We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Avoiding immunological rejection in regenerative medicine

    Eleanor M Bolton

    *Author for correspondence:

    E-mail Address: emb34@cam.ac.uk

    Department of Surgery, University of Cambridge, Box 202, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK

    &
    John Andrew Bradley

    Department of Surgery, University of Cambridge, Box 202, Addenbrooke's Hospital, Cambridge, CB2 0QQ, UK

    Published Online:https://doi.org/10.2217/rme.15.11

    One of the major goals of regenerative medicine is repair or replacement of diseased and damaged tissues by transfer of differentiated stem cells or stem cell-derived tissues. The possibility that these tissues will be destroyed by immunological rejection remains a challenge that can only be overcome through a better understanding of the nature and expression of potentially immunogenic molecules associated with cell replacement therapy and the mechanisms and pathways resulting in their immunologic rejection. This review draws on clinical experience of organ and tissue transplantation, and on transplantation immunology research to consider practical approaches for avoiding and overcoming the possibility of rejection of stem cell-derived tissues.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1 Okita K, Nagata N, Yamanaka S. Immunogenicity of induced pluripotent stem cells. Circ. Res. 109(7), 720–721 (2011).
    • 2 Kaneko S, Yamanaka S. To be immunogenic, or not to be: that's the iPSC question. Cell Stem Cell 12(4), 385–386 (2013).
    • 3 Fu X. The immunogenicity of cells derived from induced pluripotent stem cells. Cell Mol. Immunol. 11(1), 14–16 (2014).
    • 4 Araki R, Uda M, Hoki Y et al. Negligible immunogenicity of terminally differentiated cells derived from induced pluripotent or embryonic stem cells. Nature 494(7435), 100–104 (2013).•• Convincingly contradicts an earlier report by Zhao et al. (Nature 2011) claiming that autologous induced pluripotent stem cells (iPSC) are immunogenic and do not survive autologous transplantation. As well as confirming that iPSC survive autologous transplantation, these references also confirm that allogeneic stem cells are rejected immunologically.
    • 5 Guha P, Morgan JW, Mostoslavsky G, Rodrigues NP, Boyd AS. Lack of immune response to differentiated cells derived from syngeneic induced pluripotent stem cells. Cell Stem Cell 12(4), 407–412 (2013).•• Convincingly contradicts an earlier report by Zhao et al. (Nature 2011) claiming that autologous iPSC are immunogenic and do not survive autologous transplantation. As well as confirming that iPSC survive autologous transplantation, these references also confirm that allogeneic stem cells are rejected immunologically.
    • 6 Morizane A, Doi D, Kikuchi T et al. Direct comparison of autologous and allogeneic transplantation of iPSC-derived neural cells in the brain of a nonhuman primate. Stem Cell Rep. 1(4), 283–292 (2013).
    • 7 Sachamitr P, Hackett S, Fairchild PJ. Induced pluripotent stem cells: challenges and opportunities for cancer immunotherapy. Front. Immunol. 5, 176 (2014).
    • 8 Scheiner ZS, Talib S, Feigal EG. The potential for immunogenicity of autologous induced pluripotent stem cell-derived therapies. J. Biol. Chem. 289(8), 4571–4577 (2014).
    • 9 Tang C, Weissman IL, Drukker M. Immunogenicity of in vitro maintained and matured populations: potential barriers to engraftment of human pluripotent stem cell derivatives. Methods Mol. Biol. 1029, 17–31 (2013).
    • 10 Kim K, Doi A, Wen B et al. Epigenetic memory in induced pluripotent stem cells. Nature 467(7313), 285–290 (2010).
    • 11 Marchetto MC, Yeo GW, Kainohana O, Marsala M, Gage FH, Muotri AR. Transcriptional signature and memory retention of human-induced pluripotent stem cells. PLoS ONE 4(9), e7076 (2009).
    • 12 Stelzer Y, Yanuka O, Benvenisty N. Global analysis of parental imprinting in human parthenogenetic induced pluripotent stem cells. Nat. Struct. Mol. Biol. 18(6), 735–741 (2011).
    • 13 Zimmermann A, Preynat-Seauve O, Tiercy JM, Krause KH, Villard J. Haplotype-based banking of human pluripotent stem cells for transplantation: potential and limitations. Stem Cells Dev. 21(13), 2364–2373 (2012).
    • 14 Bradley JA, Bolton EM, Pedersen RA. Stem cell medicine encounters the immune system. Nat. Rev. Immunol. 2(11), 859–871 (2002).
    • 15 Drukker M, Katz G, Urbach A et al. Characterization of the expression of MHC proteins in human embryonic stem cells. Proc. Natl Acad. Sci. USA 99(15), 9864–9869 (2002).
    • 16 Drukker M, Katchman H, Katz G et al. Human embryonic stem cells and their differentiated derivatives are less susceptible to immune rejection than adult cells. Stem Cells 24(2), 221–229 (2006).
    • 17 Taylor CJ, Bolton EM, Pocock S, Sharples LD, Pedersen RA, Bradley JA. Banking on human embryonic stem cells: estimating the number of donor cell lines needed for HLA matching. Lancet 366(9502), 2019–2025 (2005).•• This was the first paper to demonstrate that human leukocyte antigen (HLA)-typed stem cell banking in a given population is achievable, and estimates the number of typed embryonic stem cells that would be required to be banked in order to supply well-matched stem cell-derived tissues to the majority of the population.
