Skip to main content
SpringerLink
Log in

The Immunogenicity of Stem Cells and Thymus-Based Strategies to Minimise Immune Rejection

  • Chapter
  • First Online:
Book cover The Immunological Barriers to Regenerative Medicine

Part of the book series: Stem Cell Biology and Regenerative Medicine ((STEMCELL))

  • 1107 Accesses

Abstract

Stem cell research is advancing at a rapid pace, offering the possibility of personalised, “made to order” reparative stem cell treatments. A major challenge, however, is the immunological rejection of the transplanted tissue or ‘allograft’ that is not derived from self. Current clinical practice for overcoming graft rejection is to administer immunosuppressive drugs. Unfortunately these are associated with a number of side effects, including severe and often prolonged immune deficiency, which can lead to complications associated with opportunistic infections. Rather than prolonged global suppression of the immune system, strategies that focus on inducing graft-specific tolerance will provide a more robust and sustained approach to enabling successful translation of stem cell therapies to the clinic.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Notes

  1. 1.

    http://emedicine.medscape.com/article/1014514-overview

References

  1. Trounson A (2006) The production and directed differentiation of human embryonic stem cells. Endocr Rev 27:208–219

    PubMed  Google Scholar 

  2. Chidgey AP, Layton D, Trounson A, Boyd RL (2008) Tolerance strategies for stem-cell-based therapies. Nature 453:330–337

    PubMed  CAS  Google Scholar 

  3. Billingham RE, Brent L, Medawar PB (1953) ‘Actively acquired tolerance’ of foreign cells. J Immunol 184:5–8

    Google Scholar 

  4. Heng TS, Goldberg GL, Gray DH, Sutherland JS, Chidgey AP, Boyd RL (2005) Effects of castration on thymocyte development in two different models of thymic involution. J Immunol 175:2982–2993

    PubMed  CAS  Google Scholar 

  5. Thomson JA, Itskovitz-Eldor J, Shapiro SS, Waknitz MA, Swiergiel JJ, Marshall VS, Jones JM (1998) Embryonic stem cell lines derived from human blastocysts. Science 282:1145–1147

    PubMed  CAS  Google Scholar 

  6. Reubinoff BE, Pera MF, Fong CY, Trounson A, Bongso A (2000) Embryonic stem cell lines from human blastocysts: somatic differentiation in vitro. Nat Biotechnol 18:399–404

    PubMed  CAS  Google Scholar 

  7. Rando TA (2006) Stem cells, ageing and the quest for immortality. Nature 441:1080–1086

    PubMed  CAS  Google Scholar 

  8. Miki T, Lehmann T, Cai H, Stolz DB, Strom SC (2005) Stem cell characteristics of amniotic epithelial cells. Stem Cells 23:1549–1559

    PubMed  CAS  Google Scholar 

  9. Kuroda Y, Kitada M, Wakao S, Nishikawa K, Tanimura Y, Makinoshima H, Goda M, Akashi H, Inutsuka A, Niwa A, Shigemoto T, Nabeshima Y, Nakahata T, Nabeshima Y-I, Fujiyoshi Y, Dezawa M (2010) Unique multipotent cells in adult human mesenchymal cell populations. Proc Natl Acad Sci U S A 107:8639–8643

    PubMed  CAS  Google Scholar 

  10. Uccelli A, Moretta L, Pistoia V (2008) Mesenchymal stem cells in health and disease. Nat Rev Immunol 8(9):726–736

    PubMed  CAS  Google Scholar 

  11. Le Blanc K, Ringdén O (2007) Immunomodulation by mesenchymal stem cells and clinical experience. J Intern Med 262:509–525

    PubMed  Google Scholar 

  12. Schächinger V, Erbs S, Elsässer A, Haberbosch W, Hambrecht R, Hölschermann H, Yu J, Corti R, Mathey DG, Hamm CW, Süselbeck T, Assmus B, Tonn T, Dimmeler S, Zeiher AM, Investigators R-A (2006) Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 355:1210–1221

    PubMed  Google Scholar 

  13. Sun L, Wang D, Liang J, Zhang H, Feng X, Wang H, Hua B, Liu B, Ye S, Hu X, Xu W, Zeng X, Hou Y, Gilkeson GS, Silver RM, Lu L, Shi S (2010) Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus. Arthritis Rheum 62:2467–2475

    PubMed  CAS  Google Scholar 

  14. Horwitz EM, Prockop DJ, Gordon PL, Koo WW, Fitzpatrick LA, Neel MD, McCarville ME, Orchard PJ, Pyeritz RE, Brenner MK (2001) Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta. Blood 97:1227–1231

