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Mitigating the Risk of Immunogenicity in the Pursuit of Induced Pluripotency

  • Paul J. Fairchild
  • Naoki Ichiryu
Chapter
Part of the Stem Cell Biology and Regenerative Medicine book series (STEMCELL)

Abstract

The advent of induced pluripotent stem (iPS) cells represents a significant milestone in the field of regenerative medicine. While the first derivation of human embryonic stem (hES) cells 8 years earlier, had made pluripotency accessible in vitro for the first time, iPS cells offered the elixir of personalised pluripotency by facilitating the generation of autologous lines, tailored to the needs of the individual. Importantly, an autologous source of iPS cells promised to circumvent the immunological barriers that have threatened to undermine the translation of cell therapies to the clinic. Nevertheless, quite apart from the practical and economic constraints of personalised medicines that may prohibit their widespread implementation, recent studies have questioned whether tissues derived from iPS cells in an autologous fashion will be ignored by the immune system of the recipient. Indeed, the up-regulation of developmental antigens upon reprogramming and their persistent expression during differentiation may render such tissues vulnerable to rejection. Here, we assess the likely impact that such findings will have on the clinical application of induced pluripotency.

Keywords

Embryonic Stem Cell Enzyme Replacement Therapy Immune Privilege Cell Replacement Therapy Human Artificial Chromosome 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

We are grateful to Tim Davies, Simon Hackett, Alison Leishman and Patty Sachamitr for helpful discussions. Work in the authors’ laboratory on the immunology of stem cell transplantation has been supported by Grant G0802538 from the Medical Research Council (UK) and seed funding from the Oxford Stem Cell Institute.