    • 18 Molne J, Bjorquist P, Andersson K et al. Blood group ABO antigen expression in human embryonic stem cells and in differentiated hepatocyte- and cardiomyocyte-like cells. Transplantation 86(10), 1407–1413 (2008).
    • 19 Taylor CJ, Peacock S, Chaudhry AN, Bradley JA, Bolton EM. Generating an iPSC bank for HLA-matched tissue transplantation based on known donor and recipient HLA types. Cell Stem Cell 11(2), 147–152 (2012).
    • 20 Taylor CJ, Bolton EM, Bradley JA. Immunological considerations for embryonic and induced pluripotent stem cell banking. Philos. Trans. R Soc. Lond. B Biol. Sci. 366(1575), 2312–2322 (2011).
    • 21 Sanchez Alvarado A, Yamanaka S. Rethinking differentiation: stem cells, regeneration, and plasticity. Cell 157(1), 110–119 (2014).
    • 22 Nakatsuji N, Nakajima F, Tokunaga K. HLA-haplotype banking and iPS cells. Nat. Biotechnol. 26(7), 739–740 (2008).
    • 23 Gourraud PA, Gilson L, Girard M, Peschanski M. The role of human leukocyte antigen matching in the development of multiethnic “haplobank” of induced pluripotent stem cell lines. Stem Cells 30(2), 180–186 (2012).
    • 24 Turner M, Leslie S, Martin NG et al. Toward the development of a global induced pluripotent stem cell library. Cell Stem Cell 13(4), 382–384 (2013).
    • 25 Hunt JS, Petroff MG, McIntire RH, Ober C. HLA-G and immune tolerance in pregnancy. FASEB J. 19(7), 681–693 (2005).
    • 26 Munn DH, Zhou M, Attwood JT et al. Prevention of allogeneic fetal rejection by tryptophan catabolism. Science 281(5380), 1191–1193 (1998).
    • 27 Aluvihare VR, Kallikourdis M, Betz AG. Regulatory T cells mediate maternal tolerance to the fetus. Nat. Immunol. 5(3), 266–271 (2004).
    • 28 Trowsdale J, Betz AG. Mother's little helpers: mechanisms of maternal-fetal tolerance. Nat. Immunol. 7(3), 241–246 (2006).
    • 29 Taylor AW, Alard P, Yee DG, Streilein JW. Aqueous humor induces transforming growth factor-beta (TGF-beta)-producing regulatory T-cells. Curr. Eye Res. 16(9), 900–908 (1997).
    • 30 Sharland A, Shastry S, Wang C et al. Kinetics of intragraft cytokine expression, cellular infiltration, and cell death in rejection of renal allografts compared with acceptance of liver allografts in a rat model: early activation and apoptosis is associated with liver graft acceptance. Transplantation 65(10), 1370–1377 (1998).
    • 31 Suarez-Alvarez B, Rodriguez RM, Calvanese V et al. Epigenetic mechanisms regulate MHC and antigen processing molecules in human embryonic and induced pluripotent stem cells. PLoS ONE 5(4), e10192 (2010).
    • 32 Land WG. Emerging role of innate immunity in organ transplantation: part II: potential of damage-associated molecular patterns to generate immunostimulatory dendritic cells. Transplant. Rev. (Orlando) 26(2), 73–87 (2012).
    • 33 Land WG. Emerging role of innate immunity in organ transplantation: part I: evolution of innate immunity and oxidative allograft injury. Transplant. Rev. (Orlando) 26(2), 60–72 (2012).
    • 34 Land WG. Emerging role of innate immunity in organ transplantation: part III: the quest for transplant tolerance via prevention of oxidative allograft injury and its consequences. Transplant. Rev. (Orlando) 26(2), 88–102 (2012).
    • 35 Peterson KM, Aly A, Lerman A, Lerman LO, Rodriguez-Porcel M. Improved survival of mesenchymal stromal cell after hypoxia preconditioning: role of oxidative stress. Life Sci. 88(1–2), 65–73 (2011).
    • 36 Zhu W, Chen J, Cong X, Hu S, Chen X. Hypoxia and serum deprivation-induced apoptosis in mesenchymal stem cells. Stem Cells 24(2), 416–425 (2006).
    • 37 Sacks SH, Zhou W. The role of complement in the early immune response to transplantation. Nat. Rev. Immunol. 12(6), 431–442 (2012).
    • 38 Kofidis T, deBruin JL, Tanaka M et al. They are not stealthy in the heart: embryonic stem cells trigger cell infiltration, humoral and T-lymphocyte-based host immune response. Eur. J. Cardiothorac. Surg. 28(3), 461–466 (2005).
    • 39 Swijnenburg RJ, Tanaka M, Vogel H et al. Embryonic stem cell immunogenicity increases upon differentiation after transplantation into ischemic myocardium. Circulation 112(9 Suppl.), I166–172 (2005).
    • 40 Nussbaum J, Minami E, Laflamme MA et al. Transplantation of undifferentiated murine embryonic stem cells in the heart: teratoma formation and immune response. FASEB J. 21(7), 1345–1357 (2007).