    PubMed  CAS  Google Scholar 

  15. Weng JY, Du X, Geng SX, Peng YW, Wang Z, Lu ZS, Wu SJ, Luo CW, Guo R, Ling W, Deng CX, Liao PJ, Xiang AP (2010) Mesenchymal stem cell as salvage treatment for refractory chronic GVHD. Bone Marrow Transplant 45(12):1732–1740

    PubMed  CAS  Google Scholar 

  16. Kaji K, Norrby K, Paca A, Mileikovsky M, Mohseni P, Woltjen K (2009) Virus-free induction of pluripotency and subsequent excision of reprogramming factors. Nature 458:771–775

    PubMed  CAS  Google Scholar 

  17. Jia F, Wilson KD, Sun N, Gupta DM, Huang M, Li Z, Panetta NJ, Chen ZY, Robbins RC, Kay MA, Longaker MT, Wu JC (2010) A nonviral minicircle vector for deriving human iPS cells. Nat Methods 7:197–199

    PubMed  CAS  Google Scholar 

  18. Martinez-Fernandez A, Nelson TJ, Yamada S, Reyes S, Alekseev AE, Perez-Terzic C, Ikeda Y, Terzic A (2009) iPS programmed without c-MYC yield proficient cardiogenesis for functional heart chimerism. Circ Res 105:648–656

    PubMed  CAS  Google Scholar 

  19. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676

    PubMed  CAS  Google Scholar 

  20. Patel M, Yang S (2010) Advances in reprogramming somatic cells to induced pluripotent stem cells. Stem Cell Rev 6:367–380

    PubMed  CAS  Google Scholar 

  21. Boyiadzis M, Pavletic S (2004) Haematopoietic stem cell transplantation: indications, clinical developments and future directions. Expert Opin Pharmacother 5:97–108

    PubMed  CAS  Google Scholar 

  22. Dickinson AM, Charron D (2005) Non-HLA immunogenetics in hematopoietic stem cell transplantation. Curr Opin Immunol 17:517–525

    PubMed  CAS  Google Scholar 

  23. Robertson NJ, Brook FA, Gardner RL, Cobbold SP, Waldmann H, Fairchild PJ (2007) Embryonic stem cell-derived tissues are immunogenic but their inherent immune privilege promotes the induction of tolerance. Proc Natl Acad Sci U S A 104:20920–20925

    PubMed  CAS  Google Scholar 

  24. Roopenian D, Choi EY, Brown A (2002) The immunogenomics of minor histocompatibility antigens. Immunol Rev 190:86–94

    PubMed  CAS  Google Scholar 

  25. Watkins WM (2001) The ABO blood group system: historical background. Transfus Med 11:243–265

    PubMed  CAS  Google Scholar 

  26. Schreuder GMT, Hurley CK, Marsh SGE, Lau M, Fernandez-Vina MA, Noreen HJ, Setterholm M, Maiers M (2005) HLA dictionary 2004: summary of HLA-A, -B, -C, -DRB1/3/4/5, -DQB1 alleles and their association with serologically defined HLA-A, -B, -C, -DR, and -DQ antigens. Hum Immunol 66:170–210

    PubMed  CAS  Google Scholar 

  27. 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

    PubMed  Google Scholar 

  28. Drukker M, Katz G, Urbach A, Schuldiner M, Markel G, Itskovitz-Eldor J, Reubinoff B, Mandelboim O, Benvenisty N (2002) Characterization of the expression of MHC proteins in human embryonic stem cells. Proc Natl Acad Sci U S A 99:9864–9869

    PubMed  CAS  Google Scholar 

  29. McLaren FH, Svendsen CN, Van der Meide P, Joly E (2001) Analysis of neural stem cells by flow cytometry: cellular differentiation modifies patterns of MHC expression. J Neuroimmunol 112:35–46

    PubMed  CAS  Google Scholar 

  30. Swijnenburg R-J, Schrepfer S, Govaert JA, Cao F, Ransohoff K, Sheikh AY, Haddad M, Connolly AJ, Davis MM, Robbins RC, Wu JC (2008) Immunosuppressive therapy mitigates immunological rejection of human embryonic stem cell xenografts. Proc Natl Acad Sci U S A 105:12991–12996

    PubMed  CAS  Google Scholar 

  31. Swijnenburg R-J, Tanaka M, Vogel H, Baker J, Kofidis T, Gunawan F, Lebl DR, Caffarelli AD, de Bruin JL, Fedoseyeva EV, Robbins RC (2005) Embryonic stem cell immunogenicity increases upon differentiation after transplantation into ischemic myocardium. Circulation 112:I166–I172