References

  1. 1.
    Thomson JA, Itskovitz-Eldor J, Shapiro SS et al (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147PubMedCrossRefGoogle Scholar
  2. 2.
    Robertson NJ, Brook F, Gardner RL, Cobbold SP, Waldmann H, Fairchild PJ (2007) Embryonic stem cell-derived tissues are immunogenic but their innate immune privilege promotes the induction of tolerance. Proc Natl Acad Sci U S A 104:20920–20925PubMedCrossRefGoogle Scholar
  3. 3.
    Swijnenburg R-J, Schrepfer S, Govaert JA et al (2008) Immunosuppressive therapy mitigates immunological rejection of human embryonic stem cell xenografts. Proc Natl Acad Sci U S A 105:12991–12996PubMedCrossRefGoogle Scholar
  4. 4.
    Wakayama T, Tabar V, Rodriguez I, Perry ACF, Studer L, Mombaerts P (2001) Differentiation of embryonic stem cell lines generated from adult somatic cells by nuclear transfer. Science 292:740–743PubMedCrossRefGoogle Scholar
  5. 5.
    Colman A, Kind A (2000) Therapeutic cloning: concepts and practicalities. Trends Biotechnol 18:192–196PubMedCrossRefGoogle Scholar
  6. 6.
    Cibelli J (2007) Is therapeutic cloning dead? Science 318:1879–1880PubMedCrossRefGoogle Scholar
  7. 7.
    Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse fibroblasts and adult fibroblast cultures by defined factors. Cell 126:663–676PubMedCrossRefGoogle Scholar
  8. 8.
    Zhao X, Li W, Zhuo L et al (2009) iPS cells produce viable mice through tetraploid complementation. Nature 461:86–90PubMedCrossRefGoogle Scholar
  9. 9.
    Boland MJ, Hazen JL, Nazor KL et al (2009) Adult mice generated from induced pluripotent stem cells. Nature 461:91–94PubMedCrossRefGoogle Scholar
  10. 10.
    Liao J, Cui C, Chen S et al (2009) Generation of induced pluripotent stem cell lines from adult rat cells. Cell Stem Cell 4:11–15PubMedCrossRefGoogle Scholar
  11. 11.
    Liu H, Zhu F, Yong J et al (2008) Generation of induced pluripotent stem cells from adult rhesus monkey fibroblasts. Cell Stem Cell 3:587–590PubMedCrossRefGoogle Scholar
  12. 12.
    Takahashi K, Tanabe K, Ohnuki M et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872PubMedCrossRefGoogle Scholar
  13. 13.
    Park I-H, Zhao R, West JA et al (2007) Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451:141–146PubMedCrossRefGoogle Scholar
  14. 14.
    Yu J, Vodyanik MA, Smuga-Otto K et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920PubMedCrossRefGoogle Scholar
  15. 15.
    Ben-Nun IF, Montague SC, Houck ML et al (2011) Induced pluripotent stem cells from highly endangered species. Nat Methods 8:829–831PubMedCrossRefGoogle Scholar
  16. 16.
    Stadtfeld M, Nagaya M, Utikal J et al (2008) Induced pluripotent stem cells generated without viral integration. Science 322:945–949PubMedCrossRefGoogle Scholar
  17. 17.
    Miyoshi N, Ishii H, Nagano H et al (2011) Reprogramming of mouse and human cells to pluripotency using mature microRNAs. Cell Stem Cell 8:633–638PubMedCrossRefGoogle Scholar
  18. 18.
    Zhou H, Wu S, Joo JY et al (2009) Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 4:381–384PubMedCrossRefGoogle Scholar
  19. 19.
    Kim D, Kim CM, Moon JI et al (2009) Generation of human induced pluripotent stem cells by direct delivery of reprogramming proteins. Cell Stem Cell 4:472–476PubMedCrossRefGoogle Scholar
  20. 20.
    Ichida JK, Blanchard J, Lam K et al (2009) A small molecule inhibitor of Tgf-β signalling replaces Sox2 in reprogramming by inducing Nanog. Cell Stem Cell 5:491–503PubMedCrossRefGoogle Scholar
  21. 21.
    Feng B, Ng J-H, Heng J-CD, Ng H–H (2009) Molecules that promote or enhance reprogramming of somatic cells to induced pluripotent stem cells. Cell Stem Cell 4:301–312PubMedCrossRefGoogle Scholar
  22. 22.
    Wu SM, Hochedlinger K (2011) Harnessing the potential of induced pluripotent stem cells for regenerative medicine. Nature Cell Biol 13:497–505PubMedCrossRefGoogle Scholar
  23. 23.
    Park I-H, Arora N, Huo H et al (2008) Disease-specific induced pluipotent stem cells. Cell 134:877–886PubMedCrossRefGoogle Scholar
  24. 24.
    Brennand KJ, Simone A, Jou J et al (2011) Modelling schizophrenia using human induced pluripotent stem cells. Nature 473:221–225PubMedCrossRefGoogle Scholar
  25. 25.