    • 41 Swijnenburg RJ, Schrepfer S, Cao F et al. In vivo imaging of embryonic stem cells reveals patterns of survival and immune rejection following transplantation. Stem Cells Dev. 17(6), 1023–1029 (2008).•• This is an elegant study that clearly demonstrates immune rejection (or survival) not only of allogeneic (or syngeneic) stem cells but also, importantly, their differentiated progeny which are rejected more rapidly than allogeneic nondifferentiated stem cells.
    • 42 Wu DC, Boyd AS, Wood KJ. Embryonic stem cells and their differentiated derivatives have a fragile immune privilege but still represent novel targets of immune attack. Stem Cells 26(8), 1939–1950 (2008).
    • 43 Robertson NJ, Brook FA, Gardner RL, Cobbold SP, Waldmann H, Fairchild PJ. Embryonic stem cell-derived tissues are immunogenic but their inherent immune privilege promotes the induction of tolerance. Proc. Natl Acad. Sci. USA 104(52), 20920–20925 (2007).
    • 44 Frenzel LP, Abdullah Z, Kriegeskorte AK et al. Role of natural-killer group 2 member D ligands and intercellular adhesion molecule 1 in natural killer cell-mediated lysis of murine embryonic stem cells and embryonic stem cell-derived cardiomyocytes. Stem Cells 27(2), 307–316 (2009).
    • 45 Dressel R, Nolte J, Elsner L et al. Pluripotent stem cells are highly susceptible targets for syngeneic, allogeneic, and xenogeneic natural killer cells. FASEB J. 24(7), 2164–2177 (2010).
    • 46 Preynat-Seauve O, de Rham C, Tirefort D, Ferrari-Lacraz S, Krause KH, Villard J. Neural progenitors derived from human embryonic stem cells are targeted by allogeneic T and natural killer cells. J. Cell Mol. Med. 13(9B), 3556–3569 (2009).
    • 47 Ma M, Ding S, Lundqvist A et al. Major histocompatibility complex-I expression on embryonic stem cell-derived vascular progenitor cells is critical for syngeneic transplant survival. Stem Cells 28(9), 1465–1475 (2010).
    • 48 Lindahl KF, Wilson DB. Histocompatibility antigen-activated cytotoxic T lymphocytes. II. Estimates of the frequency and specificity of precursors. J. Exp. Med. 145(3), 508–522 (1977).
    • 49 Lindahl KF, Wilson DB. Histocompatibility antigen-activated cytotoxic T lymphocytes. I. Estimates of the absolute frequency of killer cells generated in vitro. J. Exp. Med. 145(3), 500–507 (1977).
    • 50 Matzinger P, Bevan MJ. Hypothesis: why do so many lymphocytes respond to major histocompatibility antigens? Cell Immunol. 29(1), 1–5 (1977).
    • 51 Skinner MA, Marbrook J. An estimation of the frequency of precursor cells which generate cytotoxic lymphocytes. J. Exp. Med. 143(6), 1562–1567 (1976).
    • 52 Afzali B, Lombardi G, Lechler RI. Pathways of major histocompatibility complex allorecognition. Curr. Opin. Organ Transplant. 13(4), 438–444 (2008).
    • 53 Bedford P, Garner K, Knight SC. MHC class II molecules transferred between allogeneic dendritic cells stimulate primary mixed leukocyte reactions. Int. Immunol. 11(11), 1739–1744 (1999).
    • 54 Curry AJ, Pettigrew GJ, Negus MC et al. Dendritic cells internalise and represent conformationally intact soluble MHC class I alloantigen for generation of alloantibody. Eur. J. Immunol. 37(3), 696–705 (2007).
    • 55 Sivaganesh S, Harper SJ, Conlon TM et al. Copresentation of intact and processed MHC alloantigen by recipient dendritic cells enables delivery of linked help to alloreactive CD8 T cells by indirect-pathway CD4 T cells. J. Immunol. 190(11), 5829–5838 (2013).
    • 56 Taylor AL, Negus SL, Negus M, Bolton EM, Bradley JA, Pettigrew GJ. Pathways of helper CD4 T cell allorecognition in generating alloantibody and CD8 T cell alloimmunity. Transplantation 83(7), 931–937 (2007).
    • 57 Wood KJ, Goto R. Mechanisms of rejection: current perspectives. Transplantation 93(1), 1–10 (2012).
    • 58 Okita K, Matsumura Y, Sato Y et al. A more efficient method to generate integration-free human iPS cells. Nat. Methods 8(5), 409–412 (2011).
    • 59 Day E, Kearns PK, Taylor CJ, Bradley JA. Transplantation between monozygotic twins: how identical are they? Transplantation 98(5), 485–489 (2014).
    • 60 Rostaing L, Saliba F, Calmus Y, Dharancy S, Boillot O. Review article: use of induction therapy in liver transplantation. Transplant. Rev. (Orlando) 26(4), 246–260 (2012).
    • 61 Morgan RD, O'Callaghan JM, Knight SR, Morris PJ. Alemtuzumab induction therapy in kidney transplantation: a systematic review and meta-analysis. Transplantation 93(12), 1179–1188 (2012).
