Abstract
There is much interest in using embryonic stem cells to regenerate tissues and organs. For this approach to succeed, these stem cells or their derivatives must engraft in patients over the long term. Unless a cell transplant is derived from the patient's own cells, however, the cells will be targeted for rejection by the immune system. Although standard methods for suppressing the immune system achieve some success, rejection of the transplant is inevitable. Emerging approaches to address this issue include 're-educating' the immune system to induce tolerance to foreign cells and reducing the immune targeting of the transplant by administering 'self stem cells' instead of foreign cells, but each of these approaches has associated challenges.
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References
Goulburn, A. & Trounson, A. in Cell Therapy (eds Garcia-Olmo, D., Garcia-Verdugo, J.M., Alemany, J. & Gutiérrez-Fuentes, J.A.) 169–185 (McGraw Hill, Madrid, 2008).
Hoffman, L. M. & Carpenter, M. K. Characterization and culture of human embryonic stem cells. Nature Biotechnol. 23, 699–708 (2005).
Trounson, A. The production and directed differentiation of human embryonic stem cells. Endocr. Rev. 27, 208–219 (2006).
Okita, K., Ichisaka, T. & Yamanaka, S. Generation of germline-competent induced pluripotent stem cells. Nature 448, 313–317 (2007). This study refined previous iPS cell studies and showed that live chimaeras can be generated after transplantation of iPS cells that had been selected on the basis of Nanog expression, and it highlighted the importance of avoiding the retroviral introduction of Myc in patients.
Takahashi, K. & Yamanaka, S. Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126, 663–676 (2006). This study resulted in a major shift in stem-cell research by presenting an alternative to ES cells: 'self stem cells 2019 were induced by transfecting normal adult somatic cells with four ES-cell-related genes, generating cells that are now known as iPS cells.
Wernig, M. et al. In vitro reprogramming of fibroblasts into a pluripotent ES-cell-like state. Nature 448, 318–324 (2007).
Drukker, M. & Benvenisty, N. The immunogenicity of human embryonic stem-derived cells. Trends Biotechnol. 22, 136–141 (2004).
Simpson, E. et al. Minor H antigens: genes and peptides. Eur. J. Immunogenet. 28, 505–513 (2001).
Drukker, M. et al. Characterization of the expression of MHC proteins in human embryonic stem cells. Proc. Natl Acad. Sci. USA 99, 9864–9869 (2002).
Grinnemo, K. H. et al. Human embryonic stem cells are immunogenic in allogeneic and xenogeneic settings. Reprod. Biomed. Online 13, 712–724 (2006).
Li, L. et al. Human embryonic stem cells possess immune-privileged properties. Stem Cells 22, 448–456 (2004).
Taylor, C. J. et al. Banking on human embryonic stem cells: estimating the number of donor cell lines needed for HLA matching. Lancet 366, 2019–2025 (2005).
Robertson, N. J. et al. Embryonic stem cell-derived tissues are immunogenic but their inherent immune privilege promotes the induction of tolerance. Proc. Natl Acad. Sci. USA 104, 20920–20925 (2007).
Miki, T., Lehmann, T., Cai, H., Stolz, D. B. & Strom, S. C. Stem cell characteristics of amniotic epithelial cells. Stem Cells 23, 1549–1559 (2005).
Ilancheran, S. et al. Stem cells derived from human fetal membranes display multilineage differentiation potential. Biol. Reprod. 77, 577–588 (2007).
Rando, T. A. Stem cells, ageing and the quest for immortality. Nature 441, 1080–1086 (2006).
Jones, D. L. & Wagers, A. J. No place like home: anatomy and function of the stem cell niche. Nature Rev. Mol. Cell Biol. 9, 11–21 (2008).
Mason, D. W. et al. The fate of allogeneic and xenogeneic neuronal tissue transplanted into the third ventricle of rodents. Neuroscience 19, 685–694 (1986).
Wong, G. H., Bartlett, P. F., Clark-Lewis, I., Battye, F. & Schrader, J. W. Inducible expression of H-2 and Ia antigens on brain cells. Nature 310, 688–691 (1984).
McLaren, F. H., Svendsen, C. N., Van der Meide, P. & Joly, E. Analysis of neural stem cells by flow cytometry: cellular differentiation modifies patterns of MHC expression. J. Neuroimmunol. 112, 35–46 (2001).
