Information de reference pour ce titreAccession Number: | 00075200-201008000-00006.
|
Author: | Safinia, Niloufar; Sagoo, Pervinder; Lechler, Robert; Lombardi, Giovanna
|
Institution: | Medical Research Council (MRC) Centre for Transplantation, King's College London, King's Health Partners, Guy's Hospital, London, UK
|
Title: | |
Source: | Current Opinion in Organ Transplantation. 15(4):427-434, August 2010.
|
Abstract: | Purpose of review: The identification and characterisation of regulatory T cells (Tregs) has recently opened up exciting opportunities for Treg cell therapy in transplantation. In this review, we outline the basic biology of Tregs and discuss recent advances and challenges for the identification, isolation and expansion of these cells for cell therapy.
Recent findings: Tregs of thymic origin have been shown to be key regulators of immune responses in mice and humans, preventing autoimmunity, graft-versus-host disease and organ graft rejection in the transplantation setting. To date, a variety of different methods to isolate and expand Tregs ex vivo have been advocated. Although promising, relatively few clinical trials of human Treg cell infusion have been initiated.
Summary: Many key questions about Treg cell therapy still remain and here we provide an in-depth analysis and highlight the challenges and opportunities for immune intervention with Treg-based therapeutics in clinical transplantation.
(C) 2010 Lippincott Williams & Wilkins, Inc.
|
Author Keywords: | cellular therapy; clinical transplantation; immune tolerance; regulatory T cells.
|
References: | 1 Meier-Kriesche HU, Schold JD, Kaplan B. Long-term renal allograft survival: have we made significant progress or is it time to rethink our analytic and therapeutic strategies? Am J Transplant 2004; 4:1289-1295.
2 Dejaco C, Duftner C, Grubeck-Loebenstein B, Schirmer M. Imbalance of regulatory T cells in human autoimmune diseases. Immunology 2006; 117:289-300.
3 Sakaguchi S, Ono M, Setoguchi R, et al. Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev 2006; 212:8-27.
4 Tang Q, Henriksen KJ, Bi M, et al. In vitro-expanded antigen-specific regulatory T cells suppress autoimmune diabetes. J Exp Med 2004; 199:1455-1465.
5 Jiang S, Lechler RI, He XS, Huang JF. Regulatory T cells and transplantation tolerance. Hum Immunol 2006; 67:765-776.
6 Wood KJ, Sakaguchi S. Regulatory T cells in transplantation tolerance. Nat Rev Immunol 2003; 3:199-210.
7 Li Y, Zhao X, Cheng D, et al. The presence of Foxp3 expressing T cells within grafts of tolerant human liver transplant recipients. Transplantation 2008; 86:1837-1843.
8 Sagoo P, Lombardi G, Lechler RI. Regulatory T cells as therapeutic cells. Curr Opin Organ Transplant 2008; 13:645-653.
9 Bluestone JA. Regulatory T-cell therapy: is it ready for the clinic? Nat Rev Immunol 2005; 5:343-349.
10 Fehervari Z, Sakaguchi S. CD4+ Tregs and immune control. J Clin Invest 2004; 114:1209-1217.
11 Chen Y, Kuchroo VK, Inobe J, et al. Regulatory T cell clones induced by oral tolerance: suppression of autoimmune encephalomyelitis. Science 1994; 265:1237-1240.
12 Groux H, O'Garra A, Bigler M, et al. A CD4+ T-cell subset inhibits antigen-specific T-cell responses and prevents colitis. Nature 1997; 389:737-742.
13 Barrat FJ, Cua DJ, Boonstra A, et al. In vitro generation of interleukin 10-producing regulatory CD4+ T cells is induced by immunosuppressive drugs and inhibited by T helper type 1 (Th1)- and Th2-inducing cytokines. J Exp Med 2002; 195:603-616.
14 Levings MK, Sangregorio R, Galbiati F, et al. IFN-alpha and IL-10 induce the differentiation of human type 1 T regulatory cells. J Immunol 2001; 166:5530-5539.
15 Wang J, Huizinga TWJ, Toes REM. De novo generation and enhanced suppression of human CD4+CD25+ regulatory T cells by retinoic acid. J Immunol 2009; 183:4119-4126.
16 Gupta S, Shang W, Sun Z. Mechanisms regulating the development and function of natural regulatory T cells. Arch Immunol Ther Exp (Warsz) 2008; 56:85-102.
