Abstract
Allogeneic hematopoietic stem cell transplantation (SCT) is a well-established treatment modality for malignant and nonmalignant hematologic diseases. High-dose radio-and/or chemotherapy eradicate the hematopoietic system of the patient and induce sufficient immunosuppression to enable donor stem cell engraftment. The replacement of the recipient’s immune system with that of the donor significantly contributes to the success of this treatment, since donor immune cells facilitate stem cell engraftment, provide protection from infections, and eliminate residual malignant or nonmalignant host hematopoiesis, thereby protecting from disease relapse in patients transplanted for leukemia or lymphoma (graft-versus-leukemia effect, GVL). Mediators of these beneficial effects are mature T cells within the stem cell graft. However, donor T cells can also attack host tissues and induce a life-threatening syndrome called graft-versus-host disease (GVHD). The challenge of allogeneic SCT is to find a balance between beneficial and harmful T cell effects, which at present is only insufficiently achieved by the use of immunosuppressive drugs. In the future, it might be possible to replace or support such medications by using the intrinsic regulatory capacity of the transplanted immune system, as represented by T cell subpopulations with suppressive activity, such as CD4+CD25+ regulatory T (Treg) cells. In various mouse model systems, these cells have been shown to suppress GVHD while preserving the GVL effect. As the characterization of their human counterparts is rapidly progressing, their application in allogeneic SCT might soon be explored in clinical trials.
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References
Almeida AR, Legrand N et al (2002) Homeostasis of peripheral CD4+ T cells: IL-2R alpha and IL-2 shape a population of regulatory cells that controls CD4+ T cell numbers. J Immunol 169:4850–60
Amrolia PJ, Muccioli-Casadei G et al (2003a) Selective depletion of donor alloreactive T cells without loss of antiviral or antileukemic responses. Blood 102:2292–2299
Amrolia PJ, Reid SD et al (2003b) Allorestricted cytotoxic T cells specific for human CD45 show potent antileukemic activity. Blood 101:1007–1014
Anderson BE, McNiff J et al (2003) Memory CD4+ T cells do not induce graft-versus-host disease. J Clin Invest 112:101–108
Annacker O, Pimenta-Araujo R et al (2001) CD25+ CD4+ T cells regulate the expansion of peripheral CD4 T cells through the production of IL-10. J Immunol 166:3008–3018
Bachar-Lustig E, Reich-Zeliger S et al (2003) Anti-third-party veto CTLs overcome rejection of hematopoietic allografts: synergism with rapamycin and BM cell dose. Blood 102:1943–1950
Bader P, Kreyenberg H et al (2004) Increasing mixed chimerism is an important prognostic factor for unfavorable outcome in children with acute lymphoblastic leukemia after allogeneic stem-cell transplantation: possible role for pre-emptive immunotherapy? J Clin Oncol 22:1696–1705
Baecher-Allan C, Viglietta V et al (2004) Human CD4+CD25+ regulatory T cells. Semin Immunol 16:89–98
Belkaid Y, Piccirillo CA et al (2002) CD4+CD25+ regulatory T cells control Leishmania major persistence and immunity. Nature 420(6915):502–507
Blazar BR, Taylor PA et al (1997) Blockade of CD40 ligand-CD40 interaction impairs CD4+ T cell-mediated alloreactivity by inhibiting mature donor T cell expansion and function after bone marrow transplantation. J Immunol 158:29–39
Cederbom L, Hall H et al (2000) CD4+CD25+ regulatory T cells down-regulate costimulatory molecules on antigen-presenting cells. Eur J Immunol 30:1538–1543
Champlin RE, Passweg JR et al (2000) T-cell depletion of bone marrow transplants for leukemia from donors other than HLA-identical siblings: advantage of T-cell antibodies with narrow specificities. Blood 95:3996–4003
Chen BJ, Cui X et al (2002) Prevention of graft-versus-host disease while preserving graft-versus-leukemia effect after selective depletion of host-reactive T cells by photodynamic cell purging process. Blood 99:3083–3088
