, White DJ, Cooper DK (1997): Delayed xenograft rejection of pig-to-baboon cardiac transplants after cobra venom factor therapy. Transplantation 64:1255-1261. https://doi.org/10.1097/00007890-199711150-00005
  21. Kolber-Simonds D, Lai L, Watt SR, Denaro M, Arn S, Augenstein ML, Betthauser J, Carter DB, Greenstein JL, Hao Y, Im GS, Liu Z, Mell GD, Murphy CN, Park KW, Rieke A, Ryan DJ, Sachs DH, Forsberg EJ, Prather RS, Hawley RJ (2004): 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. 101:7335-7340. https://doi.org/10.1073/pnas.0307819101
  22. Lin SS, Kooyman DL, Daniels LJ, Daggett CW, Parker W, Lawson JH, Hoopes CW, Gullotto C, Li L, Birch P (1997): The role of natural $anti-Gal{\alpha}1-3Gal$ antibodies in hyperacute rejection of pig-tobaboon cardiac xenotransplants. Transplantation 5:212-218.
  23. Logan JS, Sharma A (1999): Potential use of genetically modified pigs as organ donors for transplantation into humans. Clin Exp Pharmacol Physiol 26:1020-1025 https://doi.org/10.1046/j.1440-1681.1999.03185.x
  24. Logan JS (2000): Prospects for xenotrasplantation. Curr Opin Immunol 12:563-568. https://doi.org/10.1016/S0952-7915(00)00139-4
  25. Lokki M L, H R Colten (1995): Genetic deficiencies of complement. Ann Med 21:451.
  26. Lublin DM, Mallinson G, Poole J, Reid ME, Thompson ES, Ferdman BR, Telen MJ, Anstee DJ, Anner MJ (1994): Molecular basis of reduced or absent expression of decay-accelerating factor in Cromer blood group phenotypes. Blood 84(4):1276-1282.
  27. Lunney JK (2007): Advances in swine biomedical model genomics. Int J Biol Sci 3:179-184.
  28. Medof ME, Lublin DM, Holers VM, Ayers DJ, Getty RR, Leykam JF, Atkinson JP, Tykocinski ML (1987): Cloning and characterization of cDNAs encoding the complete sequence of decay-accelerating factor of human complement. Proc Natl Acad Sci USA. 84(7):2007-11. https://doi.org/10.1073/pnas.84.7.2007
  29. Miyagawa S, Hirose H, Shirakura R, Naka Y, Nakata S, Kawashima Y, Seya T, Matsumoto M, Uenaka A, Kitamura H (1988): The mechanism of discordant xenograft rejection. Transplantation 46:825-830. https://doi.org/10.1097/00007890-198812000-00007
  30. Mohiuddin MM, Corcoran PC, Singh AK, Azimzadeh A, Hoyt RF Jr, Thomas ML, Eckhaus MA, Seavey C, Ayares D, Pierson RN 3rd, Horvath KA (2012): B-cell depletion extends the survival of GTKO.hCD46Tg pig heart xenografts in baboons for up to 8 months. Am J Transplant 12:763-771. https://doi.org/10.1111/j.1600-6143.2011.03846.x
  31. Natarajan K (2002): Structure and function of natural-killer-cell receptors: multiple molecular solutions to self, non self discrimination. Annu Rev Immunol 20:853. https://doi.org/10.1146/annurev.immunol.20.100301.064812
  32. Niwa H, Yamamura K, Miyazaki J (1991): Efficient selection for high-expression transfectants with a novel eukaryotic vector. Gene 108(2):193-9. https://doi.org/10.1016/0378-1119(91)90434-D
  33. Noriega V M, Tortorella D (2009): Human cytomegalovirusencoded immune modulators partner to downregulate major histocompatibility complex class I molecules. J Virol 83:1359-1367. https://doi.org/10.1128/JVI.01324-08
  34. Noriega V, Redmann V, Gardner T, Tortorella D (2012): Diverse immune evasion strategies by human cytomegalovirus. Immunol Res 54:140-151. https://doi.org/10.1007/s12026-012-8304-8
  35. Okabe M, Ikawa M, Kominami K, Nakanishi T, Nishimune Y (1997): 'Green mice' as a source of ubiquitous green cells. FEBS Lett 5; 407(3):313-9. https://doi.org/10.1016/S0014-5793(97)00313-X
  36. Phelp CJ, Koike C, Vaught TD, Boone J, Wells KD, Chen SH, Ball S, Specht SM, Polejaeva IA, Monahan JA, Jobst PM, Sharma SB, Lamborn AE, Garst AS, Moore M, Demetris AJ, Rudert WA, Bottino R, Bertera S, Trucco M, Starzl TE, Dai Y, Ayares DL (2003): Production of alpha-1,3-galactosyltransferase-deficient pigs. Science 299:411-414. https://doi.org/10.1126/science.1078942
  37. Platt JL, Fischel RJ, Matas AJ, Reif SA, Bolman RM, Bach FH (1991): Immunopathology of hyperacute xenograft rejection in a swineto-primate model. Transplantation 52:214-220. https://doi.org/10.1097/00007890-199108000-00006