    PubMed  Google Scholar 

  32. Bradley JA, Bolton EM, Pedersen RA (2002) Stem cell medicine encounters the immune system. Nat Rev Immunol 2:859–871

    PubMed  CAS  Google Scholar 

  33. Phinney DG, Prockop DJ (2007) Concise review: mesenchymal stem/multipotent stromal cells: the state of transdifferentiation and modes of tissue repair–current views. Stem Cells 25:2896–2902

    PubMed  Google Scholar 

  34. Le Blanc K, Tammik C, Rosendahl K, Zetterberg E, Ringdén O (2003) HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells. Exp Hematol 31:890–896

    PubMed  Google Scholar 

  35. Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL, Neel M, Sussman M, Orchard P, Marx JC, Pyeritz RE, Brenner MK (1999) Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 5:309–313

    PubMed  CAS  Google Scholar 

  36. Saulnier N, Piscaglia AC, Puglisi MA, Barba M, Arena V, Pani G, Alfieri S, Gasbarrini A (2010) Molecular mechanisms underlying human adipose tissue-derived stromal cells differentiation into a hepatocyte-like phenotype. Dig Liver Dis. doi:10.1016/j.dld.2010.04.013 (Official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver)

    PubMed  Google Scholar 

  37. Parekkadan B, van Poll D, Suganuma K, Carter EA, Berthiaume F, Tilles AW, Yarmush ML (2007) Mesenchymal stem cell-derived molecules reverse fulminant hepatic failure. PLoS ONE 2:e941

    PubMed  Google Scholar 

  38. Nauta AJ, Westerhuis G, Kruisselbrink AB, Lurvink EGA, Willemze R, Fibbe WE (2006) Donor-derived mesenchymal stem cells are immunogenic in an allogeneic host and stimulate donor graft rejection in a nonmyeloablative setting. Blood 108:2114–2120

    PubMed  CAS  Google Scholar 

  39. Cho PS, Messina DJ, Hirsh EL, Chi N, Goldman SN, Lo DP, Harris IR, Popma SH, Sachs DH, Huang CA (2008) Immunogenicity of umbilical cord tissue derived cells. Blood 111:430–438

    PubMed  CAS  Google Scholar 

  40. Zangi L, Margalit R, Reich-Zeliger S, Bachar-Lustig E, Beilhack A, Negrin R, Reisner Y (2009) Direct imaging of immune rejection and memory induction by allogeneic mesenchymal stromal cells. Stem Cells 27:2865–2874

    PubMed  CAS  Google Scholar 

  41. Wilmut I, Schnieke AE, McWhir J, Kind AJ, Campbell KH (1997) Viable offspring derived from fetal and adult mammalian cells. Nature 385:810–813

    PubMed  CAS  Google Scholar 

  42. Raya A, Rodríguez-Pizà I, Guenechea G, Vassena R, Navarro S, Barrero MJ, Consiglio A, Castellà M, Río P, Sleep E, González F, Tiscornia G, Garreta E, Aasen T, Veiga A, Verma IM, Surrallés J, Bueren J, Izpisúa Belmonte JC (2009) Disease-corrected haematopoietic progenitors from Fanconi anaemia induced pluripotent stem cells. Nature 460:53–59

    PubMed  CAS  Google Scholar 

  43. Boyd RL, Tucek CL, Godfrey DI, Izon DJ, Wilson TJ, Davidson NJ, Bean AG, Ladyman HM, Ritter MA, Hugo P (1993) The thymic microenvironment. Immunol Today 14:445–459

    PubMed  CAS  Google Scholar 

  44. van Ewijk W, Shores EW, Singer A (1994) Crosstalk in the mouse thymus. Immunol Today 15:214–217

    PubMed  Google Scholar 

  45. Gordon J, Wilson VA, Blair NF, Sheridan J, Farley A, Wilson L, Manley NR, Blackburn CC (2004) Functional evidence for a single endodermal origin for the thymic epithelium. Nat Immunol 5:546–553

    PubMed  CAS  Google Scholar 

  46. Rossi SW, Jenkinson WE, Anderson G, Jenkinson EJ (2006) Clonal analysis reveals a common progenitor for thymic cortical and medullary epithelium. Nature 441:988–991

    PubMed  CAS  Google Scholar 

  47. Bleul CC, Boehm T (2000) Chemokines define distinct microenvironments in the developing thymus. Eur J Immunol 30:3371–3379

    PubMed  CAS  Google Scholar 

  48. Gordon J, Bennett AR, Blackburn CC, Manley NR (2001) Gcm2 and Foxn1 mark early parathyroid- and thymus-specific domains in the developing third pharyngeal pouch. Mech Dev 103:141–143