Chen BJ, Cui X et al (2004) Transfer of allogeneic CD62L-memory T cells without graft-versus-host disease. Blood 103:1534–1541
Cobbold SP, Graca L et al (2003) Regulatory T cells in the induction and maintenance of peripheral transplantation tolerance. Transpl Int 16:66–75
Cohen JL, Trenado A et al (2002) CD4(+)CD25(+) immunoregulatory T Cells: new therapeutics for graft-versus-host disease. J Exp Med 196:401–406
Daniel C, Horvath S et al (1998) Abasis for alloreactivity: MHC helical residues broaden peptide recognition by the TCR Immunity 8:543–552
Dazzi F, Szydlo RM et al (2000) Comparison of single-dose and escalating-dose regimens of donor lymphocyte infusion for relapse after allografting for chronic myeloid leukemia. Blood 95:67–71
Dickinson AM, Wang XN et al (2002) In situ dissection of the graft-versus-host activities of cytotoxic T cells specific for minor histocompatibility antigens. Nat Med 8:410–414
Dieckmann D, Plottner H et al (2001) Ex vivo isolation and characterization of CD4(+)CD25(+) T cells with regulatory properties from human blood. J Exp Med 193:1303–1310
Edinger M, Cao YA et al (2003a) Revealing lymphoma growth and the efficacy of immune cell therapies using in vivo bioluminescence imaging. Blood 101:640–648
Edinger M, Hoffmann P et al (2003b) 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
Ermann J, Hoffmann P et al. (2005) Only the CD62L+ subpopulation of CD4+CD25+ regulatory T cells protects from lethal acute GVHD. Blood 105:2220–2226
Ermann J, Szanya V et al (2001) CD4(+)CD25(+) T cells facilitate the induction of T cell anergy. J Immunol 167:4271–4275
Falkenburg JH, van de Corput L et al (2003) Minor histocompatibility antigens in human stem cell transplantation. Exp Hematol 31:743–751
Ferrara JL (2000) Pathogenesis of acute graft-versus-host disease: cytokines and cellular effectors. J Hematother Stem Cell Res 9:299–306
Ferrara JL, Levy R et al (1999) Pathophysiologic mechanisms of acute graft-vs.-host disease. Biol Blood Marrow Transplant 5:347–356
Fisson S, Darrasse-Jeze G et al (2003) Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state. J Exp Med 198:737–746
Gavin MA, Clarke SR et al (2002) Homeostasis and anergy of CD4+CD25+ suppressor T cells in vivo. Nat Immunol 3:33–41
Godfrey WR, Ge YG et al (2004) In vitro-expanded human CD4(+)CD25(+) T-regulatory cells can markedly inhibit allogeneic dendritic cell-stimulated MLR cultures. Blood 104:453–461
Goulmy E (1997) Human minor histocompatibility antigens: new concepts for marrow transplantation and adoptive immunotherapy. Immunol Rev 157:125–140
Graca L, Cobbold SP et al (2002) Identification of regulatory T cells in tolerated allografts. J Exp Med 195:1641–1646
Gratwohl A, Brand R et al (2002) Graft-versus-host disease and outcome in HLA-identical sibling transplantations for chronic myeloid leukemia. Blood 100:3877–3886
Green EA, Choi Y et al (2002) Pancreatic lymph node-derived CD4(+)CD25(+) Treg cells: highly potent regulators of diabetes that require TRANCE-RANK signals. Immunity 16:183–191
Guglielmi C, Arcese W et al (2002) Donor lymphocyte infusion for relapsed chronic myelogenous leukemia: prognostic relevance of the initial cell dose. Blood 100:397–405
Guinan EC, Boussiotis VA et al (1999) Transplantation of anergic histoincompatible bone marrow allografts. N Engl J Med 340:1704–1714
Hanash AM, Levy RB (2003) Donor CD4+CD25+ T cells facilitate hematopoietic engraftment independent of host resistance and allo-antigen recognition (abstract) Blood 102:38a
Heemskerk MH, Hoogeboom M et al (2003) Redirection of antileukemic reactivity of peripheral T lymphocytes using gene transfer of minor histocompatibility antigen HA-2-specific T-cell receptor complexes expressing a conserved alpha joining region. Blood 102:3530–3540
Hertenstein B, Hampl W et al (1995) In vivo/ex vivo T cell depletion for GVHD prophylaxis influences onset and course of active cytomegalovirus infection and disease after BMT. Bone Marrow Transplant 15:387–393
Heslop HE, Brenner MK et al (1994) Administration of neomycin-resistance-gene-marked EBV-specific cytotoxic T lymphocytes to recipients of mismatched-related or phenotypically similar unrelated donor marrow grafts. Hum Gene Ther 5:381–397
