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Stem Cell Reviews

, 1:151 | Cite as

Human embryonic stem cells

Potential tool for achieving immunotolerance?
  • Pablo Menendez
  • Clara Bueno
  • Lisheng Wang
  • Mickie Bhatia
Original Article

Abstract

The derivation of human embryonic stem cells (hESCs), whose in vitro differentiation might be directed toward different cell types, has raised the hope for cell replacement therapies. Despite the emerging reports to differentiate hESCs into specific lineages and then to distinct mature cell subsets, there are still several issues that need to be resolved before transplantation of these cells can be realized. In this context, immune rejection by the host immune system has been considered to be one of the greatest hurdles for cellular transplantation. However, recent data support the concept that hESCs and/or their differentiated derivatives possess immune-privileged properties, suggesting that cells derived from hESC may provide a potential tool for induction of immunetolerance. Currently, our understanding of the tolerogenic potential of hESCs is limited to assessment by in vitro assays or xenogenic transplantation approaches in vivo. Human ESCs express low levels of major histocompatability complex (MHC)-I antigens and lack expression of MHC-II antigens and costimulatory molecules, and are not recognized by natural killer cells and inhibit T-cell induced-stimulation by third-party antigen-presenting cells. Upon injection into immunocompetent mice, hESCs are unable to induce an immune response as demonstrated by their inability to induce an inflammatory response. Based on these initial observations, further studies in hESCs immunobiology are warranted and may reveal unique mechanisms that account for the immunological properties of hESCs. Here, we explore the prospect of using hESCs and their derivatives for immunomodulation and tolerance induction.