    PubMed  CAS  Google Scholar 

  49. Nehls M, Pfeifer D, Schorpp M, Hedrich H, Boehm T (1994) New member of the winged-helix protein family disrupted in mouse and rat nude mutations. Nature 372:103–107

    PubMed  CAS  Google Scholar 

  50. D-m Su, Navarre S, Oh W-j, Condie BG, Manley NR (2003) A domain of Foxn1 required for crosstalk-dependent thymic epithelial cell differentiation. Nat Immunol 4:1128–1135

    Google Scholar 

  51. Balciunaite G, Keller MP, Balciunaite E, Piali L, Zuklys S, Mathieu YD, Gill J, Boyd R, Sussman DJ, Holländer GA (2002) Wnt glycoproteins regulate the expression of FoxN1, the gene defective in nude mice. Nat Immunol 3:1102–1108

    PubMed  CAS  Google Scholar 

  52. Bleul CC, Boehm T (2005) BMP signaling is required for normal thymus development. J Immunol 175:5213–5221

    PubMed  CAS  Google Scholar 

  53. Klug DB, Carter C, Gimenez-Conti IB, Richie ER (2002) Cutting edge: thymocyte-independent and thymocyte-dependent phases of epithelial patterning in the fetal thymus. J Immunol 169:2842–2845

    PubMed  CAS  Google Scholar 

  54. Ritter MA, Boyd RL (1993) Development in the thymus: it takes two to tango. Immunol Today 14:462–469

    PubMed  CAS  Google Scholar 

  55. Gill J, Malin M, Holländer GA, Boyd R (2002) Generation of a complete thymic microenvironment by MTS24(+) thymic epithelial cells. Nat Immunol 3:635–642

    PubMed  CAS  Google Scholar 

  56. Schwarz BA, Sambandam A, Maillard I, Harman BC, Love PE, Bhandoola A (2007) Selective thymus settling regulated by cytokine and chemokine receptors. J Immunol 178:2008–2017

    PubMed  CAS  Google Scholar 

  57. Rossi FMV, Corbel SY, Merzaban JS, Carlow DA, Gossens K, Duenas J, So L, Yi L, Ziltener HJ (2005) Recruitment of adult thymic progenitors is regulated by P-selectin and its ligand PSGL-1. Nat Immunol 6:626–634

    PubMed  CAS  Google Scholar 

  58. Matzinger P, Guerder S (1989) Does T-cell tolerance require a dedicated antigen-presenting cell? Nature 338:74–76

    PubMed  CAS  Google Scholar 

  59. Gallegos AM, Bevan MJ (2004) Central tolerance to tissue-specific antigens mediated by direct and indirect antigen presentation. J Exp Med 200:1039–1049

    PubMed  CAS  Google Scholar 

  60. Starr TK, Jameson SC, Hogquist KA (2003) Positive and negative selection of T cells. Annu Rev Immunol 21:139–176

    PubMed  CAS  Google Scholar 

  61. Powell JD (2006) The induction and maintenance of T cell anergy. Clin Immunol 120:239–246

    PubMed  CAS  Google Scholar 

  62. McGargill MA, Derbinski JM, Hogquist KA (2000) Receptor editing in developing T cells. Nat Immunol 1:336–341

    PubMed  CAS  Google Scholar 

  63. Baldwin TA, Hogquist KA, Jameson SC (2004) The fourth way? Harnessing aggressive tendencies in the thymus. J Immunol 173:6515–6520

    PubMed  CAS  Google Scholar 

  64. Derbinski J, Schulte A, Kyewski B, Klein L (2001) Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self. Nat Immunol 2:1032–1039

    PubMed  CAS  Google Scholar 

  65. Anderson MS, Venanzi ES, Klein L, Chen Z, Berzins SP, Turley SJ, von Boehmer H, Bronson R, Dierich A, Benoist C, Mathis D (2002) Projection of an immunological self shadow within the thymus by the aire protein. Science 298:1395–1401

    PubMed  CAS  Google Scholar 

  66. Khattri R, Cox T, Yasayko S-A, Ramsdell F (2003) An essential role for scurfin in CD4+CD25+T regulatory cells. Nat Immunol 4:337–342

    PubMed  CAS  Google Scholar 

  67. Jordan MS, Boesteanu A, Reed AJ, Petrone AL, Holenbeck AE, Lerman MA, Naji A, Caton AJ (2001) Thymic selection of CD4+CD25+ regulatory T cells induced by an agonist self-peptide. Nat Immunol 2:301–306

    PubMed  CAS  Google Scholar 

  68. Hsieh C-S, Liang Y, Tyznik AJ, Self SG, Liggitt D, Rudensky AY (2004) Recognition of the peripheral self by naturally arising CD25+CD4+ T cell receptors. Immunity 21:267–277