Ho VT, Soiffer RJ (2001) The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation. Blood 98:3192–204
Hoffmann P, Eder R et al (2004) Large-scale in vitro expansion of polyclonal human CD4(+)CD25high regulatory T cells. Blood 104:895–903
Hoffmann P, Edinger M et al (2002b) CD4+CD25+ regulatory T cells act in secondary lymphoid organs to protect from lethal acute GVHD (abstract) Blood 100:143a
Hoffmann P, Ermann J et al (2002a) 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
Huehn J, Siegmund K et al (2004) Developmental stage phenotype, and migration distinguish naive-and effector/memory-like CD4+ regulatory T cells. J Exp Med 199:303–313
Iellem A, Mariani M et al (2001) Unique chemotactic response profile and specific expression of chemokine receptors CCR4 and CCR8 by CD4(+)CD25(+) regulatory T cells. J Exp Med 194:847–853
Ildstad ST, Sachs DH (1984) Reconstitution with syngeneic plus allogeneic or xenogeneic bone marrow leads to specific acceptance of allografts or xenografts. Nature 307(5947):168–170
Jiang S, Camara N et al (2003) Induction of allopeptide-specific human CD4+CD25+ regulatory T cells ex vivo. Blood 102:2180–2186
Joffre O, Gorsse N et al (2004) Induction of antigen-specific tolerance to bone marrow allografts with CD4+CD25+ T lymphocytes. Blood 103:4216–4221
Johnson BD, Becker EE et al (1999) Role of immunoregulatory donor T cells in suppression of graft-versus-host disease following donor leukocyte infusion therapy. J Immunol 163:6479–6487
Johnson BD, Konkol MC et al (2002) CD25+ immunoregulatory T-cells of donor origin suppress alloreactivity after BMT. Biol Blood Marrow Transplant 8:525–535
Jones SC, Murphy GF et al (2003) Post-hematopoietic cell transplantation control of graft-versus-host disease by donor CD4(+)25(+) T cells to allow an effective graft-versus-leukemia response. Biol Blood Marrow Transplant 9:243–256
Jonuleit H, Schmitt E et al (2000) Induction of interleukin 10-producing, nonproliferating CD4(+) T cells with regulatory properties by repetitive stimulation with allogeneic immature human dendritic cells. J Exp Med 192:1213–1222
Jonuleit H, Schmitt E et al (2001) Identification and functional characterization of human CD4(+)CD25(+) T cells with regulatory properties isolated from peripheral blood. J Exp Med 193:1285–1294
Klein L, Khazaie K et al (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
Kolb HJ, Mittermuller J et al (1990) Donor leukocyte transfusions for treatment of recurrent chronic myelogenous leukemia in marrow transplant patients. Blood 76:2462–2465
Kubsch S, Graulich E et al (2003) Suppressor activity of anergic T cells induced by IL-10-treated human dendritic cells: association with IL-2-and CTLA-4-dependent G1 arrest of the cell cycle regulated by p27Kip1. Eur J Immunol 33:1988–1997
Lechler RI, Garden OA et al (2003) The complementary roles of deletion and regulation in transplantation tolerance. Nat Rev Immunol 3:147–158
Lehmann J, Huehn J et al (2002) Expression of the integrin alpha Ebeta 7 identifies unique subsets of CD25+ as well as CD25− regulatory T cells. Proc Natl Acad Sci U S A 99:13031–13036
Levings MK, Sangregorio R et al (2001) Human CD25(+)CD4(+) t regulatory cells suppress naive and memory T cell proliferation and can be expanded in vitro without loss of function. J Exp Med 193:1295–1302
Li B, New JY et al (2004) Delaying acute graft-versus-host disease in mouse bone marrow transplantation by treating donor cells with antibodies directed at L-selectin and alpha4-integrin prior to infusion. Scand J Immunol 59:464–468
Li B, New JY et al (2001) Blocking L-selectin and alpha4-integrin changes donor cell homing pattern and ameliorates murine acute graft versus host disease. Eur J Immunol 31:617–624
Li XC, Strom TB et al (2001) T cell death and transplantation tolerance. Immunity 14:407–416
Malek TR, Yu A et al (2002) CD4 regulatory T cells prevent lethal autoimmunity in IL-2Rbeta-deficient mice. Implications for the nonredundant function of IL-2. Immunity 17:167–178