Index Entries

Human embryonic stem cells immunogenicity transplantation immunotolerance 

References

  1. 1.
    Reubinoff BE, Pera MF, Fong CY, et al. Nat Biotechnol 2000;18:399–404.PubMedCrossRefGoogle Scholar
  2. 2.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS, et al. Science 1998;282:1145–1147.PubMedCrossRefGoogle Scholar
  3. 3.
    Watt FM, Hogan BL. Science 2000;287:1427–1430.PubMedCrossRefGoogle Scholar
  4. 4.
    Clark AT, Bodnar MS, Fox M, et al. Hum Mol Genet 2004;13:727–739.PubMedCrossRefGoogle Scholar
  5. 5.
    Gerami-Naini B, Dovzhenko OV, Durning M, et al. Endocrinology 2004;145:1517–1524.PubMedCrossRefGoogle Scholar
  6. 6.
    Xu RH, Chen X, Li DS, et al. Nat Biotechnol 2004;20:1261–1264.CrossRefGoogle Scholar
  7. 7.
    Carpenter MK, Inokuma MS, Denham J, et al. Exp Neurol 2001;172:383–397.PubMedCrossRefGoogle Scholar
  8. 8.
    Reubinoff BE, Inokuma MS, Denham J, et al. Nat Biotechnol 2001;19:1134–1140.PubMedCrossRefGoogle Scholar
  9. 9.
    Schiedlmeier B, Klump H, Will E, et al. Blood 2003;101:1759–1768.PubMedCrossRefGoogle Scholar
  10. 10.
    Levenberg S, Golub JS, Amit M, et al. Proc Natl Acad Sci USA 2002;99:4391–4396.PubMedCrossRefGoogle Scholar
  11. 11.
    Wang L, Shojaei F, Levac K, et al. Immunity 2004;21:31–41.PubMedCrossRefGoogle Scholar
  12. 12.
    He JQ, Ma Y, Lee Y, et al. Circ Res 2003;93:32–39.PubMedCrossRefGoogle Scholar
  13. 13.
    Kehat I, Kenyagin-Karsenti D, Snir M, et al. J Clin Invest 2001;108:407–414.PubMedCrossRefGoogle Scholar
  14. 14.
    Mummery C, Ward-van Oostwaard D, Doevendans P, et al. J Anat 2002;200:233–242.PubMedCrossRefGoogle Scholar
  15. 15.
    Chadwick K, Wang L, Li L, et al. Blood 2003;102:906–915.PubMedCrossRefGoogle Scholar
  16. 16.
    Kaufman DS, Hanson ET, Lewis RL, Auerbach R, Thomson JA. Proc Natl Acad Sci USA 2001;98:716–721.CrossRefGoogle Scholar
  17. 17.
    Green H, Easley K, Iuchi S. Proc Natl Acad Sci USA 2003;100:625–630.Google Scholar
  18. 18.
    Rambhatla L, Chiu CP, Kundu P, Peng Y, Carpenter MK. Cell Transplant 2003;12:1–11.PubMedGoogle Scholar
  19. 19.
    Sottile V, Seuwen K, Kneissel M. Calcif Tissue Int 2004;75:329–337.PubMedCrossRefGoogle Scholar
  20. 20.
    Rathjen PD, Lake J, Whyatt LM, Bettess MD, Rathjen J. Reprod Fertil Dev 1998;10:31–47.PubMedCrossRefGoogle Scholar
  21. 21.
    Brivanlou AH, Gage FH, Jaenisch R, Jessell T, Melton D, Rossant J. Science 2003;300:913–916.PubMedCrossRefGoogle Scholar
  22. 22.
    Wekerle T, Sykes M. Annu Rev Med 2001;52:353–370.PubMedCrossRefGoogle Scholar
  23. 23.
    Thomas ED. J Clin Oncol 1983;1:517–531.PubMedGoogle Scholar
  24. 24.
    Couriel D, Caldera H, Champlin R, Komanduri K. Cancer 2004;101:1936–1946.PubMedCrossRefGoogle Scholar
  25. 25.
    Zeiser R, Marks R, Bertz H, Finke J. Ann Hematol 2004;83:551–565.PubMedCrossRefGoogle Scholar
  26. 26.
    Watkins WM. Transfus Med 2001;11:243–265.PubMedCrossRefGoogle Scholar
  27. 27.
    Roopenian D, Choi EY, Brown A. Immunol Rev 2002;190:86–94.PubMedCrossRefGoogle Scholar
  28. 28.
    Horton R. Wilming L, Rand V, et al. Nat Rev Genet 2004;5:889–899.PubMedCrossRefGoogle Scholar
  29. 29.
