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Regulatory T cells in graft-versus-host disease

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Abstract

Alloreactive T cells present in a bone marrow transplant are responsible for graft-vs-host disease, but their depletion is associated with impaired engraftment, immunosuppression, and loss of the graft-vs-leukemia effect. The subpopulation of CD4+CD25+ immunoregulatory T cells was first identified based on its crucial role in the control of autoimmune processes, but they also play a role in alloreactive responses. Moreover, these cells could be used to develop innovative strategies in the field of transplantation and particularly to prevent graft-vs-host disease. Indeed, high numbers of CD4+CD25+ immunoregulatory T cells can modulate graft-vs-host disease if administered at the same time as allogeneic hematopoietic stem cell transplantation in mice. This review discusses various important issues regarding the possible use of CD4+CD25+ immunoregulatory T cells to modulate alloreactivity in hematopoietic stem cell transplantation.

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References

  1. Thomas ED, Storb R, Clift RA, Fefer A, Johnson L, Neiman PE, Lerner KG, Glucksberg H, Buckner CD (1975) Bone-marrow transplantation (second of two parts). N Engl J Med 292:895–902

    Article  PubMed  CAS  Google Scholar 

  2. Thomas E, Storb R, Clift RA, Fefer A, Johnson FL, Neiman PE, Lerner KG, Glucksberg H, Buckner CD (1975) Bone-marrow transplantation (first of two parts). N Engl J Med 292:832–843

    Article  PubMed  CAS  Google Scholar 

  3. Sprent J, Schaefer M, Lo D, Korngold R (1986) Properties of purified T cell subsets. II. In vivo responses to class I vs. class II H-2 differences. J Exp Med 163:998–1011

    Article  PubMed  CAS  Google Scholar 

  4. Ferrara JL, Levy R, Chao NJ (1999) Pathophysiologic mechanisms of acute graft-vs.-host disease. Biol Blood Marrow Transplant 5:347–356

    Article  PubMed  CAS  Google Scholar 

  5. Krenger W, Hill GR, Ferrara JL (1997) Cytokine cascades in acute graft-versus-host disease. Transplantation 64:553–558

    Article  PubMed  CAS  Google Scholar 

  6. Gould DS, Auchincloss H Jr (1999) Direct and indirect recognition: the role of MHC antigens in graft rejection. Immunol Today 20:77–82

    Article  PubMed  CAS  Google Scholar 

  7. Shlomchik WD, Couzens MS, Tang CB, McNiff J, Robert ME, Liu J, Shlomchik MJ, Emerson SG (1999) Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science 285:412–415

    Article  PubMed  CAS  Google Scholar 

  8. Teshima T, Ordemann R, Reddy P, Gagin S, Liu C, Cooke KR, Ferrara JL (2002) Acute graft-versus-host disease does not require alloantigen expression on host epithelium. Nat Med 8:575–581

    Article  PubMed  CAS  Google Scholar 

  9. Murai M, Yoneyama H, Ezaki T, Suematsu M, Terashima Y, Harada A, Hamada H, Asakura H, Ishikawa H, Matsushima K (2003) Peyer’s patch is the essential site in initiating murine acute and lethal graft-versus-host reaction. Nat Immunol 4:154–160

    Article  PubMed  CAS  Google Scholar 

  10. Merad M, Hoffmann P, Ranheim E, Slaymaker S, Manz MG, Lira SA, Charo I, Cook DN, Weissman IL, Strober S, Engleman EG (2004) Depletion of host Langerhans cells before transplantation of donor alloreactive T cells prevents skin graft-versus-host disease. Nat Med 10:510–517

    Article  PubMed  CAS  Google Scholar 

  11. Zhang Y, Louboutin JP, Zhu J, Rivera AJ, Emerson SG (2002) Preterminal host dendritic cells in irradiated mice prime CD8+T cell-mediated acute graft-versus-host disease. J Clin Invest 109:1335–1344

    PubMed  CAS  Google Scholar 

  12. Matte CC, Liu J, Cormier J, Anderson BE, Athanasiadis I, Jain D, McNiff J, Shlomchik WD (2004) Donor APCs are required for maximal GVHD but not for GVL. Nat Med 10:987–992