Bao, S. S., King, N. J. & dos Remedios, C. G. Elevated MHC class I and II antigens in cultured human embryonic myoblasts following stimulation with γ-interferon. Immunol. Cell Biol. 68, 235–241 (1990).
Mantegazza, R. et al. Modulation of MHC class II antigen expression in human myoblasts after treatment with IFN-γ. Neurology 41, 1128–1132 (1991).
Tremblay, J. P. et al. Results of a triple blind clinical study of myoblast transplantations without immunosuppressive treatment in young boys with Duchenne muscular dystrophy. Cell Transplant. 2, 99–112 (1993).
Guerette, B., Asselin, I., Vilquin, J. T., Roy, R. & Tremblay, J. P. Lymphocyte infiltration following allo- and xenomyoblast transplantation in mice. Transplant. Proc. 26, 3461–3462 (1994).
Friedenstein, A. J., Gorskaja, J. F. & Kulagina, N. N. Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp. Hematol. 4, 267–274 (1976).
Bieback, K., Kern, S., Kluter, H. & Eichler, H. Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood. Stem Cells 22, 625–634 (2004).
in 't Anker, P. S. et al. Isolation of mesenchymal stem cells of fetal or maternal origin from human placenta. Stem Cells 22, 1338–1345 (2004).
Zuk, P. A. et al. Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng. 7, 211–228 (2001).
in 't Anker, P. S. et al. Amniotic fluid as a novel source of mesenchymal stem cells for therapeutic transplantation. Blood 102, 1548–1549 (2003).
Prockop, D. J. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science 276, 71–74 (1997).
Horwitz, E. M. et al. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: implications for cell therapy of bone. Proc. Natl Acad. Sci. USA 99, 8932–8937 (2002).
Burt, R. K. et al. Clinical applications of blood-derived and marrow-derived stem cells for nonmalignant diseases. J. Am. Med. Assoc. 299, 925–936 (2008).
Di Nicola, M. et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99, 3838–3843 (2002). This study showed the immunosuppressive properties of human bone-marrow stromal cells and became the catalyst for the use of such cells (now known as MSCs) to dampen inflammatory conditions, including graft-versus-host disease.
Romieu-Mourez, R., Francois, M., Boivin, M. N., Stagg, J. & Galipeau, J. Regulation of MHC class II expression and antigen processing in murine and human mesenchymal stromal cells by IFN-γ, TGF-β, and cell density. J. Immunol. 179, 1549–1558 (2007).
Le Blanc, K., Tammik, C., Rosendahl, K., Zetterberg, E. & Ringden, O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp. Hematol. 31, 890–896 (2003).
Miyara, M. & Sakaguchi, S. Natural regulatory T cells: mechanisms of suppression. Trends Mol. Med. 13, 108–116 (2007).
Kawai, T. et al. HLA-mismatched renal transplantation without maintenance immunosuppression. N. Engl. J. Med. 358, 353–361 (2008). This paper showed, in a clinical setting, proof of principle that tolerance can be induced to an allogeneic bone-marrow transplant, resulting in the complete withdrawal of immunosuppressive agents from the treatment regimens of these patients.
Hince, M. et al. The role of sex steroids and gonadectomy in the control of thymic involution. Cell. Immunol. doi:10.1016/j.cellimm.2007.10.007 (in the press).
Ildstad, S. T. & Sachs, D. H. Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts. Nature 307, 168–170 (1984).
Ildstad, S. T., Wren, S. M., Bluestone, J. A., Barbieri, S. A. & Sachs, D. H. Characterization of mixed allogeneic chimeras. Immunocompetence, in vitro reactivity, and genetic specificity of tolerance. J. Exp. Med. 162, 231–244 (1985).
Fandrich, F. et al. Preimplantation-stage stem cells induce long-term allogeneic graft acceptance without supplementary host conditioning. Nature Med. 8, 171–178 (2002).
Kaufman, D. S., Hanson, E. T., Lewis, R. L., Auerbach, R. & Thomson, J. A. Hematopoietic colony-forming cells derived from human embryonic stem cells. Proc. Natl Acad. Sci. USA 98, 10716–10721 (2001).
Burt, R. K. et al. Embryonic stem cells as an alternate marrow donor source: engraftment without graft-versus-host disease. J. Exp. Med. 199, 895–904 (2004).
Verda, L. et al. Hematopoietic mixed chimerism derived from allogeneic embryonic stem cells prevents autoimmune diabetes mellitus in Nod mice. Stem Cells 26, 381–386 (2008).