    Dimos JT, Rodolfa KT, Niakan KK et al (2008) Induced pluripotent stem cells generated from patients with ALS can be differentiated into motor neurons. Science 321:1218–1220PubMedCrossRefGoogle Scholar
  26. 26.
    Hanna J, Wernig M, Markoulaki S et al (2007) Treatment of sickle cell anemia mouse model with iPSC generated from autologous skin. Science 318:1920–1923PubMedCrossRefGoogle Scholar
  27. 27.
    Raya A, Rodriguez-Piza I, Guenechea G et al (2009) Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 460:53–59PubMedCrossRefGoogle Scholar
  28. 28.
    An MC, Zhang N, Scott G et al (2012) Genetic correction of Huntington’s disease phenotypes in induced pluripotent stem cells. Cell Stem Cell 11:1–11CrossRefGoogle Scholar
  29. 29.
    Kirouac DC, Zandstra PW (2008) The systematic production of cells for cell therapies. Cell Stem Cell 3:369–381PubMedCrossRefGoogle Scholar
  30. 30.
    Gore A, Li Z, Fung H-L et al (2011) Somatic coding mutations in human induced pluripotent stem cells. Nature 471:63–67PubMedCrossRefGoogle Scholar
  31. 31.
    Miura K, Okada Y, Aoi T et al (2009) Variation in the safety of induced pluripotent stem cell lines. Nat Biotechnol 27:743–745PubMedCrossRefGoogle Scholar
  32. 32.
    Ben-David U, Benvenisty N (2011) The tumorigenicity of human embryonic and induced pluripotent stem cells. Nat Rev Cancer 11:268–277PubMedCrossRefGoogle Scholar
  33. 33.
    Nakatsuji N, Nakajima F, Tokunaga K (2008) HLA-haplotype banking and iPS cells. Nat Biotechnol 26:739–740PubMedCrossRefGoogle Scholar
  34. 34.
    Petersdorf EW (2008) Optimal HLA matching in hematopoietic cell transplantation. Curr Opin Immunol 20:588–593PubMedCrossRefGoogle Scholar
  35. 35.
    Navarro V, Herrine S, Katopes C, Colombe B, Spain CV (2006) The effect of HLA class I (A and B) and class II (DR) compatibility on liver transplantation outcomes: an analysis of the OPTN database. Liver Transpl 12:652–658PubMedCrossRefGoogle Scholar
  36. 36.
    Fairchild PJ, Cartland S, Nolan KF, Waldmann H (2004) Embryonic stem cells and the challenge of transplantation tolerance. Trends Immunol 25:465–470PubMedCrossRefGoogle Scholar
  37. 37.
    Drukker M, Katz G, Urbach A et al (2002) Characterisation of the expression of MHC proteins in human embryonic stem cells. Proc Natl Acad Sci U S A 99:9864–9869PubMedCrossRefGoogle Scholar
  38. 38.
    Lui KO, Boyd AS, Cobbold SP, Waldmann H, Fairchild PJ (2010) A role for regulatory T cells in acceptance of embryonic stem cell-derived tissues transplanted across an MHC barrier. Stem Cells 28:1905–1914PubMedCrossRefGoogle Scholar
  39. 39.
    Fairchild PJ (2010) The challenge of immunogenicity in the quest for induced pluripotency. Nat Rev Immunol 10:868–875PubMedCrossRefGoogle Scholar
  40. 40.
    Staerk J, Dawlaty MM, Gao Q et al (2010) Reprogramming of human peripheral blood cells to induced pluripotent stem cells. Cell Stem Cell 7:20–24PubMedCrossRefGoogle Scholar
  41. 41.
    Aasen T, Raya A, Barrero MJ et al (2008) Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol 26:1276–1284PubMedCrossRefGoogle Scholar
  42. 42.
    Zhou T, Benda C, Duzinger S et al (2011) Generation of induced pluripotent stem cells from urine. J Am Soc Nephrol 22:1221–1228PubMedCrossRefGoogle Scholar
  43. 43.
    Taylor CJ, Bolton EM, Pocock S, Sharples LD, Pedersen RA, Bradley JA (2005) Banking on human embryonic stem cells: estimating the number of donor cell lines needed for HLA matching. Lancet 366:2019–2025PubMedCrossRefGoogle Scholar
  44. 44.
    Lin G, Xie Y, Ouyang Q et al (2009) HLA-matching potential of an established human embryonic stem cell bank in China. Cell Stem Cell 5:461–465PubMedCrossRefGoogle Scholar
  45. 45.
    Fluri DA, Tonge PD, Song H et al (2012) Derivation, expansion and differentiation of induced pluripotent stem cells in continuous suspension cultures. Nat Methods 9:509–516PubMedCrossRefGoogle Scholar
  46. 46.
    Zhao T, Zhang Z-N, Rong Z, Xu Y (2011) Immunogenicity of induced pluripotent stem cells. Nature 474:212–215PubMedCrossRefGoogle Scholar
  47. 47.
    Chen Y-T, Venditti CA, Theiler G et al (2005) Identification of CT46/HORMAD1, an immunogenic cancer/testis antigen encoding a putative meiosis-related protein. Cancer Immunity 5:1–8Google Scholar
  48. 48.
    Apostolou E, Hochedlinger K (2011) iPS cells under attack. Nature 474:165–166PubMedCrossRefGoogle Scholar
  49. 49.