Merad M, Hoffmann P et al (2004) Depletion of host Langerhans cells before transplantation of donor alloreactive T cells prevents skin graft-versus-host disease. Nat Med 10:510–517
Michalek J, Collins RH et al (2003) Clinical-scale selective depletion of alloreactive T cells using an anti-CD25 immunotoxin. Neoplasma 50:296–299
Misra N, Bayry J et al (2004) Cutting edge: human CD4+CD25+ T cells restrain the maturation and antigen-presenting function of dendritic cells. J Immunol 172:4676–4680
Miura Y, Thoburn CJ et al (2004) Association of Foxp3 regulatory gene expression with graft-versus-host disease. Blood 104:2187–2193
Molldrem JJ, Lee PP et al (2000) Evidence that specific T lymphocytes may participate in the elimination of chronic myelogenous leukemia. Nat Med 6:1018–1023
Moore KW, de Waal Malefyt R et al (2001) Interleukin-10 and the interleukin-10 receptor. Annu Rev Immunol 19:683–765
Mottet C, Uhlig HH et al (2003) Cutting edge: cure of colitis by CD4+CD25+ regulatory T cells. J Immunol 170:3939–3943
Murai M, Yoneyama H et al (2003) Peyer’s patch is the essential site in initiating murine acute and lethal graft-versus-host reaction. Nat Immunol 4:154–160
Obst R, Netuschil N et al (2000) The role of peptides in T cell alloreactivity is determined by self-major histocompatibility complex molecules. J Exp Med 191:805–812
Orsini E, Alyea EP et al (2000) Conversion to full donor chimerism following donor lymphocyte infusion is associated with disease response in patients with multiple myeloma. Biol Blood Marrow Transplant 6:375–386
Patterson J, Prentice HG et al (1986) Graft rejection following HLA matched Tlymphocyte depleted bone marrow transplantation. Br J Haematol 63:221–230
Piccirillo CA, Shevach EM (2004) Naturally-occurring CD4+CD25+ immunoregulatory T cells: central players in the arena of peripheral tolerance. Semin Immunol 16:81–88
Porter DL, Collins RH Jr et al (1999) Long-term follow-up of patients who achieved complete remission after donor leukocyte infusions. Biol Blood Marrow Transplant 5:253–261
Rauser G, Einsele H et al (2004) Rapid generation of combined CMV-specific CD4+ and CD8+ T-cell lines for adoptive transfer into recipients of allogeneic stem cell transplants. Blood 103:3565–3572
Read S, Malmstrom V et al (2000) Cytotoxic T lymphocyte-associated antigen 4 plays an essential role in the function of CD25(+)CD4(+) regulatory cells that control intestinal inflammation. J Exp Med 192:295–302
Riddell SR, Murata M et al (2002) Minor histocompatibility antigens—targets of graft versus leukemia responses. Int J Hematol 76Suppl 2:155–161
Rocha B, von Boehmer H (1991) Peripheral selection of the T cell repertoire. Science 251:1225–1228
Roncarolo MG, Bacchetta R et al (2001) Type 1 T regulatory cells. Immunol Rev 182:68–79
Sakaguchi S (2000) Regulatory T cells: key controllers of immunologic self-tolerance. Cell 101:455–458
Sakaguchi S (2004) Naturally arising CD4+ regulatory T cells for immunologic self-tolerance and negative control of immune responses. Annu Rev Immunol 22:531–562
Salaun J, Bandeira A et al (1990) Thymic epithelium tolerizes for histocompatibility antigens. Science 247:1471–1474
Salomon B, Lenschow DJ et al (2000) B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 12:431–440
Savage P, Gao L et al (2004) Use of B cell-bound HLA-A2 class I monomers to generate high-avidity, allo-restricted CTLs against the leukemia-associated protein Wilms tumor antigen. Blood 103:4613–4615
Sebastiani S, Allavena P et al (2001) Chemokine receptor expression and function in CD4+ T lymphocytes with regulatory activity. J Immunol 166:996–1002
Serrano J, Roman J et al (2000) Molecular analysis of lineage-specific chimerism and minimal residual disease by RT-PCR of p210(BCR-ABL) and p190(BCR-ABL) after allogeneic bone marrow transplantation for chronic myeloid leukemia: increasing mixed myeloid chimerism and p190(BCR-ABL) detection precede cytogenetic relapse. Blood 95:2659–2665
Shlomchik WD, Couzens MS et al (1999) Prevention of graft versus host disease by inactivation of host antigen-presenting cells. Science 285:412–415
Sprent J, Kishimoto H (2001) The thymus and central tolerance. Philos Trans R Soc Lond B Biol Sci 356:609–616