Alexander, S. I. et al. Chimerism and tolerance in a recipient of a deceased-donor liver transplant. N. Engl. J. Med. 358, 369–374 (2008).
Scadden, D. T. The stem-cell niche as an entity of action. Nature 441, 1075–1079 (2006).
Flores, K. G., Li, J., Sempowski, G. D., Haynes, B. F. & Hale, L. P. Analysis of the human thymic perivascular space during aging. J. Clin. Invest. 104, 1031–1039 (1999).
Greenstein, B. D., Fitzpatrick, F. T., Kendall, M. D. & Wheeler, M. J. Regeneration of the thymus in old male rats treated with a stable analogue of LHRH. J. Endocrinol. 112, 345–350 (1987). This paper provided, in an animal model, proof of principle that the thymus can be regenerated in an aged individual by using reversible chemical castration.
Olsen, N. J. & Kovacs, W. J. Effects of androgens on T and B lymphocyte development. Immunol. Res. 23, 281–288 (2001).
Sutherland, J. S. et al. Activation of thymic regeneration in mice and humans following androgen blockade. J. Immunol. 175, 2741–2753 (2005). This study showed a fundamentally new clinical approach for treating immunodeficiency states in humans, regenerating the immune system after bone-marrow transplantation or a damaging chemotherapy regimen.
Heng, T. S. et al. Effects of castration on thymocyte development in two different models of thymic involution. J. Immunol. 175, 2982–2993 (2005).
Goldberg, G. L. et al. Enhanced immune reconstitution by sex steroid ablation following allogeneic hemopoietic stem cell transplantation. J. Immunol. 178, 7473–7484 (2007).
Goldberg, G. L. et al. Sex steroid ablation enhances lymphoid recovery following autologous hematopoietic stem cell transplantation. Transplantation 80, 1604–1613 (2005).
Sutherland, J. S. et al. Enhanced immune system regeneration in humans following allogeneic or autologous hemopoietic stem cell transplantation by temporary sex steroid blockade. Clin. Cancer Res. 14, 1138–1149 (2008).
Min, D. et al. Sustained thymopoiesis and improvement in functional immunity induced by exogenous KGF administration in murine models of aging. Blood 109, 2529–2537 (2007).
Min, D. et al. Protection from thymic epithelial cell injury by keratinocyte growth factor: a new approach to improve thymic and peripheral T-cell reconstitution after bone marrow transplantation. Blood 99, 4592–4600 (2002).
Rossi, S. W. et al. Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells. Blood 109, 3803–3811 (2007).
Seggewiss, R. et al. Keratinocyte growth factor augments immune reconstitution after autologous hematopoietic progenitor cell transplantation in rhesus macaques. Blood 110, 441–449 (2007).
Napolitano, L. A. et al. Growth hormone enhances thymic function in HIV-1-infected adults. J. Clin. Invest. 118, 1085–1098 (2008).
Alpdogan, O. et al. Administration of interleukin-7 after allogeneic bone marrow transplantation improves immune reconstitution without aggravating graft-versus-host disease. Blood 98, 2256–2265 (2001).
Wils, E. J. et al. Flt3 ligand expands lymphoid progenitors prior to recovery of thymopoiesis and accelerates T cell reconstitution after bone marrow transplantation. J. Immunol. 178, 3551–3557 (2007).
Okamoto, Y., Douek, D. C., McFarland, R. D. & Koup, R. A. Effects of exogenous interleukin-7 on human thymus function. Blood 99, 2851–2858 (2002).
Rutella, S., Danese, S. & Leone, G. Tolerogenic dendritic cells: cytokine modulation comes of age. Blood 108, 1435–1440 (2006).
Jiang, X. X. et al. Human mesenchymal stem cells inhibit differentiation and function of monocyte-derived dendritic cells. Blood 105, 4120–4126 (2005).
Zhang, W. et al. Effects of mesenchymal stem cells on differentiation, maturation, and function of human monocyte-derived dendritic cells. Stem Cells Dev. 13, 263–271 (2004).
Sakaguchi, S. Naturally arising Foxp3-expressing CD25+CD4+ regulatory T cells in immunological tolerance to self and non-self. Nature Immunol. 6, 345–352 (2005).
Roncarolo, M. G. et al. Interleukin-10-secreting type 1 regulatory T cells in rodents and humans. Immunol. Rev. 212, 28–50 (2006).