    PubMed  CAS  Google Scholar 

  69. Fisson S, Darrasse-Jèze G, Litvinova E, Septier F, Klatzmann D, Liblau R, Salomon BL (2003) Continuous activation of autoreactive CD4+CD25+ regulatory T cells in the steady state. J Exp Med 198:737–746

    PubMed  CAS  Google Scholar 

  70. Klein L, Khazaie K, von Boehmer H (2003) In vivo dynamics of antigen-specific regulatory T cells not predicted from behavior in vitro. Proc Natl Acad Sci U S A 100:8886–8891

    PubMed  CAS  Google Scholar 

  71. von Boehmer H (2005) Mechanisms of suppression by suppressor T cells. Nat Immunol 6:338–344

    Google Scholar 

  72. Mempel TR, Pittet MJ, Khazaie K, Weninger W, Weissleder R, von Boehmer H, von Andrian UH (2006) Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation. Immunity 25:129–141

    PubMed  CAS  Google Scholar 

  73. Apostolou I, Sarukhan A, Klein L, von Boehmer H (2002) Origin of regulatory T cells with known specificity for antigen. Nat Immunol 3:756–763

    PubMed  CAS  Google Scholar 

  74. Kretschmer K, Heng TSP, von Boehmer H (2006) De novo production of antigen-specific suppressor cells in vivo. Nat Protoc 1:653–661

    PubMed  CAS  Google Scholar 

  75. Foss DL, Donskoy E, Goldschneider I (2001) The importation of hematogenous precursors by the thymus is a gated phenomenon in normal adult mice. J Exp Med 193:365–374

    PubMed  CAS  Google Scholar 

  76. Owen RD (1945) Immunogenetic consequences of vascular anastomoses between bovine twins. Science 102:400–401

    PubMed  CAS  Google Scholar 

  77. Anderson D, Billingham RE, Lampkin GH, Medwar PB (1951) The use of skin grafting to distinguish between monozygotic and dizygotic twins in cattle. Heredity 5:379–397

    Google Scholar 

  78. Billingham RE, Brent L, Medawar PB (1953) Actively acquired tolerance of foreign cells. Nature 172:603–606

    PubMed  CAS  Google Scholar 

  79. Marrack P, Lo D, Brinster R, Palmiter R, Burkly L, Flavell RH, Kappler J (1988) The effect of thymus environment on T cell development and tolerance. Cell 53:627–634

    PubMed  CAS  Google Scholar 

  80. Sharabi Y, Sachs DH (1989) Engraftment of allogeneic bone marrow following administration of anti-T cell monoclonal antibodies and low-dose irradiation. Transplant Proc 21:233–235

    PubMed  CAS  Google Scholar 

  81. Knobler HY, Sagher U, Peled IJ, Wexler MR, Steiner D, Rubinstein N, Weshler Z, Or R, Slavin S (1985) Tolerance to donor-type skin in the recipient of a bone marrow allograft. Treatment of skin ulcers in chronic graft-versus-host disease with skin grafts from the bone marrow donor. Transplantation 40:223–225

    PubMed  CAS  Google Scholar 

  82. Sayegh MH, Fine NA, Smith JL, Rennke HG, Milford EL, Tilney NL (1991) Immunologic tolerance to renal allografts after bone marrow transplants from the same donors. Ann Intern Med 114:954–955

    PubMed  CAS  Google Scholar 

  83. Koshiba T, Li Y, Takemura M, Wu Y, Sakaguchi S, Minato N, Wood KJ, Haga H, Ueda M, Uemoto S (2007) Clinical, immunological, and pathological aspects of operational tolerance after pediatric living-donor liver transplantation. Transpl Immunol 17:94–97

    PubMed  CAS  Google Scholar 

  84. Weng L, Dyson J, Dazzi F (2007) Low-intensity transplant regimens facilitate recruitment of donor-specific regulatory T cells that promote hematopoietic engraftment. Proc Natl Acad Sci U S A 104:8415–8420

    PubMed  CAS  Google Scholar 

  85. Joffre O, Santolaria T, Calise D, Al Saati T, Hudrisier D, Romagnoli P, van Meerwijk JPM (2008) Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+regulatory T lymphocytes. Nat Med 14:88–92

    PubMed  CAS  Google Scholar 

  86. Hoffmann P, Ermann J, Edinger M, Fathman CG, Strober S (2002) Donor-type CD4(+)CD25(+) regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med 196:389–399

    PubMed  CAS  Google Scholar 

  87. Cohen JL, Trenado A, Vasey D, Klatzmann D, Salomon BL (2002) CD4(+)CD25(+) immunoregulatory T Cells: new therapeutics for graft-versus-host disease. J Exp Med 196:401–406