    • 62 Rush D. The impact of calcineurin inhibitors on graft survival. Transplant. Rev. (Orlando) 27(3), 93–95 (2013).
    • 63 Salvadori M, Bertoni E. Is it time to give up with calcineurin inhibitors in kidney transplantation? World J. Transplant. 3(2), 7–25 (2013).
    • 64 Russ GR. Optimising the use of mTOR inhibitors in renal transplantation. Transplant. Res. 2(Suppl. 1), S4 (2013).
    • 65 Gurk-Turner C, Manitpisitkul W, Cooper M. A comprehensive review of everolimus clinical reports: a new mammalian target of rapamycin inhibitor. Transplantation 94(7), 659–668 (2012).
    • 66 Davies NM, Grinyo J, Heading R, Maes B, Meier-Kriesche HU, Oellerich M. Gastrointestinal side effects of mycophenolic acid in renal transplant patients: a reappraisal. Nephrol. Dial. Transplant. 22(9), 2440–2448 (2007).
    • 67 Jordan SC, Kahwaji J, Toyoda M, Vo A. B-cell immunotherapeutics: emerging roles in solid organ transplantation. Curr. Opin. Organ Transplant. 16(4), 416–424 (2011).
    • 68 Wojciechowski D, Vincenti F. Belatacept in kidney transplantation. Curr. Opin. Organ Transplant. 17(6), 640–647 (2012).
    • 69 Kotton CN. CMV: prevention, diagnosis and therapy. Am. J. Transplant. 13(Suppl. 3), 24–40; quiz 40 (2013).
    • 70 Shoham S, Marr KA. Invasive fungal infections in solid organ transplant recipients. Future Microbiol. 7(5), 639–655 (2012).
    • 71 Euvrard S, Kanitakis J, Claudy A. Skin cancers after organ transplantation. N. Engl. J. Med. 348(17), 1681–1691 (2003).
    • 72 Taylor AL, Marcus R, Bradley JA. Post-transplant lymphoproliferative disorders (PTLD) after solid organ transplantation. Crit. Rev. Oncol. Hematol. 56(1), 155–167 (2005).
    • 73 Green M, Michaels MG. Epstein-Barr virus infection and posttransplant lymphoproliferative disorder. Am. J. Transplant. 13(Suppl. 3), 41–54; quiz 54 (2013).
    • 74 Euvrard S, Morelon E, Rostaing L et al. Sirolimus and secondary skin-cancer prevention in kidney transplantation. N. Engl. J. Med. 367(4), 329–339 (2012).
    • 75 Pearl JI, Lee AS, Leveson-Gower DB et al. Short-term immunosuppression promotes engraftment of embryonic and induced pluripotent stem cells. Cell Stem Cell 8(3), 309–317 (2011).• This study demonstrates that survival of transplanted mouse or human embryonic stem cells (ESC) and iPSC may be achieved by treating the (mouse) recipient with immunosuppressive agents that inhibit costimulatory molecules and suppress T cell activation. This promotes the possibility that clinically relevant drug therapy may be used to prevent rejection of mismatched stem cell derived tissues.
    • 76 Swijnenburg RJ, Schrepfer S, Govaert JA et al. Immunosuppressive therapy mitigates immunological rejection of human embryonic stem cell xenografts. Proc. Natl Acad. Sci. USA 105(35), 12991–12996 (2008).
    • 77 Grinnemo KH, Genead R, Kumagai-Braesch M et al. Costimulation blockade induces tolerance to HESC transplanted to the testis and induces regulatory T-cells to HESC transplanted into the heart. Stem Cells 26(7), 1850–1857 (2008).
    • 78 Ludwig B, Reichel A, Steffen A et al. Transplantation of human islets without immunosuppression. Proc. Natl Acad. Sci. USA 110(47), 19054–19058 (2013).
    • 79 McCall M, Shapiro AM. Update on islet transplantation. Cold Spring Harb. Perspect. Med. 2(7), a007823 (2012).
    • 80 Posselt AM, Szot GL, Frassetto LA et al. Islet transplantation in type 1 diabetic patients using calcineurin inhibitor-free immunosuppressive protocols based on T-cell adhesion or costimulation blockade. Transplantation 90(12), 1595–1601 (2010).
    • 81 Nienhuis AW. Development of gene therapy for blood disorders: an update. Blood 122(9), 1556–1564 (2013).
    • 82 Mitani K. Gene targeting in human-induced pluripotent stem cells with adenoviral vectors. Methods Mol. Biol. 1114, 163–167 (2014).
    • 83 Gonzalez S, Castanotto D, Li H et al. Amplification of RNAi‐‐targeting HLA mRNAs. Mol. Ther. 11(5), 811–818 (2005).
    • 84 Zhao J, Bolton EM, Ormiston ML, Bradley JA, Morrell NW, Lever AM. Late outgrowth endothelial progenitor cells engineered for improved survival and maintenance of function in transplant-related injury. Transpl. Int. 25(2), 229–241 (2012).
    • 85 Zhao J, Pettigrew GJ, Bolton EM et al. Lentivirus-mediated gene transfer of viral interleukin-10 delays but does not prevent cardiac allograft rejection. Gene Ther. 12(20), 1509–1516 (2005).
