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.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
References
Thomson JA, Itskovitz-Eldor J, Shapiro SS et al (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147
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 104:20920–20925
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 105:12991–12996
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 292:740–743
Colman A, Kind A (2000) Therapeutic cloning: concepts and practicalities. Trends Biotechnol 18:192–196
Cibelli J (2007) Is therapeutic cloning dead? Science 318:1879–1880
Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse fibroblasts and adult fibroblast cultures by defined factors. Cell 126:663–676
Zhao X, Li W, Zhuo L et al (2009) iPS cells produce viable mice through tetraploid complementation. Nature 461:86–90
Boland MJ, Hazen JL, Nazor KL et al (2009) Adult mice generated from induced pluripotent stem cells. Nature 461:91–94
Liao J, Cui C, Chen S et al (2009) Generation of induced pluripotent stem cell lines from adult rat cells. Cell Stem Cell 4:11–15
Liu H, Zhu F, Yong J et al (2008) Generation of induced pluripotent stem cells from adult rhesus monkey fibroblasts. Cell Stem Cell 3:587–590
Takahashi K, Tanabe K, Ohnuki M et al (2007) Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131:861–872
Park I-H, Zhao R, West JA et al (2007) Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451:141–146
Yu J, Vodyanik MA, Smuga-Otto K et al (2007) Induced pluripotent stem cell lines derived from human somatic cells. Science 318:1917–1920
Ben-Nun IF, Montague SC, Houck ML et al (2011) Induced pluripotent stem cells from highly endangered species. Nat Methods 8:829–831
Stadtfeld M, Nagaya M, Utikal J et al (2008) Induced pluripotent stem cells generated without viral integration. Science 322:945–949
Miyoshi N, Ishii H, Nagano H et al (2011) Reprogramming of mouse and human cells to pluripotency using mature microRNAs. Cell Stem Cell 8:633–638
Zhou H, Wu S, Joo JY et al (2009) Generation of induced pluripotent stem cells using recombinant proteins. Cell Stem Cell 4:381–384
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 4:472–476
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 5:491–503
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 4:301–312
Wu SM, Hochedlinger K (2011) Harnessing the potential of induced pluripotent stem cells for regenerative medicine. Nature Cell Biol 13:497–505
Park I-H, Arora N, Huo H et al (2008) Disease-specific induced pluipotent stem cells. Cell 134:877–886
Brennand KJ, Simone A, Jou J et al (2011) Modelling schizophrenia using human induced pluripotent stem cells. Nature 473:221–225
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 321:1218–1220
Hanna J, Wernig M, Markoulaki S et al (2007) Treatment of sickle cell anemia mouse model with iPSC generated from autologous skin. Science 318:1920–1923
Raya A, Rodriguez-Piza I, Guenechea G et al (2009) Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 460:53–59
An MC, Zhang N, Scott G et al (2012) Genetic correction of Huntington’s disease phenotypes in induced pluripotent stem cells. Cell Stem Cell 11:1–11
Kirouac DC, Zandstra PW (2008) The systematic production of cells for cell therapies. Cell Stem Cell 3:369–381
Gore A, Li Z, Fung H-L et al (2011) Somatic coding mutations in human induced pluripotent stem cells. Nature 471:63–67
Miura K, Okada Y, Aoi T et al (2009) Variation in the safety of induced pluripotent stem cell lines. Nat Biotechnol 27:743–745
Ben-David U, Benvenisty N (2011) The tumorigenicity of human embryonic and induced pluripotent stem cells. Nat Rev Cancer 11:268–277
Nakatsuji N, Nakajima F, Tokunaga K (2008) HLA-haplotype banking and iPS cells. Nat Biotechnol 26:739–740
Petersdorf EW (2008) Optimal HLA matching in hematopoietic cell transplantation. Curr Opin Immunol 20:588–593
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 12:652–658
Fairchild PJ, Cartland S, Nolan KF, Waldmann H (2004) Embryonic stem cells and the challenge of transplantation tolerance. Trends Immunol 25:465–470
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 99:9864–9869