    PubMed  CAS  Google Scholar 

  88. Adeegbe D, Levy RB, Malek TR (2010) Allogeneic T regulatory cell-mediated transplantation tolerance in adoptive therapy depends on dominant peripheral suppression and central tolerance. Blood 115:1932–1940

    PubMed  CAS  Google Scholar 

  89. 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

    PubMed  CAS  Google Scholar 

  90. Ildstad ST, Sachs DH (1984) Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts. Nature 307:168–170

    PubMed  CAS  Google Scholar 

  91. Gruver AL, Hudson LL, Sempowski GD (2007) Immunosenescence of ageing. J Pathol 211:144–156

    PubMed  CAS  Google Scholar 

  92. Gray DHD, Seach N, Ueno T, Milton MK, Liston A, Lew AM, Goodnow CC, Boyd RL (2006) Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells. Blood 108:3777–3785

    PubMed  CAS  Google Scholar 

  93. Min H, Montecino-Rodriguez E, Dorshkind K (2004) Reduction in the developmental potential of intrathymic T cell progenitors with age. J Immunol 173:245–250

    PubMed  CAS  Google Scholar 

  94. Naylor K, Li G, Vallejo AN, Lee W-W, Koetz K, Bryl E, Witkowski J, Fulbright J, Weyand CM, Goronzy JJ (2005) The influence of age on T cell generation and TCR diversity. J Immunol 174:7446–7452

    PubMed  CAS  Google Scholar 

  95. de Mello-Coelho V, Savino W, Postel-Vinay MC, Dardenne M (1998) Role of prolactin and growth hormone on thymus physiology. Dev Immunol 6:317–323

    PubMed  Google Scholar 

  96. Andrew D, Aspinall R (2002) Age-associated thymic atrophy is linked to a decline in IL-7 production. Exp Gerontol 37:455–463

    PubMed  CAS  Google Scholar 

  97. Hince M, Sakkal S, Vlahos K, Dudakov J, Boyd R, Chidgey A (2008) The role of sex steroids and gonadectomy in the control of thymic involution. Cell Immunol 252:122–138

    PubMed  CAS  Google Scholar 

  98. Linton PJ, Dorshkind K (2004) Age-related changes in lymphocyte development and function. Nat Immunol 5:133–139

    PubMed  CAS  Google Scholar 

  99. Rossi SW, Chidgey AP, Parnell SM, Jenkinson WE, Scott HS, Boyd RL, Jenkinson EJ, Anderson G (2007) Redefining epithelial progenitor potential in the developing thymus. Eur J Immunol 37:2411–2418

    PubMed  CAS  Google Scholar 

  100. Sutherland JS, Goldberg GL, Hammett MV, Uldrich AP, Berzins SP, Heng TS, Blazar BR, Millar JL, Malin MA, Chidgey AP, Boyd RL (2005) Activation of thymic regeneration in mice and humans following androgen blockade. J Immunol 175:2741–2753

    PubMed  CAS  Google Scholar 

  101. Gill J, Malin M, Sutherland J, Gray D, Hollander G, Boyd R (2003) Thymic generation and regeneration. Immunol Rev 195:28–50

    PubMed  CAS  Google Scholar 

  102. Dudakov JA, Goldberg GL, Reiseger JJ, Vlahos K, Chidgey AP, Boyd RL (2009) Sex steroid ablation enhances hematopoietic recovery following cytotoxic antineoplastic therapy in aged mice. J Immunol 183:7084–7094

    PubMed  CAS  Google Scholar 

  103. Heng TSP, Goldberg GL, Gray DHD, Sutherland JS, Chidgey AP, Boyd RL (2005) Effects of castration on thymocyte development in two different models of thymic involution. J Immunol 175:2982–2993

    PubMed  CAS  Google Scholar 

  104. Sutherland JS, Spyroglou L, Muirhead JL, Heng TS, Prieto-Hinojosa A, Prince HM, Chidgey AP, Schwarer AP, Boyd RL (2008) 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

    PubMed  CAS  Google Scholar 

  105. Dudakov JA, Goldberg GL, Reiseger JJ, Chidgey AP, Boyd RL (2009) Withdrawal of sex steroids reverses age- and chemotherapy-related defects in bone marrow lymphopoiesis. J Immunol 182:6247–6260

    PubMed  CAS  Google Scholar 

  106. Goldberg GL, Sutherland JS, Hammet MV, Milton MK, Heng TSP, Chidgey AP, Boyd RL (2005) Sex steroid ablation enhances lymphoid recovery following autologous hematopoietic stem cell transplantation. Transplantation 80:1604–1613