  38. Platt JL (1996) The immunological barriers to xenotransplantation. Crit Rev Immunol 16:331-358.
  39. Platt JL, Lin SS, McGregor CGA (1998): Acute vascular rejection. Xenotransplantation 5:169-175. https://doi.org/10.1111/j.1399-3089.1998.tb00024.x
  40. Pruitt SK, Bollinger RR, Collins BH, Marsh HC Jr, Rudolph AR, Baldwin WM III, Sanfilippo F (1997): Effect of continuous complement inhibition using soluble complement receptor type 1 survival of pigto-primate cardiac xenograft. Transplantation 63:900-902. https://doi.org/10.1097/00007890-199703270-00017
  41. Reddehase M J, Weiland F, Munch K, Jonjic S, Luske A, Koszinowski U H (1985): Interstitial murine cytomegalovirus pneumonia after irradiation: characterization of cells that limit viral replication during established infection of the lungs. J Virol 55:264-273.
  42. Rispat G, Slaoui M, Weber D, Salemink P, Berthoux C, Shrivastava R (1993): Haematological and plasma bio-chemical values for healthy Yucatan micropigs. Lab Anim 27:368-373. https://doi.org/10.1258/002367793780745561
  43. Russell J H, T J Ley (2002): Lymphocyte-mediated cytotoxicity. Annu Rev Immunol 20:370.
  44. Sachs DH, Stjes M, Robson SC, Cooper DK (2001) Xenotransplantation. Adv Immunol 79:129-223.
  45. Shultz LD, Ishikawa F, Greiner DL (2007): Humanized mice in translational biomedical research. Nat Rev Immunol 7:118-130. https://doi.org/10.1038/nri2017
  46. Tanemura M, Chong AS, Disesa VJ, Galili U (2002): Direct killing of xenograft cells by $CD8^{+}$ T cell of discordant xenograft recipients. Transplantation 74:1587-1595. https://doi.org/10.1097/00007890-200212150-00017
  47. Taniguchi S, Neethling FA, Korchagina EY, Bovin N, Ye Y, Kobayashi T, Niekrasz M, Li s, Koren E, Oriol R, Cooper DKC (1998): In vivo immunoadsorption of antipig antibodies in baboons using a specific $Gal{\alpha}1-3Gal$ column. Transplantation 62:1379-1384.
  48. Kagi D (1994): Fas and perforin as major mechanisms of T-cell-mediated cytotoxicity. Science 265:528. https://doi.org/10.1126/science.7518614
  49. Kawamoto K, Tanemura M, Nishida T, Fukuzawa M, Ito T (2006): Significant inhibition of human $CD8^{+}$ cytotoxic T lymphocyte-mediated xenocytotoxicity by overexpression of the human decoy Fas antigen. Transplantation 81:789-796. https://doi.org/10.1097/01.tp.0000199266.07237.25
  50. Wiertz EJ, Jones TR, Sun L, Bogyo M, Geuze HJ, Ploegh HL (1996): The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol. Cell 84:769-779. https://doi.org/10.1016/S0092-8674(00)81054-5