    • 86 Raya A, Rodriguez-Piza I, Guenechea G et al. Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 460(7251), 53–59 (2009).•• This is an important demonstration that contemporary gene targeting approaches may be used to correct inherited disorders in pluripotent stem cell lines that could subsequently be differentiated to produce therapeutic tissue for regenerative medicine.
    • 87 Yusa K, Rashid ST, Strick-Marchand H et al. Targeted gene correction of alpha1-antitrypsin deficiency in induced pluripotent stem cells. Nature 478(7369), 391–394 (2011).
    • 88 Matrai J, Chuah MK, VandenDriessche T. Recent advances in lentiviral vector development and applications. Mol. Ther. 18(3), 477–490 (2010).
    • 89 Gaj T, Gersbach CA, Barbas CF, 3rd. ZFN, TALEN, and CRISPR/Cas-based methods for genome engineering. Trends Biotechnol. 31(7), 397–405 (2013).
    • 90 Figueiredo C, Wedekind D, Muller T et al. MHC universal cells survive in an allogeneic environment after incompatible transplantation. Biomed. Res. Int. 2013, 796046 (2013).
    • 91 Torikai H, Reik A, Soldner F et al. Toward eliminating HLA class I expression to generate universal cells from allogeneic donors. Blood 122(8), 1341–1349 (2013).• This is a proof-of-principle study that demonstrates the feasibility of manipulating HLA expression in pluripotent stem cell lines, with a view to creating ‘universal donor’ tissues that do not express HLA and therefore will not be rejected – but with the proviso that such cells must also not be susceptible to natural killer (NK) cell cytotoxicity.
    • 92 Qian S, Fu F, Li Y et al. Impact of donor MHC class I or class II antigen deficiency on first- and second-set rejection of mouse heart or liver allografts. Immunology 88(1), 124–129 (1996).
    • 93 Hacke K, Falahati R, Flebbe-Rehwaldt L, Kasahara N, Gaensler KM. Suppression of HLA expression by lentivirus-mediated gene transfer of siRNA cassettes and in vivo chemoselection to enhance hematopoietic stem cell transplantation. Immunol. Res. 44(1–3), 112–126 (2009).
    • 94 Figueiredo C, Seltsam A, Blasczyk R. Class-, gene-, and group-specific HLA silencing by lentiviral shRNA delivery. J. Mol. Med. (Berl). 84(5), 425–437 (2006).
    • 95 Beilke JN, Benjamin J, Lanier LL. The requirement for NKG2D in NK cell-mediated rejection of parental bone marrow grafts is determined by MHC class I expressed by the graft recipient. Blood 116(24), 5208–5216 (2010).
    • 96 Rolstad B. The early days of NK cells: an example of how a phenomenon led to detection of a novel immune receptor system – lessons from a rat model. Front. Immunol. 5, 283 (2014).
    • 97 Belanger S, Tu MM, Rahim MM et al. Impaired natural killer cell self-education and ‘missing-self’ responses in Ly49-deficient mice. Blood 120(3), 592–602 (2012).
    • 98 Matheux F, Villard J. Cellular and gene therapy for major histocompatibility complex class II deficiency. News Physiol. Sci. 19, 154–158 (2004).
    • 99 Jaimes Y, Seltsam A, Eiz-Vesper B, Blasczyk R, Figueiredo C. Regulation of HLA class II expression prevents allogeneic T-cell responses. Tissue Antigens 77(1), 36–44 (2011).
    • 100 Ke B, Buelow R, Shen XD et al. Heme oxygenase 1 gene transfer prevents CD95/Fas ligand-mediated apoptosis and improves liver allograft survival via carbon monoxide signaling pathway. Hum. Gene Ther. 13(10), 1189–1199 (2002).
    • 101 Li J, Meinhardt A, Roehrich ME et al. Indoleamine 2,3-dioxygenase gene transfer prolongs cardiac allograft survival. Am. J. Physiol. Heart Circ. Physiol. 293(6), H3415–H3423 (2007).
    • 102 Olthoff KM, Judge TA, Gelman AE et al. Adenovirus-mediated gene transfer into cold-preserved liver allografts: survival pattern and unresponsiveness following transduction with CTLA4Ig. Nat. Med. 4(2), 194–200 (1998).
    • 103 Kim YH, Lim DG, Wee YM et al. Viral IL-10 gene transfer prolongs rat islet allograft survival. Cell Transplant. 17(6), 609–618 (2008).
    • 104 Tomasoni S, Azzollini N, Casiraghi F, Capogrossi MC, Remuzzi G, Benigni A. CTLA4Ig gene transfer prolongs survival and induces donor-specific tolerance in a rat renal allograft. J. Am. Soc. Nephrol. 11(4), 747–752 (2000).
    • 105 Dudler J, Li J, Pagnotta M, Pascual M, von Segesser LK, Vassalli G. Gene transfer of programmed death ligand-1.Ig prolongs cardiac allograft survival. Transplantation 82(12), 1733–1737 (2006).
    • 106 Friedenstein AJ, Gorskaja JF, Kulagina NN. Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp. Hematol. 4(5), 267–274 (1976).
    • 107 Pittenger MF, Mackay AM, Beck SC et al. Multilineage potential of adult human mesenchymal stem cells. Science 284(5411), 143–147 (1999).