    PubMed  Google Scholar 

  107. Goldberg GL, Alpdogan O, Muriglan SJ, Hammett MV, Milton MK, Eng JM, Hubbard VM, Kochman A, Willis LM, Greenberg AS, Tjoe KH, Sutherland JS, Chidgey A, van den Brink MRM, Boyd RL (2007) Enhanced immune reconstitution by sex steroid ablation following allogeneic hemopoietic stem cell transplantation. J Immunol 178:7473–7484

    PubMed  CAS  Google Scholar 

  108. Goldberg GL, Dudakov JA, Reiseger JJ, Seach N, Ueno T, Vlahos K, Hammett MV, Young LF, Heng TSP, Boyd RL, Chidgey AP (2010) Sex steroid ablation enhances immune reconstitution following cytotoxic antineoplastic therapy in young mice. J Immunol 184:6014–6024

    PubMed  CAS  Google Scholar 

  109. Erickson M, Morkowski S, Lehar S, Gillard G, Beers C, Dooley J, Rubin JS, Rudensky A, Farr AG (2002) Regulation of thymic epithelium by keratinocyte growth factor. Blood 100:3269–3278

    PubMed  CAS  Google Scholar 

  110. Alpdogan O, Hubbard VM, Smith OM, Patel N, Lu S, Goldberg GL, Gray DH, Feinman J, Kochman AA, Eng JM, Suh D, Muriglan SJ, Boyd RL, van den Brink MRM (2006) Keratinocyte growth factor (KGF) is required for postnatal thymic regeneration. Blood 107:2453–2460

    PubMed  CAS  Google Scholar 

  111. Rossi SW, Jeker LT, Ueno T, Kuse S, Keller MP, Zuklys S, Gudkov AV, Takahama Y, Krenger W, Blazar BR, Holländer GA (2007) Keratinocyte growth factor (KGF) enhances postnatal T-cell development via enhancements in proliferation and function of thymic epithelial cells. Blood 109:3803–3811

    PubMed  CAS  Google Scholar 

  112. Rossi S, Blazar BR, Farrell CL, Danilenko DM, Lacey DL, Weinberg KI, Krenger W, Holländer GA (2002) Keratinocyte growth factor preserves normal thymopoiesis and thymic microenvironment during experimental graft-versus-host disease. Blood 100:682–691

    PubMed  CAS  Google Scholar 

  113. Kelly RM, Highfill SL, Panoskaltsis-Mortari A, Taylor PA, Boyd RL, Hollander GA, Blazar BR (2008) Keratinocyte growth factor and androgen blockade work in concert to protect against conditioning regimen-induced thymic epithelial damage and enhance T-cell reconstitution after murine bone marrow transplantation. Blood 111:5734–5744

    PubMed  CAS  Google Scholar 

  114. de Mello-Coelho V, Villa-Verde DM, Dardenne M, Savino W (1997) Pituitary hormones modulate cell-cell interactions between thymocytes and thymic epithelial cells. J Neuroimmunol 76:39–49

    PubMed  Google Scholar 

  115. Youm Y-H, Yang H, Sun Y, Smith RG, Manley NR, Vandanmagsar B, Dixit VD (2009) Deficient ghrelin receptor-mediated signaling compromises thymic stromal cell microenvironment by accelerating thymic adiposity. J Biol Chem 284:7068–7077

    PubMed  CAS  Google Scholar 

  116. Dixit VD, Yang H, Sun Y, Weeraratna AT, Youm Y-H, Smith RG, Taub DD (2007) Ghrelin promotes thymopoiesis during aging. J Clin Invest 117:2778–2790

    PubMed  CAS  Google Scholar 

  117. Napolitano LA, Schmidt D, Gotway MB, Ameli N, Filbert EL, Ng MM, Clor JL, Epling L, Sinclair E, Baum PD, Li K, Killian ML, Bacchetti P, McCune JM (2008) Growth hormone enhances thymic function in HIV-1-infected adults. J Clin Invest 118:1085–1098

    PubMed  CAS  Google Scholar 

  118. Carlo-Stella C, Di Nicola M, Milani R, Longoni P, Milanesi M, Bifulco C, Stucchi C, Guidetti A, Cleris L, Formelli F, Garotta G, Gianni AM (2004) Age- and irradiation-associated loss of bone marrow hematopoietic function in mice is reversed by recombinant human growth hormone. Exp Hematol 32:171–178

    PubMed  CAS  Google Scholar 

  119. Clark R (1997) The somatogenic hormones and insulin-like growth factor-1: stimulators of lymphopoiesis and immune function. Endocr Rev 18:157–179