17 Sakaguchi S, Sakaguchi N, Shimizu J, et al. Immunologic tolerance maintained by CD25+CD4+ regulatory T cells: their common role in controlling autoimmunity, tumor immunity, and transplantation tolerance. Immunol Rev 2001; 182:18-32.
18 Sanchez-Fueyo A, Sandner S, Habicht A, et al. Specificity of CD4+CD25+ regulatory T cell function in alloimmunity. J Immunol 2006; 176:329-334.
19 Shevach EM. Certified professionals: CD4+CD25+ suppressor T cells. J Exp Med 2001; 193:F41-F46.
20 Coenen JJ, Koenen HJ, van Rijssen E, et al. Rapamycin, and not cyclosporin A, preserves the highly suppressive CD27+ subset of human CD4+CD25+ regulatory T cells. Blood 2006; 107:1018-1023.
21 Hoffmann P, Eder R, Boeld TJ, et al. Only the CD45RA+ subpopulation of CD4+CD25 high T cells gives rise to homogeneous regulatory T-cell lines upon in vitro expansion. Blood 2006; 108:4260-4267.
22** Miyara M, Yoshioka Y, Kitoh A, et al. Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor. Immunity 2009; 30:899-911. This study dissected FoxP3+ cells into subsets: CD45RA+FoxP3lo-resting Tregs (rTregs) and CD45RA-FoxP3hi-activated Tregs (aTregs), both of which were suppressive in vitro, and cytokine-secreting CD45RA-FoxP3lo nonsuppressive T cells. They further analysed the Treg cell differentiation dynamics and interactions in normal and disease states.
23 Fletcher JM, Lonergan R, Costelloe L, et al. CD39+Foxp3+ regulatory T cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis. J Immunol 2009; 183:7602-7610.
24 Baecher-Allan C, Brown JA, Freeman GJ, Hafler DA. CD4+CD25 high regulatory cells in human peripheral blood. J Immunol 2001; 167:1245-1253.
25 Dieckmann D, Plottner H, Berchtold S, et al. Ex vivo isolation and characterization of CD4+CD25+ T cells with regulatory properties from human blood. J Exp Med 2001; 193:1303-1310.
26 Jonuleit H, Schmitt E, Stassen M, et al. Identification and functional characterization of human CD4+CD25+ T cells with regulatory properties isolated from peripheral blood. J Exp Med 2001; 193:1285-1294.
27 Shevach EM, Tran DQ, Davidson TS, Andersson J. The critical contribution of TGF-beta to the induction of Foxp3 expression and regulatory T cell function. Eur J Immunol 2008; 38:915-917.
28 Ito T, Hanabuchi S, Wang YH, et al. Two functional subsets of FOXP3+ regulatory T cells in human thymus and periphery. Immunity 2008; 28:870-880.
29 Ziegler SF. FOXP3: of mice and men. Annu Rev Immunol 2006; 24:209-226.
30 Fontenot JD, Gavin MA, Rudensky AY. Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 2003; 4:330-336.
31 Bacchetta R, Passerini L, Gambineri E, et al. Defective regulatory and effector T cell functions in patients with FOXP3 mutations. J Clin Invest 2006; 116:1713-1722.
32 Wildin RS, Ramsdell F, Peake J, et al. X-linked neonatal diabetes mellitus, enteropathy and endocrinopathy syndrome is the human equivalent of mouse scurfy. Nat Genet 2001; 27:18-20.
33 Liu W, Putnam AL, Xu-Yu Z, et al. CD127 expression inversely correlates with FoxP3 and suppressive function of human CD4+ Treg cells. J Exp Med 2006; 203:1701-1711.
34 Seddiki N, Santner-Nanan B, Martinson J, et al. Expression of interleukin (IL)-2 and IL-7 receptors discriminates between human regulatory and activated T cells. J Exp Med 2006; 203:1693-1700.
35 Fuller MJ, Hildeman DA, Sabbaj S, et al. Cutting edge: emergence of CD127 high functionally competent memory T cells is compromised by high viral loads and inadequate T cell help. J Immunol 2005; 174:5926-5930.
36 Ng WF, Duggan PJ, Ponchel F, et al. Human CD4+CD25+ cells: a naturally occurring population of regulatory T cells. Blood 2001; 98:2736-2744.
37 Nakamura K, Kitani A, Strober W. Cell contact-dependent immunosuppression by CD4+CD25+ regulatory T cells is mediated by cell surface-bound transforming growth factor beta. J Exp Med 2001; 194:629-644.