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 28:1905–1914
Fairchild PJ (2010) The challenge of immunogenicity in the quest for induced pluripotency. Nat Rev Immunol 10:868–875
Staerk J, Dawlaty MM, Gao Q et al (2010) Reprogramming of human peripheral blood cells to induced pluripotent stem cells. Cell Stem Cell 7:20–24
Aasen T, Raya A, Barrero MJ et al (2008) Efficient and rapid generation of induced pluripotent stem cells from human keratinocytes. Nat Biotechnol 26:1276–1284
Zhou T, Benda C, Duzinger S et al (2011) Generation of induced pluripotent stem cells from urine. J Am Soc Nephrol 22:1221–1228
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 366:2019–2025
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 5:461–465
Fluri DA, Tonge PD, Song H et al (2012) Derivation, expansion and differentiation of induced pluripotent stem cells in continuous suspension cultures. Nat Methods 9:509–516
Zhao T, Zhang Z-N, Rong Z, Xu Y (2011) Immunogenicity of induced pluripotent stem cells. Nature 474:212–215
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 5:1–8
Apostolou E, Hochedlinger K (2011) iPS cells under attack. Nature 474:165–166
Okita K, Nagata N, Yamanaka S (2011) Immunogenicity of induced pluripotent stem cells. Circ Res 109:720–721
Dhodapkar KM, Feldman D, Matthews P et al (2010) Natural immunity to pluripotency antigen OCT4 in humans. Proc Natl Acad Sci U S A 107:8718–8723
Dhodapkar MV (2010) Immunity to stemness genes in human cancer. Curr Opin Immunol 22:245–250
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 204:831–840
Vierbuchen T, Wernig M (2011) Direct lineage conversions: unnatural but useful? Nature Biotechnol 29:892–907
Vierbuchen T, Ostermeier A, Pang ZP, Kokubu Y, Sudhof TC, Wernig M (2010) Direct conversion of fibroblasts to functional neurons by defined factors. Nature 463:1035–1041
Caiazzo M, Dell’Anno MT, Dvoretskova E et al (2011) Direct generation of functional dopaminergic neurons from mouse and human fibroblasts. Nature 476:224–227
Szabo E, Rampalli S, Risueno RM et al (2010) Direct conversion of human fibroblasts to multiline age blood progenitors. Nature 468:521–526
Ieda M, Fu J-D, Delgado-Olguin P et al (2010) Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell 142:375–386
Qian L, Huang Y, Spencer CI et al (2012) In vivo reprogramming of murine cardiac fibroblasts into induced cardiomyocytes. Nature 485:593–598
Kazuki Y, Hiratsuka M, Takiguchi M et al (2010) Complete genetic correction of iPS cells from Duchenne muscular dystrophy. Mol Therapy 18:386–393
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 107:7886–7891
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 20:4851–4864
Ponder K (2008) Immune response hinders therapy for lysosomal storage diseases. J Clin Invest 118:2686–2689
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 118:2868–2876
Wang J, Lozier J, Johnson G et al (2008) Neutralizing antibodies to therapeutic enzymes: considerations for testing, prevention and treatment. Nat Biotechnol 26:901–908
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 113:1754–1762
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 12:711–720
Gluckman E, Rocha V (2009) Cord blood transplantation: state of the art. Haematologica 94:451–454
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 5:353–357
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 117:4773–4777
Qin S, Cobbold SP, Pope H et al (1993) ‘Infectious’ transplantation tolerance. Science 259:974–977
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.
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2013 Springer Science+Business Media New York
About this chapter
Cite this chapter
Fairchild, P.J., Ichiryu, N. (2013). Mitigating the Risk of Immunogenicity in the Pursuit of Induced Pluripotency . In: Fairchild, P. (eds) The Immunological Barriers to Regenerative Medicine. Stem Cell Biology and Regenerative Medicine. Humana Press, New York, NY. https://doi.org/10.1007/978-1-4614-5480-9_5
Download citation
DOI: https://doi.org/10.1007/978-1-4614-5480-9_5
Published:
Publisher Name: Humana Press, New York, NY
Print ISBN: 978-1-4614-5479-3
Online ISBN: 978-1-4614-5480-9
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)