    PubMed  CAS  Google Scholar 

  120. Corpas E, Harman SM, Blackman MR (1993) Human growth hormone and human aging. Endocr Rev 14:20–39

    PubMed  CAS  Google Scholar 

  121. Alpdogan O, Muriglan SJ, Kappel BJ, Doubrovina E, Schmaltz C, Schiro R, Eng JM, Greenberg AS, Willis LM, Rotolo JA, O’Reilly RJ, van den Brink MRM (2003) Insulin-like growth factor-I enhances lymphoid and myeloid reconstitution after allogeneic bone marrow transplantation. Transplantation 75:1977–1983

    PubMed  CAS  Google Scholar 

  122. Mayack SR, Shadrach JL, Kim FS, Wagers AJ (2010) Systemic signals regulate ageing and rejuvenation of blood stem cell niches. Nature 463:495–500

    PubMed  CAS  Google Scholar 

  123. Sportès C, Gress RE, Mackall CL (2009) Perspective on potential clinical applications of recombinant human interleukin-7. Ann N Y Acad Sci 1182:28–38

    PubMed  Google Scholar 

  124. Alves NL, Richard-Le Goff O, Huntington ND, Sousa AP, Ribeiro VSG, Bordack A, Vives FL, Peduto L, Chidgey A, Cumano A, Boyd R, Eberl G, Di Santo JP (2009) Characterization of the thymic IL-7 niche in vivo. Proc Natl Acad Sci U S A 106:1512–1517

    PubMed  CAS  Google Scholar 

  125. Andrew D, Aspinall R (2001) Il-7 and not stem cell factor reverses both the increase in apoptosis and the decline in thymopoiesis seen in aged mice. J Immunol 166:1524–1530

    PubMed  CAS  Google Scholar 

  126. Mackall CL, Fry TJ, Bare C, Morgan P, Galbraith A, Gress RE (2001) IL-7 increases both thymic-dependent and thymic-independent T-cell regeneration after bone marrow transplantation. Blood 97:1491–1497

    PubMed  CAS  Google Scholar 

  127. Alpdogan O, Muriglan SJ, Eng JM, Willis LM, Greenberg AS, Kappel BJ, van den Brink MRM (2003) IL-7 enhances peripheral T cell reconstitution after allogeneic hematopoietic stem cell transplantation. J Clin Invest 112:1095–1107

    PubMed  CAS  Google Scholar 

  128. Sportès C, Hakim FT, Memon SA, Zhang H, Chua KS, Brown MR, Fleisher TA, Krumlauf MC, Babb RR, Chow CK, Fry TJ, Engels J, Buffet R, Morre M, Amato RJ, Venzon DJ, Korngold R, Pecora A, Gress RE, Mackall CL (2008) Administration of rhIL-7 in humans increases in vivo TCR repertoire diversity by preferential expansion of naïve T cell subsets. J Exp Med 205:1701–1714

    PubMed  Google Scholar 

  129. Wils E-J, Braakman E, Verjans GMGM, Rombouts EJC, Broers AEC, Niesters HGM, Wagemaker G, Staal FJT, Löwenberg B, Spits H, Cornelissen JJ (2007) Flt3 ligand expands lymphoid progenitors prior to recovery of thymopoiesis and accelerates T cell reconstitution after bone marrow transplantation. J Immunol 178:3551–3557

    PubMed  CAS  Google Scholar 

  130. Kenins L, Gill JW, Holländer GA, Wodnar-Filipowicz A (2010) Flt3 ligand-receptor interaction is important for maintenance of early thymic progenitor numbers in steady-state thymopoiesis. Eur J Immunol 40:81–90

    PubMed  CAS  Google Scholar 

  131. Kenins L, Gill JW, Boyd RL, Holländer GA, Wodnar-Filipowicz A (2008) Intrathymic expression of Flt3 ligand enhances thymic recovery after irradiation. J Exp Med 205:523–531

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Monash Immunology and Stem Cell Laboratories (MISCL), Monash University, Strip-1, Building 75, Clayton, Victoria, 3800, Australia

    Jessica Morison, Tracy Heng, Ann Chidgey & Richard Boyd

Authors
  1. Jessica Morison
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tracy Heng
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ann Chidgey
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Richard Boyd
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Richard Boyd .

Editor information

Editors and Affiliations

  1. Carlton Rd. 30, Oxford, OX2 7SB, United Kingdom

    Paul J. Fairchild

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media New York

About this chapter

Cite this chapter

Morison, J., Heng, T., Chidgey, A., Boyd, R. (2013). The Immunogenicity of Stem Cells and Thymus-Based Strategies to Minimise Immune Rejection. 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_11

Download citation

Publish with us

Policies and ethics

Search

Navigation