    Article  PubMed  CAS  Google Scholar 

  13. Anderson BE, McNiff JM, Jain D, Blazar BR, Shlomchik WD, Shlomchik MJ (2005) Distinct roles for donor- and host-derived antigen-presenting cells and costimulatory molecules in murine chronic graft-versus-host disease: requirements depend on target organ. Blood 105:2227–2234

    Article  PubMed  CAS  Google Scholar 

  14. Martin PJ, Hansen JA, Buckner CD, Sanders JE, Deeg HJ, Stewart P, Appelbaum FR, Clift R, Fefer A, Witherspoon RP et al (1985) Effects of in vitro depletion of T cells in HLA-identical allogeneic marrow grafts. Blood 66:664–672

    PubMed  CAS  Google Scholar 

  15. Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ, Rimm AA, Ringden O, Rozman C, Truitt RL, Zwaan FE, Bortin MM (1990) Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75:555–562

    PubMed  CAS  Google Scholar 

  16. Storb R, Deeg HJ, Pepe M, Appelbaum F, Anasetti C, Beatty P, Bensinger W, Berenson R, Buckner CD, Clift R et al (1989) Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: long-term follow-up of a controlled trial. Blood 73:1729–1734

    PubMed  CAS  Google Scholar 

  17. Kernan NA, Bartsch G, Ash RC, Beatty PG, Champlin R, Filipovich A, Gajewski J, Hansen JA, Henslee-Downey J, McCullough J et al (1993) Analysis of 462 transplantations from unrelated donors facilitated by the National Marrow Donor Program. N Engl J Med 328:593–602

    Article  PubMed  CAS  Google Scholar 

  18. Bacigalupo A, Van Lint MT, Occhini D, Gualandi F, Lamparelli T, Sogno G, Tedone E, Frassoni F, Tong J, Marmont AM (1991) Increased risk of leukemia relapse with high-dose cyclosporine A after allogeneic marrow transplantation for acute leukemia. Blood 77:1423–1428

    PubMed  CAS  Google Scholar 

  19. Blaise D, Olive D, Michallet M, Marit G, Leblond V, Maraninchi D (1995) Impairment of leukaemia-free survival by addition of interleukin-2-receptor antibody to standard graft-versus-host prophylaxis. Lancet 345:1144–1146

    Article  PubMed  CAS  Google Scholar 

  20. Ash RC, Casper JT, Chitambar CR, Hansen R, Bunin N, Truitt RL, Lawton C, Murray K, Hunter J, Baxter-Lowe LA et al (1990) Successful allogeneic transplantation of T-cell-depleted bone marrow from closely HLA-matched unrelated donors. N Engl J Med 322:485–494

    Article  PubMed  CAS  Google Scholar 

  21. Goldman JM, Gale RP, Horowitz MM, Biggs JC, Champlin RE, Gluckman E, Hoffmann RG, Jacobsen SJ, Marmont AM, McGlave PB et al (1988) Bone marrow transplantation for chronic myelogenous leukemia in chronic phase. Increased risk for relapse associated with T-cell depletion. Ann Intern Med 108:806–814

    PubMed  CAS  Google Scholar 

  22. Kolb HJ, Mittermuller J, Clemm C, Holler E, Ledderose G, Brehm G, Heim M, Wilmanns W (1990) Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 76:2462–2465

    PubMed  CAS  Google Scholar 

  23. Sakaguchi S, Sakaguchi N, Asano M, Itoh M, Toda M (1995) Immunologic self-tolerance maintained by activated T cells expressing IL-2 receptor alpha-chains (CD25). Breakdown of a single mechanism of self-tolerance causes various autoimmune diseases. J Immunol 155:1151–1164

    PubMed  CAS  Google Scholar 

  24. Aluvihare VR, Kallikourdis M, Betz AG (2004) Regulatory T cells mediate maternal tolerance to the fetus. Nat Immunol 5:266–271

    Article  PubMed  CAS  Google Scholar 

  25. Darrasse-Jeze G, Klatzmann D, Charlotte F, Salomon BL, Cohen JL (2006) CD4+CD25+ regulatory/suppressor T cells prevent allogeneic fetus rejection in mice. Immunol Lett 102:106–109