38 Huang CT, Workman CJ, Flies D, et al. Role of LAG-3 in regulatory T cells. Immunity 2004; 21:503-513.
39 Shimizu J, Yamazaki S, Takahashi T, et al. Stimulation of CD25+CD4+ regulatory T cells through GITR breaks immunological self-tolerance. Nat Immunol 2002; 3:135-142.
40 Mellor AL, Munn DH. IDO expression by dendritic cells: tolerance and tryptophan catabolism. Nat Rev Immunol 2004; 4:762-774.
41 Gondek DC, Lu LF, Quezada SA, et al. Cutting edge: contact-mediated suppression by CD4+CD25+ regulatory cells involves a granzyme B-dependent, perforin-independent mechanism. J Immunol 2005; 174:1783-1786.
42 Grossman WJ, Verbsky JW, Barchet W, et al. Human T regulatory cells can use the perforin pathway to cause autologous target cell death. Immunity 2004; 21:589-601.
43* Boissonnas A, Scholer-Dahirel A, Simon-Blancal V, et al. Foxp3+ T cells induce perforin-dependent dendritic cell death in tumor-draining lymph nodes. Immunity 2010; 32:266-278. This interesting study showed that Tregs are capable of limiting the onset of effective antitumor immunity by inducing the death of DCs in the tumor draining lymph node through a perforin-dependent process.
44 Collison LW, Workman CJ, Kuo TT, et al. The inhibitory cytokine IL-35 contributes to regulatory T-cell function. Nature 2007; 450:566-569.
45 Graca L, Cobbold SP, Waldmann H. Identification of regulatory T cells in tolerated allografts. J Exp Med 2002; 195:1641-1646.
46 Taylor PA, Noelle RJ, Blazar BR. CD4+CD25+ immune regulatory cells are required for induction of tolerance to alloantigen via costimulatory blockade. J Exp Med 2001; 193:1311-1318.
47 Afzali B, Lechler RI, Hernandez-Fuentes MP. Allorecognition and the alloresponse: clinical implications. Tissue Antigens 2007; 69:545-556.
48 Auchincloss H Jr, Lee R, Shea S, et al. The role of 'indirect' recognition in initiating rejection of skin grafts from major histocompatibility complex class II-deficient mice. Proc Natl Acad Sci U S A 1993; 90:3373-3377.
49 Wise MP, Bemelman F, Cobbold SP, Waldmann H. Linked suppression of skin graft rejection can operate through indirect recognition. J Immunol 1998; 161:5813-5816.
50 Game DS, Hernandez-Fuentes MP, Chaudhry AN, Lechler RI. CD4+CD25+ regulatory T cells do not significantly contribute to direct pathway hyporesponsiveness in stable renal transplant patients. J Am Soc Nephrol 2003; 14:1652-1661.
51 Salama AD, Najafian N, Clarkson MR, et al. Regulatory CD25+ T cells in human kidney transplant recipients. J Am Soc Nephrol 2003; 14:1643-1651.
52 Quezada SA, Fuller B, Jarvinen LZ, et al. Mechanisms of donor-specific transfusion tolerance: preemptive induction of clonal T-cell exhaustion via indirect presentation. Blood 2003; 102:1920-1926.
53 Spadafora-Ferreira M, Caldas C, Fae KC, et al. CD4+CD25+Foxp3+ indirect alloreactive T cells from renal transplant patients suppress both the direct and indirect pathways of allorecognition. Scand J Immunol 2007; 66:352-361.
54 Yamada A, Chandraker A, Laufer TM, et al. Recipient MHC class II expression is required to achieve long-term survival of murine cardiac allografts after costimulatory blockade. J Immunol 2001; 167:5522-5526.
55 Hara M, Kingsley CI, Niimi M, et al. IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo. J Immunol 2001; 166:3789-3796.
56 Zelenika D, Adams E, Humm S, et al. Regulatory T cells overexpress a subset of Th2 gene transcripts. J Immunol 2002; 168:1069-1079.
57 Wysocki CA, Jiang Q, Panoskaltsis-Mortari A, et al. Critical role for CCR5 in the function of donor CD4+CD25+ regulatory T cells during acute graft-versus-host disease. Blood 2005; 106:3300-3307.