    Starzl TE. Proc Natl Acad Sci USA 2004;101:607–614.CrossRefGoogle Scholar
  30. 30.
    Mach B, Steimle V, Martinez-Soria E, Reith W. Annu Rev Immunol 1996;14:301–331.PubMedCrossRefGoogle Scholar
  31. 31.
    Turner D. The human leucocyte antigen (HLA) system. Vox Sang 2004;87:87–90.PubMedCrossRefGoogle Scholar
  32. 32.
    Harding FA, McArthur JG, Gross JA, Raulet DH, Allison JP. Nature 1992;356:607–609.PubMedCrossRefGoogle Scholar
  33. 33.
    Fraser JD, Irving BA, Crabtree GR, Weiss A. Science 1991;251:313–316.PubMedCrossRefGoogle Scholar
  34. 34.
    June CH, Bluestone JA, Nadler LM, Thompson CB. Immunol Today 1994;15:321–331.PubMedCrossRefGoogle Scholar
  35. 35.
    Freeman GJ, Gribben JG, Boussiotis VA, Science 1993;262:909–911.PubMedCrossRefGoogle Scholar
  36. 36.
    Azuma M, Yagita H, Okumura K, Phillips JH, Lanier LL, Somoza C. Nature 1993;366:76–79.PubMedCrossRefGoogle Scholar
  37. 37.
    Menendez P, Perez-Simon JA, Mateos MV, Br J Haematol 2002;119:135–143.PubMedCrossRefGoogle Scholar
  38. 38.
    Triulzi DJ, Nalesnik MA. Transfusion 2001;41:419–426.PubMedCrossRefGoogle Scholar
  39. 39.
    Bacigalupo A, Palandri F. Hematol J 2004;5:189–196.PubMedCrossRefGoogle Scholar
  40. 40.
    Fandrich F, Dresske B, Bader M, Schulze M. J Mol Med 2002;80:343–350.PubMedCrossRefGoogle Scholar
  41. 41.
    Basara N, Gunzelmann S, Willenbacher W, Fauser AA, Kiehl MG. Transplant Proc 2001;33:2220–2222.PubMedCrossRefGoogle Scholar
  42. 42.
    Billingham RE, Brent L, Medawar PB. Nature 1953;172:603–606.PubMedCrossRefGoogle Scholar
  43. 43.
    Sharabi Y, Sachs DH. J Exp Med 1989;169:493–502.PubMedCrossRefGoogle Scholar
  44. 44.
    Ildstad ST, Sachs DH. Nature 1984;307:168–170.PubMedCrossRefGoogle Scholar
  45. 45.
    Ildstad ST, Wren SM, Bluestone JA, Barbieri SA, Sachs DH. J Exp Med 1985;162:231–244.PubMedCrossRefGoogle Scholar
  46. 46.
    Brocker T, Riedinger M, Karjalainen K. J Exp Med 1997;185:541–550.PubMedCrossRefGoogle Scholar
  47. 47.
    Fandrich F, Lin X, Chai GX. Nat Med 2002;8:171–178.PubMedCrossRefGoogle Scholar
  48. 48.
    Drukker M, Katz G, Urbach A, Proc Natl Acad Sci USA 2002;99:9864–9869.PubMedCrossRefGoogle Scholar
  49. 49.
    Drukker M. Springer Semin Immunopathol 2004;29:201–213.CrossRefGoogle Scholar
  50. 50.
    Owen RD. Science 1945;102:400–401.CrossRefPubMedGoogle Scholar
  51. 51.
    Slavin S. Int J Hematol 2002;76:172–175.PubMedCrossRefGoogle Scholar
  52. 52.
    Tafuri A, Alferink J, Moller P, Hammerling GJ, Arnold B. Science 1995;270:630–633.PubMedCrossRefGoogle Scholar
  53. 53.
    Carosella ED, Moreau P, Le Maoult J, Le Discorde M, Dausset J, Rouas-Freiss N. Adv Immunol 2003;81:199–252.PubMedGoogle Scholar
  54. 54.
    Vacchio MS, Jiang SP. Crit Rev Immunol 1999;19;461–480.PubMedGoogle Scholar
  55. 55.
    Huddleston H, Schust DJ. Am J Reprod Immunol 2004;51:283–289.PubMedCrossRefGoogle Scholar
  56. 56.
    Mellor AL, Munn DH. Annu Rev Immunol 2000;18:367–391.PubMedCrossRefGoogle Scholar
  57. 57.
    Fairchild PJ, Cartland S, Nolan KF, Waldmann H. Trends Immunol 2004;25:465–470.PubMedCrossRefGoogle Scholar
  58. 58.