    Article  PubMed  CAS  Google Scholar 

  26. Graca L, Thompson S, Lin CY, Adams E, Cobbold SP, Waldmann H (2002) Both CD4(+)CD25(+) and CD4(+)CD25(−) regulatory cells mediate dominant transplantation tolerance. J Immunol 168:5558–5565

    PubMed  CAS  Google Scholar 

  27. Graca L, Cobbold SP, Waldmann H (2002) Identification of regulatory T cells in tolerated allografts. J Exp Med 195:1641–1646

    Article  PubMed  CAS  Google Scholar 

  28. Gregori S, Casorati M, Amuchastegui S, Smiroldo S, Davalli AM, Adorini L (2001) Regulatory t cells induced by 1alpha,25-dihydroxyvitamin d(3) and mycophenolate mofetil treatment mediate transplantation tolerance. J Immunol 167:1945–1953

    PubMed  CAS  Google Scholar 

  29. Hara M, Kingsley CI, Niimi M, Read S, Turvey SE, Bushell AR, Morris PJ, Powrie F, Wood KJ (2001) IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo. J Immunol 166:3789–3796

    PubMed  CAS  Google Scholar 

  30. Chiffoleau E, Beriou G, Dutartre P, Usal C, Soulillou JP, Cuturi MC (2002) Role for thymic and splenic regulatory CD4+ T cells induced by donor dendritic cells in allograft tolerance by LF15-0195 treatment. J Immunol 168:5058–5069

    PubMed  CAS  Google Scholar 

  31. Joffre O, Gorsse N, Romagnoli P, Hudrisier D, van Meerwijk JP (2004) Induction of antigen-specific tolerance to bone marrow allografts with CD4+CD25+ T lymphocytes. Blood 103:4216–4221

    Article  PubMed  CAS  Google Scholar 

  32. Hanash AM, Levy RB (2005) Donor CD4+CD25+ T cells promote engraftment and tolerance following MHC-mismatched hematopoietic cell transplantation. Blood 105:1828–1836

    Article  PubMed  CAS  Google Scholar 

  33. Steiner D, Brunicki N, Blazar BR, Bachar-Lustig E, Reisner Y (2006) Tolerance induction by third-party “off-the-shelf” CD4+CD25+ Treg cells. Exp Hematol 34:66–71

    Article  PubMed  CAS  Google Scholar 

  34. Taylor PA, Lees CJ, Blazar BR (2002) The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood 99:3493–3499

    Article  PubMed  CAS  Google Scholar 

  35. 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

    Article  PubMed  CAS  Google Scholar 

  36. 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

    Article  PubMed  CAS  Google Scholar 

  37. Valzasina B, Guiducci C, Dislich H, Killeen N, Weinberg AD, Colombo MP (2005) Triggering of OX40 (CD134) on CD4(+)CD25+ T cells blocks their inhibitory activity: a novel regulatory role for OX40 and its comparison with GITR. Blood 105:2845–2851

    Article  PubMed  CAS  Google Scholar 

  38. Ermann J, Hoffmann P, Edinger M, Dutt S, Blankenberg FG, Higgins JP, Negrin RS, Fathman CG, Strober S (2005) Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD. Blood 105:2220–2226

    Article  PubMed  CAS  Google Scholar 

  39. Jones SC, Murphy GF, Korngold R (2003) Post-hematopoietic cell transplantation control of graft-versus-host disease by donor CD425 T cells to allow an effective graft-versus-leukemia response. Biol Blood Marrow Transplant 9:243–256

    Article  PubMed  Google Scholar 

  40. Edinger M, Hoffmann P, Ermann J, Drago K, Fathman CG, Strober S, Negrin RS (2003) CD4+CD25+ regulatory T cells preserve graft-versus-tumor activity while inhibiting graft-versus-host disease after bone marrow transplantation. Nat Med 9:1144–1150

    Article  PubMed  CAS  Google Scholar 

  41. Viglietta V, Baecher-Allan C, Weiner HL, Hafler DA (2004) Loss of functional suppression by CD4+CD25+ regulatory T cells in patients with multiple sclerosis. J Exp Med 199:971–979