    • 108 Fraser JK, Wulur I, Alfonso Z, Hedrick MH. Fat tissue: an underappreciated source of stem cells for biotechnology. Trends Biotechnol. 24(4), 150–154 (2006).
    • 109 Schallmoser K, Rohde E, Reinisch A et al. Rapid large-scale expansion of functional mesenchymal stem cells from unmanipulated bone marrow without animal serum. Tissue Eng. Part C Methods. 14(3), 185–196 (2008).
    • 110 Kuhbier JW, Weyand B, Radtke C, Vogt PM, Kasper C, Reimers K. Isolation, characterization, differentiation, and application of adipose-derived stem cells. Adv. Biochem. Eng. Biotechnol. 123, 55–105 (2010).
    • 111 Ankrum J, Karp JM. Mesenchymal stem cell therapy: two steps forward, one step back. Trends Mol. Med. 16(5), 203–209 (2010).
    • 112 Lalu MM, McIntyre L, Pugliese C et al. Safety of cell therapy with mesenchymal stromal cells (SafeCell): a systematic review and meta-analysis of clinical trials. PLoS ONE 7(10), e47559 (2012).
    • 113 Lalu MM, McIntyre LL, Stewart DJ. Mesenchymal stromal cells: cautious optimism for their potential role in the treatment of acute lung injury. Crit. Care Med. 40(4), 1373–1375 (2012).
    • 114 Krampera M, Glennie S, Dyson J et al. Bone marrow mesenchymal stem cells inhibit the response of naive and memory antigen-specific T cells to their cognate peptide. Blood 101(9), 3722–3729 (2003).
    • 115 Glennie S, Soeiro I, Dyson PJ, Lam EW, Dazzi F. Bone marrow mesenchymal stem cells induce division arrest anergy of activated T cells. Blood 105(7), 2821–2827 (2005).
    • 116 Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringden O. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand. J. Immunol. 57(1), 11–20 (2003).
    • 117 Ryan JM, Barry FP, Murphy JM, Mahon BP. Mesenchymal stem cells avoid allogeneic rejection. J. Inflamm. (Lond). 2, 8 (2005).
    • 118 Le Blanc K, Frassoni F, Ball L et al. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 371(9624), 1579–1586 (2008).
    • 119 Ringden O, Uzunel M, Rasmusson I et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 81(10), 1390–1397 (2006).
    • 120 Ding Y, Xu D, Feng G, Bushell A, Muschel RJ, Wood KJ. Mesenchymal stem cells prevent the rejection of fully allogenic islet grafts by the immunosuppressive activity of matrix metalloproteinase-2 and -9. Diabetes 58(8), 1797–1806 (2009).
    • 121 Casiraghi F, Azzollini N, Cassis P et al. Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic heart transplant through the generation of regulatory T cells. J. Immunol. 181(6), 3933–3946 (2008).
    • 122 Inoue S, Popp FC, Koehl GE et al. Immunomodulatory effects of mesenchymal stem cells in a rat organ transplant model. Transplantation 81(11), 1589–1595 (2006).
    • 123 Peng Y, Ke M, Xu L et al. Donor-derived mesenchymal stem cells combined with low-dose tacrolimus prevent acute rejection after renal transplantation: a clinical pilot study. Transplantation 95(1), 161–168 (2013).
    • 124 Ramasamy R, Tong CK, Seow HF, Vidyadaran S, Dazzi F. The immunosuppressive effects of human bone marrow-derived mesenchymal stem cells target T cell proliferation but not its effector function. Cell Immunol. 251(2), 131–136 (2008).
    • 125 Di Nicola M, Carlo-Stella C, Magni M et al. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 99(10), 3838–3843 (2002).
    • 126 Corcione A, Benvenuto F, Ferretti E et al. Human mesenchymal stem cells modulate B-cell functions. Blood 107(1), 367–372 (2006).
    • 127 Beyth S, Borovsky Z, Mevorach D et al. Human mesenchymal stem cells alter antigen-presenting cell maturation and induce T-cell unresponsiveness. Blood 105(5), 2214–2219 (2005).
    • 128 Augello A, Tasso R, Negrini SM et al. Bone marrow mesenchymal progenitor cells inhibit lymphocyte proliferation by activation of the programmed death 1 pathway. Eur. J. Immunol. 35(5), 1482–1490 (2005).
    • 129 Krampera M, Cosmi L, Angeli R et al. Role for interferon-gamma in the immunomodulatory activity of human bone marrow mesenchymal stem cells. Stem Cells 24(2), 386–398 (2006).
    • 130 Madec AM, Mallone R, Afonso G et al. Mesenchymal stem cells protect NOD mice from diabetes by inducing regulatory T cells. Diabetologia 52(7), 1391–1399 (2009).
    • 131 Sato K, Ozaki K, Oh I et al. Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells. Blood 109(1), 228–234 (2007).
    • 132 Ramasamy R, Fazekasova H, Lam EW, Soeiro I, Lombardi G, Dazzi F. Mesenchymal stem cells inhibit dendritic cell differentiation and function by preventing entry into the cell cycle. Transplantation 83(1), 71–76 (2007).