58 Huang JH, Cardenas-Navia LI, Caldwell CC, et al. Requirements for T lymphocyte migration in explanted lymph nodes. J Immunol 2007; 178:7747-7755.
59 Zhang N, Schroppel B, Lal G, et al. Regulatory T cells sequentially migrate from inflamed tissues to draining lymph nodes to suppress the alloimmune response. Immunity 2009; 30:322-323.
60 Dijke IE, Weimar W, Baan CC. Regulatory T cells after organ transplantation: where does their action take place? Hum Immunol 2008; 69:389-398.
61 Ochando JC, Yopp AC, Yang Y, et al. Lymph node occupancy is required for the peripheral development of alloantigen-specific Foxp3+ regulatory T cells. J Immunol 2005; 174:6993-7005.
62 Billingham RE, Brent L, Medawar PB. Quantitative studies on tissue transplantation immunity. II. The origin, strength and duration of actively and adoptively acquired immunity. Proc R Soc Lond B Biol Sci 1954; 143:58-80.
63 Dudley ME, Rosenberg SA. Adoptive-cell-transfer therapy for the treatment of patients with cancer. Nat Rev Cancer 2003; 3:666-675.
64 Porter DL, June CH. T-cell reconstitution and expansion after hematopoietic stem cell transplantation: 'T' it up! Bone Marrow Transplant 2005; 35:935-942.
65 Hall BM, Pearce NW, Gurley KE, Dorsch SE. Specific unresponsiveness in rats with prolonged cardiac allograft survival after treatment with cyclosporine. III. Further characterization of the CD4+ suppressor cell and its mechanisms of action. J Exp Med 1990; 171:141-157.
66 June CH, Blazar BR. Clinical application of expanded CD4+CD25+ cells. Semin Immunol 2006; 18:78-88.
67 Hanash AM, Levy RB. Donor CD4+CD25+ T cells promote engraftment and tolerance following MHC-mismatched hematopoietic cell transplantation. Blood 2005; 105:1828-1836.
68 Joffre O, Gorsse N, Romagnoli P, et al. Induction of antigen-specific tolerance to bone marrow allografts with CD4+CD25+ T lymphocytes. Blood 2004; 103:4216-4221.
69 Cohen JL, Trenado A, Vasey D, et al. CD4+CD25+ immunoregulatory T cells: new therapeutics for graft-versus-host disease. J Exp Med 2002; 196:401-406.
70 Hoffmann P, Ermann J, Edinger M, et al. Donor-type CD4+CD25+ regulatory T cells suppress lethal acute graft-versus-host disease after allogeneic bone marrow transplantation. J Exp Med 2002; 196:389-399.
71 Sanchez-Fueyo A, Weber M, Domenig C, et al. Tracking the immunoregulatory mechanisms active during allograft tolerance. J Immunol 2002; 168:2274-2281.
72 Joffre O, Santolaria T, Calise D, et al. Prevention of acute and chronic allograft rejection with CD4+CD25+Foxp3+ regulatory T lymphocytes. Nat Med 2008; 14:88-92.
73 Tsang JY, Tanriver Y, Jiang S, et al. Indefinite mouse heart allograft survival in recipient treated with CD4+CD25+ regulatory T cells with indirect allospecificity and short term immunosuppression. Transpl Immunol 2009; 21:203-209.
74 Raimondi G, Sumpter TL, Matta BM, et al. Mammalian target of rapamycin inhibition and alloantigen-specific regulatory T cells synergize to promote long-term graft survival in immunocompetent recipients. J Immunol 2010; 184:624-636.
75 Roncarolo MG, Battaglia M. Regulatory T-cell immunotherapy for tolerance to self antigens and alloantigens in humans. Nat Rev Immunol 2007; 7:585-598.
76 Wichlan DG, Roddam PL, Eldridge P, et al. Efficient and reproducible large-scale isolation of human CD4+CD25+ regulatory T cells with potent suppressor activity. J Immunol Methods 2006; 315:27-36.
77 Peters JH, Preijers FW, Woestenenk R, et al. Clinical grade Treg: GMP isolation, improvement of purity by CD127 depletion, Treg expansion, and Treg cryopreservation. PLoS One 2008; 3:e3161.
78 Putnam AL, Brusko TM, Lee MR, et al. Expansion of human regulatory T-cells from patients with type 1 diabetes. Diabetes 2009; 58:652-662.
79 Hoffmann P, Boeld TJ, Eder R, et al. Isolation of CD4+CD25+ regulatory T cells for clinical trials. Biol Blood Marrow Transplant 2006; 12:267-274.