Joffre, O. et al. Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes. Nature Med. 14, 88–92 (2008).
Yamazaki, S., Inaba, K., Tarbell, K. V. & Steinman, R. M. Dendritic cells expand antigen-specific Foxp3+ CD25+ CD4+ regulatory T cells including suppressors of alloreactivity. Immunol. Rev. 212, 314–329 (2006).
Yamazaki, S. et al. Effective expansion of alloantigen-specific Foxp3+ CD25+ CD4+ regulatory T cells by dendritic cells during the mixed leukocyte reaction. Proc. Natl Acad. Sci. USA 103, 2758–2763 (2006).
Zhan, X. et al. Functional antigen-presenting leucocytes derived from human embryonic stem cells in vitro. Lancet 364, 163–171 (2004).
Lee, M. K. et al. Promotion of allograft survival by CD4+CD25+ regulatory T cells: evidence for in vivo inhibition of effector cell proliferation. J. Immunol. 172, 6539–6544 (2004).
Byrne, J. A. et al. Producing primate embryonic stem cells by somatic cell nuclear transfer. Nature 450, 497–502 (2007).
French, A. J. et al. Development of human cloned blastocysts following somatic cell nuclear transfer with adult fibroblasts. Stem Cells 26, 485–493 (2008).
French, A. J., Wood, S. H. & Trounson, A. O. Human therapeutic cloning (NTSC): applying research from mammalian reproductive cloning. Stem Cell Rev. 2, 265–276 (2006).
Park, I. H. et al. Reprogramming of human somatic cells to pluripotency with defined factors. Nature 451, 141–146 (2008).
Takahashi, K., Okita, K., Nakagawa, M. & Yamanaka, S. Induction of pluripotent stem cells from fibroblast cultures. Nature Protocols 2, 3081–3089 (2007).
Takahashi, K. et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell 131, 861–872 (2007). This study induced pluripotency in somatic cells from adult humans, enabling patient-specific and disease-specific iPS cells to be generated and raising the possibility of their use in regenerative medicine.
Nakagawa, M. et al. Generation of induced pluripotent stem cells without Myc from mouse and human fibroblasts. Nature Biotechnol. 26, 101–106 (2008). This paper described an important step in adapting iPS cells for clinical application by removing the requirement for transfection with tumour-inducing genes such as Myc.
Yu, J. et al. Induced pluripotent stem cell lines derived from human somatic cells. Science 318, 1917–1920 (2007).
Anderson, G., Lane, P. J. & Jenkinson, E. J. Generating intrathymic microenvironments to establish T-cell tolerance. Nature Rev. Immunol. 7, 954–963 (2007).
Derbinski, J., Schulte, A., Kyewski, B. & Klein, L. Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nature Immunol. 2, 1032–1039 (2001).
Gabler, J., Arnold, J. & Kyewski, B. Promiscuous gene expression and the developmental dynamics of medullary thymic epithelial cells. Eur. J. Immunol. 37, 3363–3372 (2007).
Gillard, G. O. & Farr, A. G. Features of medullary thymic epithelium implicate postnatal development in maintaining epithelial heterogeneity and tissue-restricted antigen expression. J. Immunol. 176, 5815–5824 (2006).
Rossi, S. W. et al. RANK signals from CD4+3− inducer cells regulate development of Aire-expressing epithelial cells in the thymic medulla. J. Exp. Med. 204, 1267–1272 (2007).
Sakaguchi, S. et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol. Rev. 212, 8–27 (2006).
Spence, P. J. & Green, E. A. Foxp3+ regulatory T cells promiscuously accept thymic signals critical for their development. Proc. Natl Acad. Sci. USA 105, 973–978 (2008).
Acknowledgements
We acknowledge generous research support from the National Health and Medical Research Council of Australia, the Australian Stem Cell Centre and Norwood Immunology.
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R.L.B. is chief scientific officer, and A.P.C. is a scientific consultant, for Norwood Immunology, which funds the clinical trials of LHRH-A cited in this review.
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Correspondence should be addressed to A.C. (ann.chidgey@med.monash.edu.au).
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Chidgey, A., Layton, D., Trounson, A. et al. Tolerance strategies for stem-cell-based therapies. Nature 453, 330–337 (2008). https://doi.org/10.1038/nature07041
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DOI: https://doi.org/10.1038/nature07041
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