    • 133 Probst HC, McCoy K, Okazaki T, Honjo T, van den Broek M. Resting dendritic cells induce peripheral CD8+ T cell tolerance through PD-1 and CTLA-4. Nat. Immunol. 6(3), 280–286 (2005).
    • 134 Reis e Sousa C. Dendritic cells in a mature age. Nat. Rev. Immunol. 6(6), 476–483 (2006).
    • 135 Albert ML, Jegathesan M, Darnell RB. Dendritic cell maturation is required for the cross-tolerization of CD8+ T cells. Nat. Immunol. 2(11), 1010–1017 (2001).
    • 136 Penna G, Adorini L. 1 Alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J. Immunol. 164(5), 2405–2411 (2000).
    • 137 Hackstein H, Morelli AE, Larregina AT et al. Aspirin inhibits in vitro maturation and in vivo immunostimulatory function of murine myeloid dendritic cells. J. Immunol. 166(12), 7053–7062 (2001).
    • 138 Woltman AM, de Fijter JW, Kamerling SW, Paul LC, Daha MR, van Kooten C. The effect of calcineurin inhibitors and corticosteroids on the differentiation of human dendritic cells. Eur. J. Immunol. 30(7), 1807–1812 (2000).
    • 139 Piemonti L, Monti P, Allavena P et al. Glucocorticoids affect human dendritic cell differentiation and maturation. J. Immunol. 162(11), 6473–6481 (1999).
    • 140 Vieira PL, Kalinski P, Wierenga EA, Kapsenberg ML, de Jong EC. Glucocorticoids inhibit bioactive IL-12p70 production by in vitro-generated human dendritic cells without affecting their T cell stimulatory potential. J. Immunol. 161(10), 5245–5251 (1998).
    • 141 Ramirez F, Fowell DJ, Puklavec M, Simmonds S, Mason D. Glucocorticoids promote a TH2 cytokine response by CD4+ T cells in vitro. J. Immunol. 156(7), 2406–2412 (1996).
    • 142 Chen T, Guo J, Yang M et al. Cyclosporin A impairs dendritic cell migration by regulating chemokine receptor expression and inhibiting cyclooxygenase-2 expression. Blood 103(2), 413–421 (2004).
    • 143 Hoves S, Krause SW, Herfarth H et al. Elimination of activated but not resting primary human CD4+ and CD8+ T cells by Fas ligand (FasL/CD95L)-expressing Killer-dendritic cells. Immunobiology 208(5), 463–475 (2004).
    • 144 Feili-Hariri M, Falkner DH, Gambotto A et al. Dendritic cells transduced to express interleukin-4 prevent diabetes in nonobese diabetic mice with advanced insulitis. Hum. Gene Ther. 14(1), 13–23 (2003).
    • 145 Salama AD, Womer KL, Sayegh MH. Clinical transplantation tolerance: many rivers to cross. J. Immunol. 178(9), 5419–5423 (2007).
    • 146 Mirenda V, Berton I, Read J et al. Modified dendritic cells coexpressing self and allogeneic major histocompatability complex molecules: an efficient way to induce indirect pathway regulation. J. Am. Soc. Nephrol. 15(4), 987–997 (2004).
    • 147 Wang Z, Shufesky WJ, Montecalvo A, Divito SJ, Larregina AT, Morelli AE. In situ targeting of dendritic cells with donor-derived apoptotic cells restrains indirect allorecognition and ameliorates allograft vasculopathy. PLoS ONE 4(3), e4940 (2009).
    • 148 Sakaguchi S, Fukuma K, Kuribayashi K, Masuda T. Organ-specific autoimmune diseases induced in mice by elimination of T cell subset. I. Evidence for the active participation of T cells in natural self-tolerance; deficit of a T cell subset as a possible cause of autoimmune disease. J. Exp. Med. 161(1), 72–87 (1985).
    • 149 Fowell D, Mason D. Evidence that the T cell repertoire of normal rats contains cells with the potential to cause diabetes. Characterization of the CD4+ T cell subset that inhibits this autoimmune potential. J. Exp. Med. 177(3), 627–636 (1993).
    • 150 Hori S, Nomura T, Sakaguchi S. Control of regulatory T cell development by the transcription factor Foxp3. Science 299(5609), 1057–1061 (2003).
    • 151 Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat. Immunol. 4(4), 330–336 (2003).
    • 152 Yoshizaki A, Miyagaki T, Di Lillo DJ et al. Regulatory B cells control T-cell autoimmunity through IL-21-dependent cognate interactions. Nature 491(7423), 264–268 (2012).
    • 153 Mauri C, Bosma A. Immune regulatory function of B cells. Annu. Rev. Immunol. 30, 221–241 (2012).
    • 154 Powrie F, Mason D. OX-22high CD4+ T cells induce wasting disease with multiple organ pathology: prevention by the OX-22low subset. J. Exp. Med. 172(6), 1701–1708 (1990).
    • 155 Kim JM, Rasmussen JP, Rudensky AY. Regulatory T cells prevent catastrophic autoimmunity throughout the lifespan of mice. Nat. Immunol. 8(2), 191–197 (2007).
    • 156 Levings MK, Roncarolo MG. Phenotypic and functional differences between human CD4+CD25+ and type 1 regulatory T cells. Curr. Top Microbiol. Immunol. 293, 303–326 (2005).