    Okita K, Nagata N, Yamanaka S (2011) Immunogenicity of induced pluripotent stem cells. Circ Res 109:720–721PubMedCrossRefGoogle Scholar
  50. 50.
    Dhodapkar KM, Feldman D, Matthews P et al (2010) Natural immunity to pluripotency antigen OCT4 in humans. Proc Natl Acad Sci U S A 107:8718–8723PubMedCrossRefGoogle Scholar
  51. 51.
    Dhodapkar MV (2010) Immunity to stemness genes in human cancer. Curr Opin Immunol 22:245–250PubMedCrossRefGoogle Scholar
  52. 52.
    Spisek R, Kukreja A, Chen LC et al (2007) Frequent and specific immunity to the embryonal stem cell-associated antigen SOX2 in patients with monoclonal gammopathy. J Exp Med 204:831–840PubMedCrossRefGoogle Scholar
  53. 53.
    Vierbuchen T, Wernig M (2011) Direct lineage conversions: unnatural but useful? Nature Biotechnol 29:892–907CrossRefGoogle Scholar
  54. 54.
    Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Sudhof TC, Wernig M (2010) Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463:1035–1041PubMedCrossRefGoogle Scholar
  55. 55.
    Caiazzo M, Dell’Anno MT, Dvoretskova E et al (2011) Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 476:224–227PubMedCrossRefGoogle Scholar
  56. 56.
    Szabo E, Rampalli S, Risueno RM et al (2010) Direct conversion of human fibroblasts to multiline age blood progenitors. Nature 468:521–526PubMedCrossRefGoogle Scholar
  57. 57.
    Ieda M, Fu J-D, Delgado-Olguin P et al (2010) Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142:375–386PubMedCrossRefGoogle Scholar
  58. 58.
    Qian L, Huang Y, Spencer CI et al (2012) In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature 485:593–598PubMedCrossRefGoogle Scholar
  59. 59.
    Kazuki Y, Hiratsuka M, Takiguchi M et al (2010) Complete genetic correction of iPS cells from Duchenne muscular dystrophy. Mol Therapy 18:386–393CrossRefGoogle Scholar
  60. 60.
    Meng X-L, Shen J-S, Kawagoe S, Ohashi T, Brady RO, Eto Y (2010) Induced pluripotent stem cells derived from mouse models of lysosomal storage disorders. Proc Natl Acad Sci U S A 107:7886–7891PubMedCrossRefGoogle Scholar
  61. 61.
    Huang H-P, Chen P-H, Hwu W-L et al (2011) Human Pompe disease-induced pluripotent stem cells for pathogenesis modelling, drug testing and disease marker identification. Hum Mol Genet 20:4851–4864PubMedCrossRefGoogle Scholar
  62. 62.
    Ponder K (2008) Immune response hinders therapy for lysosomal storage diseases. J Clin Invest 118:2686–2689PubMedGoogle Scholar
  63. 63.
    Dickson P, Peinovich M, McEntee M et al (2008) Immune tolerance improves the efficacy of enzyme replacement therapy in canine mucopolysaccharidosis I. J Clin Invest 118:2868–2876PubMedGoogle Scholar
  64. 64.
    Wang J, Lozier J, Johnson G et al (2008) Neutralizing antibodies to therapeutic enzymes: considerations for testing, prevention and treatment. Nat Biotechnol 26:901–908PubMedCrossRefGoogle Scholar
  65. 65.
    Chen T-C, Waldmann H, Fairchild PJ (2004) Induction of dominant transplantation tolerance by an altered peptide ligand of the male antigen, Dby. J Clin Invest 113:1754–1762PubMedGoogle Scholar
  66. 66.
    Scott D, Addey C, Ellis P et al (2000) Dendritic cells permit identification of genes encoding MHC class II-restricted epitopes of transplantation antigens. Immunity 12:711–720PubMedCrossRefGoogle Scholar
  67. 67.
    Gluckman E, Rocha V (2009) Cord blood transplantation: state of the art. Haematologica 94:451–454PubMedCrossRefGoogle Scholar
  68. 68.
    Giorgetti A, Montserrat N, Rodriguez-Piza I, Azqueta C, Veiga A, Izpisúa-Belmonte JC (2009) Generation of induced pluripotent stem cells from human cord blood using OCT4 and SOX2. Cell Stem Cell 5:353–357PubMedCrossRefGoogle Scholar
  69. 69.
    Broxmeyer HE, Lee MR, Hangoc G et al (2011) Hematopoietic stem/progenitor cells, generation of induced pluripotent stem cells, and isolation of endothelial progenitors from 21- to 23.5-year cryopreserved cord blood. Blood 117:4773–4777PubMedCrossRefGoogle Scholar
  70. 70.
    Qin S, Cobbold SP, Pope H et al (1993) ‘Infectious’ transplantation tolerance. Science 259:974–977PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2013

Authors and Affiliations

  1. 1.University of Oxford, Sir William Dunn School of PathologyOxfordUK

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