Sprent J, Schaefer M et al (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
Sprent J, Webb SR (1995) Intrathymic and extrathymic clonal deletion of T cells. Curr Opin Immunol 7:196–205
Steinbrink K, Wolfl M et al (1997) Induction of tolerance by IL-10-treated dendritic cells. J Immunol 159:4772–4780
Suchin EJ, Langmuir PB et al (2001) Quantifying the frequency of alloreactive T cells in vivo: new answers to an old question. J Immunol 166:973–981
Suri-Payer E, Cantor H (2001) Differential cytokine requirements for regulation of autoimmune gastritis and colitis by CD4(+)CD25(+) T cells. J Autoimmun 16:115–123
Sykes M, Sachs DH (2001) Mixed chimerism. Philos Trans R Soc Lond B Biol Sci 356:707–726
Szanya V, Ermann J et al (2002) The subpopulation of CD4+CD25+ splenocytes that delays adoptive transfer of diabetes expresses L-selectin and high levels of CCR7. J Immunol 169:2461–2465
Takahashi T, Kuniyasu Y et al (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
Tan P, Anasetti C et al (1993) Induction of alloantigen-specific hyporesponsiveness in human T lymphocytes by blocking interaction of CD28 with its natural ligand B7/BB1. J Exp Med 177:165–173
Taylor PA, Friedman TM et al (2002a) Tolerance induction of alloreactive T cells via ex vivo blockade of the CD40:CD40L costimulatory pathway results in the generation of a potent immune regulatory cell. Blood 99:4601–4609
Taylor PA, Lees CJ et al (2002b) The infusion of ex vivo activated and expanded CD4(+)CD25(+) immune regulatory cells inhibits graft-versus-host disease lethality. Blood 99:3493–3499
Taylor PA, Lees CJ et al (2003) Endogenous host or exogenous donor CD4+CD25+ cells promote donor BM engraftment: association with TGF-beta production regulation of GITR signaling (abstract). Blood 102:37a
Taylor PA, Noelle RJ et al (2001) CD4(+)CD25(+) immune regulatory cells are required for induction of tolerance to alloantigen via costimulatory blockade. J Exp 193:1311–1318
Terabe M, Berzofsky JA (2004) Immunoregulatory T cells in tumor immunity. Opin Immunol 16:157–162
Teshima T, Ordemann R et al (2002) Acute graft-versus-host disease does not require alloantigen expression on host epithelium. Nat Med 8:575–581
Thornton AM, Shevach EM (2000) Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol 164:183–190
Trenado A, Charlotte F et al (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
Truitt RL, Johnson BD (1995) Principles of graft-vs.-leukemia reactivity. Biol Blood Marrow Transplant 1:61–68
Vogelsang GB, Lee L et al (2003) Pathogenesis and treatment of graft-versus-disease after bone marrow transplant. Annu Rev Med 54:29–52
Waldmann H, Graca L et al (2004) Regulatory T cells and organ transplantation. Semin Immunol 16:119–126
Walker LS, Chodos A et al (2003) Antigen-dependent proliferation of CD4+ CD25+ regulatory T cells in vivo. J Exp Med 198:249–258
Wang XN, Proctor SJ et al (1996) Frequency analysis of recipient-reactive helper cytotoxic T lymphocyte precursors using a combined single limiting dilution assay. Transpl Immunol 4:247–251
Yamazaki S, Iyoda T et al (2003) Direct expansion of functional CD25+ CD4+ regulatory T cells by antigen-processing dendritic cells. J Exp Med 198:235–247
Zeng D, Lan F et al (2004) Suppression of graft-versus-host disease by naturally occurring regulatory T cells. Transplantation 77:S9–S11
Zeng D, Lewis D et al (1999) Bone marrow NK1.1(−) and NK1.1(+) T cells reciprocally regulate acute graft versus host disease. J Exp Med 189:1073–1081
Zhang ZX, Yang L et al (2000) Identification of a previously unknown antigen-specific regulatory T cell and its mechanism of suppression. Nat Med 6:782–789
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Hoffmann, P., Ermann, J., Edinger, M. (2005). CD4+CD25+ Regulatory T Cells in Hematopoietic Stem Cell Transplantation. In: Compans, R., et al. CD4+CD25+ Regulatory T Cells: Origin, Function and Therapeutic Potential. Current Topics in Microbiology and Immunology, vol 293. Springer, Berlin, Heidelberg. https://doi.org/10.1007/3-540-27702-1_12
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