    • 157 Wang J, Ioan-Facsinay A, van der Voort EI, Huizinga TW, Toes RE. Transient expression of FOXP3 in human activated nonregulatory CD4+ T cells. Eur. J. Immunol. 37(1), 129–138 (2007).
    • 158 Waldmann H, Chen TC, Graca L et al. Regulatory T cells in transplantation. Semin. Immunol. 18(2), 111–119 (2006).
    • 159 Mizoguchi A, Bhan AK. A case for regulatory B cells. J. Immunol. 176(2), 705–710 (2006).
    • 160 Ding Q, Yeung M, Camirand G et al. Regulatory B cells are identified by expression of TIM-1 and can be induced through TIM-1 ligation to promote tolerance in mice. J. Clin. Invest. 121(9), 3645–3656 (2011).
    • 161 Maseda D, Candando KM, Smith SH et al. Peritoneal cavity regulatory B cells (B10 cells) modulate IFN-gamma+CD4+ T cell numbers during colitis development in mice. J. Immunol. 191(5), 2780–2795 (2013).
    • 162 Kalampokis I, Yoshizaki A, Tedder TF. IL-10-producing regulatory B cells (B10 cells) in autoimmune disease. Arthritis Res. Ther. 15(Suppl.1), S1 (2013).
    • 163 Geissler EK. The ONE study compares cell therapy products in organ transplantation: introduction to a review series on suppressive monocyte-derived cells. Transplant. Res. 1(1), 11 (2012).
    • 164 Leventhal J, Abecassis M, Miller J et al. Chimerism and tolerance without GVHD or engraftment syndrome in HLA-mismatched combined kidney and hematopoietic stem cell transplantation. Sci. Transl. Med. 4(124), 124ra128 (2012).
    • 165 Owen RD. Immunogenetic consequences of vascular anastomoses between Bovine twins. Science 102(2651), 400–401 (1945).
    • 166 Billingham RE, Brent L, Medawar PB. Actively acquired tolerance of foreign cells. Nature 172(4379), 603–606 (1953).
    • 167 Ildstad ST, Sachs DH. Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts. Nature 307(5947), 168–170 (1984).
    • 168 Tomita Y, Sachs DH, Khan A, Sykes M. Additional monoclonal antibody (mAB) injections can replace thymic irradiation to allow induction of mixed chimerism and tolerance in mice receiving bone marrow transplantation after conditioning with anti-T cell mABs and 3-Gy whole body irradiation. Transplantation 61(3), 469–477 (1996).
    • 169 Wekerle T, Kurtz J, Ito H et al. Allogeneic bone marrow transplantation with co-stimulatory blockade induces macrochimerism and tolerance without cytoreductive host treatment. Nat. Med. 6(4), 464–469 (2000).
    • 170 Huang CA, Fuchimoto Y, Scheier-Dolberg R, Murphy MC, Neville DM, Jr., Sachs DH. Stable mixed chimerism and tolerance using a nonmyeloablative preparative regimen in a large-animal model. J. Clin. Invest. 105(2), 173–181 (2000).
    • 171 Kawai T, Cosimi AB, Spitzer TR et al. HLA-mismatched renal transplantation without maintenance immunosuppression. N. Engl. J. Med. 358(4), 353–361 (2008).•• This important clinical study demonstrates that clinical transplantation tolerance is achievable using a cell-based therapy to suppress immunity.
    • 172 Mathes DW, Chang J, Hwang B et al. Simultaneous transplantation of hematopoietic stem cells and a vascularized composite allograft leads to tolerance. Transplantation 98(2), 131–138 (2014).
    • 173 Mathes DW, Hwang B, Graves SS et al. Tolerance to vascularized composite allografts in canine mixed hematopoietic chimeras. Transplantation 92(12), 1301–1308 (2011).
    • 174 Scandling JD, Busque S, Dejbakhsh-Jones S et al. Tolerance and chimerism after renal and hematopoietic-cell transplantation. N. Engl. J. Med. 358(4), 362–368 (2008).
    • 175 Spitzer TR, McAfee SL, Dey BR et al. Nonmyeloablative haploidentical stem-cell transplantation using anti-CD2 monoclonal antibody (MEDI-507)-based conditioning for refractory hematologic malignancies. Transplantation 75(10), 1748–1751 (2003).
    • 176 Takasato M, Er PX, Becroft M et al. Directing human embryonic stem cell differentiation towards a renal lineage generates a self-organizing kidney. Nat. Cell Biol. 16(1), 118–126 (2014).
    • 177 Lui KO, Zangi L, Silva EA et al. Driving vascular endothelial cell fate of human multipotent Isl1+ heart progenitors with VEGF modified mRNA. Cell Res. 23(10), 1172–1186 (2013).
    • 178 Lippmann ES, Azarin SM, Kay JE et al. Derivation of blood-brain barrier endothelial cells from human pluripotent stem cells. Nat. Biotechnol. 30(8), 783–791 (2012).
    • 179 Volk H-D, Blackburn, Exploiting the regulatory T cell repertoire for the induction of tolerance in regenerative medicine. Regen. Med. 10(3), 305–315 (2015).