    Article  PubMed  CAS  Google Scholar 

  42. Xia G, Kovochich M, Truitt RL, Johnson BD (2004) Tracking ex vivo-expanded CD4+CD25+ and CD8+CD25+ regulatory T cells after infusion to prevent donor lymphocyte infusion-induced lethal acute graft-versus-host disease. Biol Blood Marrow Transplant 10:748–760

    Article  PubMed  Google Scholar 

  43. Tang Q, Henriksen KJ, Bi M, Finger EB, Szot G, Ye J, Masteller EL, McDevitt H, Bonyhadi M, Bluestone JA (2004) In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med 199:1455–1465

    Article  PubMed  CAS  Google Scholar 

  44. Taylor PA, Panoskaltsis-Mortari A, Swedin JM, Lucas PJ, Gress RE, Levine BL, June CH, Serody JS, Blazar BR (2004) L-Selectin(hi) but not the L-selectin(lo) CD4+25+ T-regulatory cells are potent inhibitors of GVHD and BM graft rejection. Blood 104:3804–3812

    Article  PubMed  CAS  Google Scholar 

  45. Godfrey WR, Ge YG, Spoden DJ, Levine BL, June CH, Blazar BR, Porter SB (2004) In vitro-expanded human CD4(+)CD25(+) T-regulatory cells can markedly inhibit allogeneic dendritic cell-stimulated MLR cultures. Blood 104:453–461

    Article  PubMed  CAS  Google Scholar 

  46. Trenado A, Sudres M, Tang Q, Maury S, Charlotte F, Gregoire S, Bonyhadi M, Klatzmann D, Salomon BL, Cohen JL (2006) Ex vivo-expanded CD4+CD25+ immunoregulatory T cells prevent graft-versus-host-disease by inhibiting activation/differentiation of pathogenic T cells. J Immunol 176:1266–1273

    PubMed  CAS  Google Scholar 

  47. Trenado A, Charlotte F, Fisson S, Yagello M, Klatzmann D, Salomon BL, Cohen JL (2003) Recipient-type specific CD4+CD25+ regulatory T cells favor immune reconstitution and control graft-versus-host disease while maintaining graft-versus-leukemia. J Clin Invest 112:1688–1696

    PubMed  CAS  Google Scholar 

  48. Takahashi T, Kuniyasu Y, Toda M, Sakaguchi N, Itoh M, Iwata M, Shimizu J, Sakaguchi S (1998) Immunologic self-tolerance maintained by CD25+CD4+ naturally anergic and suppressive T cells: induction of autoimmune disease by breaking their anergic/suppressive state. Int Immunol 10:1969–1980

    Article  PubMed  CAS  Google Scholar 

  49. Thornton AM, Shevach EM (2000) Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol 164:183–190

    PubMed  CAS  Google Scholar 

  50. Shevach EM, McHugh RS, Piccirillo CA, Thornton AM (2001) Control of T-cell activation by CD4+ CD25+ suppressor T cells. Immunol Rev 182:58–67

    Article  PubMed  CAS  Google Scholar 

  51. Piccirillo CA, Shevach EM (2001) Cutting edge: control of CD8+ T cell activation by CD4+CD25+ immunoregulatory cells. J Immunol 167:1137–1140

    PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Biologie et Thérapeutique des Pathologies Immunitaires, Université Pierre et Marie Curie/Centre National de la Recherche Scientifique UMR 7087, Paris, France

    Benoît L. Salomon, Muriel Sudres & José L. Cohen

  2. CNRS/UPMC UMR 7087, Hôpital Pitié-Salpêtrière, 83, bd. de l’Hôpital, F-75651, Paris, Cedex 13, France

    Benoît L. Salomon

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  1. Benoît L. Salomon
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  2. Muriel Sudres
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  3. José L. Cohen
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Correspondence to Benoît L. Salomon.

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Salomon, B.L., Sudres, M. & Cohen, J.L. Regulatory T cells in graft-versus-host disease. Springer Semin Immun 28, 25–29 (2006). https://doi.org/10.1007/s00281-006-0020-9

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