    Fairchild PJ, Cartland S, Nolan KF, Waldmann H. Int Immunopharmacol 2005;5:13–21.PubMedCrossRefGoogle Scholar
  59. 59.
    Moreau P, Paul P, Rouas-Freiss N, Kirszenbaum M, Dausset J, Carosella ED. Am J Reprod Immunol 1998;40:136–144.PubMedGoogle Scholar
  60. 60.
    Kovats S, Main EK, Librach C, et al. Science 1990;248:220–223.PubMedCrossRefGoogle Scholar
  61. 61.
    Moretta L, Bottino C, Cantoni C, Mingari MC, Moretta A. Curr Opin Pharmacol 2001;1:387–391.PubMedCrossRefGoogle Scholar
  62. 62.
    Li L, Baroja ML, Majumdar A, et al. Stem Cells 2004;22:448–456.PubMedCrossRefGoogle Scholar
  63. 63.
    Sirard C, Laneuville P, Dick JE. Blood 1994;83:1575–1585.PubMedGoogle Scholar
  64. 64.
    Martin MJ, Muotri A, Gage F, Varki A. Nat Med 2005;11:228–232.PubMedCrossRefGoogle Scholar
  65. 65.
    Simon C, Escobedo C, Valbuena D. Fertil Steril 2005;83:246–249.PubMedCrossRefGoogle Scholar
  66. 66.
    Drukker M, Benvenisty N. Trends Biotechnol 2004;22:136–141.PubMedCrossRefGoogle Scholar
  67. 67.
    Shizuru JA, Weissman IL, Kernoff R, Masek M, Scheffold YC. Proc Natl Acad Sci USA 2000;97:9555–9560.PubMedCrossRefGoogle Scholar
  68. 68.
    Andrews PW. Biochim Biophys Acta 1988;948:17–36.PubMedGoogle Scholar
  69. 69.
    Lebkowski JS, Gold J, Xu C, Funk W, Chiu CP, Carpenter MK. Cancer J 2001;7(Suppl 2):S83-S93.PubMedGoogle Scholar
  70. 70.
    Kyba M, Perlingeiro RC, Daley GQ. Cell 2002;109:29–37.PubMedCrossRefGoogle Scholar
  71. 71.
    Kaufman DS, Thomson JA. J Anat 2002;200:243–248.PubMedCrossRefGoogle Scholar
  72. 72.
    Kyba M, Daley GQ. Exp Hematol 2003;31:994–1006.PubMedGoogle Scholar
  73. 73.
    Kyba M, Perlingeiro RC, Hoover RR, Lu CW, Pierce J, Daley GQ. Proc Natl Acad Sci USA 2003;100:904–910.CrossRefGoogle Scholar
  74. 74.
    Zhan X, Dravid G, Ye Z, et al. Lancet 2004;364:163–171.PubMedCrossRefGoogle Scholar
  75. 75.
    Fairchild PJ, Brook FA, Gardner RL, Graca L, et al. Curr Biol 2000;10:1515–1518.PubMedCrossRefGoogle Scholar
  76. 76.
    Fairchild PJ, Waldmann H. Curr Opin Immunol 2000;12:528–535.PubMedCrossRefGoogle Scholar
  77. 77.
    Fairchild PJ, Nolan KF, Cartland S, Graca L, Waldmann H. Transplantation 2003;76:606–608.PubMedCrossRefGoogle Scholar
  78. 78.
    Fairchild PJ, Nolan KF, Waldmann H. Methods Enzymol 2003;365:169–186.PubMedCrossRefGoogle Scholar
  79. 79.
    Senju S, Hirata S, Matsuyoshi H, et al. Blood 2003;101:3501–3508.PubMedCrossRefGoogle Scholar
  80. 80.
    Chang CC, Ciubotariu R, Manavalan JS, et al. Nat Immunol 2002;3:237–243.PubMedCrossRefGoogle Scholar
  81. 81.
    Akbari O, Freeman GJ, Meyer EH, et al. Nat Med 2002;8:1024–1032.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2005

Authors and Affiliations

  • Pablo Menendez
    • 1
  • Clara Bueno
    • 2
  • Lisheng Wang
    • 1
  • Mickie Bhatia
    • 1
    • 3
  1. 1.Krembil Centre for Stem Cell Biology and Regenerative MedicineRobarts Research InstituteLondonCanada
  2. 2.FOCIS Centre for Clinical Immunology and ImmunotherapeuticsRobarts Research InstituteLondonCanada
  3. 3.Department of Microbiology and ImmunologyUniversity of Western OntarioLondonCanada

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