80 Gottenberg JE, Lavie F, Abbed K, et al. CD4+CD25+ high regulatory T cells are not impaired in patients with primary Sjogren's syndrome. J Autoimmun 2005; 24:235-242.
81 Salomon B, Lenschow DJ, Rhee L, et al. B7/CD28 costimulation is essential for the homeostasis of the CD4+CD25+ immunoregulatory T cells that control autoimmune diabetes. Immunity 2000; 12:431-440.
82 Sakaguchi S. Regulatory T cells: key controllers of immunologic self-tolerance. Cell 2000; 101:455-458.
83 Taams LS, Vukmanovic-Stejic M, Smith J, et al. Antigen-specific T cell suppression by human CD4+CD25+ regulatory T cells. Eur J Immunol 2002; 32:1621-1630.
84 Hoffmann P, Eder R, Kunz-Schughart LA, et al. Large-scale in vitro expansion of polyclonal human CD4+CD25high regulatory T cells. Blood 2004; 104:895-903.
85 Karakhanova S, Munder M, Schneider M, et al. Highly efficient expansion of human CD4+CD25+ regulatory T cells for cellular immunotherapy in patients with graft-versus-host disease. J Immunother 2006; 29:336-349.
86 Godfrey WR, Ge YG, Spoden DJ, et al. In vitro-expanded human CD4+CD25+ T-regulatory cells can markedly inhibit allogeneic dendritic cell-stimulated MLR cultures. Blood 2004; 104:453-461.
87 Levings MK, Sangregorio R, Roncarolo MG. 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 2001; 193:1295-1302.
88 Basu S, Golovina T, Mikheeva T, et al. Cutting edge: Foxp3-mediated induction of pim 2 allows human T regulatory cells to preferentially expand in rapamycin. J Immunol 2008; 180:5794-5798.
89 Battaglia M, Stabilini A, Migliavacca B, et al. Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol 2006; 177:8338-8347.
90 Strauss L, Whiteside TL, Knights A, et al. Selective survival of naturally occurring human CD4+CD25+Foxp3+ regulatory T cells cultured with rapamycin. J Immunol 2007; 178:320-329.
91 Strauss L, Czystowska M, Szajnik M, et al. Differential responses of human regulatory T cells (Treg) and effector T cells to rapamycin. PLoS One 2009; 4:e5994.
92 Segundo DS, Ruiz JC, Izquierdo M, et al. Calcineurin inhibitors, but not rapamycin, reduce percentages of CD4+CD25+FOXP3+ regulatory T cells in renal transplant recipients. Transplantation 2006; 82:550-557.
93 Komatsu N, Mariotti-Ferrandiz ME, Wang Y, et al. Heterogeneity of natural Foxp3+ T cells: a committed regulatory T-cell lineage and an uncommitted minor population retaining plasticity. Proc Natl Acad Sci U S A 2009; 106:1903-1908.
94 Chung Y, Chang SH, Martinez GJ, et al. Critical regulation of early Th17 cell differentiation by interleukin-1 signaling. Immunity 2009; 30:576-587.
95 Koenen HJ, Smeets RL, Vink PM, et al. Human CD25highFoxp3+ regulatory T cells differentiate into IL-17-producing cells. Blood 2008; 112:2340-2352.
96 Radhakrishnan S, Cabrera R, Schenk EL, et al. Reprogrammed FoxP3+ T regulatory cells become IL-17+ antigen-specific autoimmune effectors in vitro and in vivo. J Immunol 2008; 181:3137-3147.
97 Voo KS, Wang YH, Santori FR, et al. Identification of IL-17-producing FOXP3+ regulatory T cells in humans. Proc Natl Acad Sci U S A 2009; 106:4793-4798.
98 Yang XO, Nurieva R, Martinez GJ, et al. Molecular antagonism and plasticity of regulatory and inflammatory T cell programs. Immunity 2008; 29:44-56.
99 Deknuydt F, Bioley G, Valmori D, Ayyoub M. IL-1beta and IL-2 convert human Treg into TH17 cells. Clin Immunol 2009; 131:298-307.
100 Afzali B, Mitchell P, Lechler RI, et al. Translational mini-review series on Th17 cells: induction of interleukin-17 production by regulatory T cells. Clin Exp Immunol 2010; 159:120-130.
101 O'Connor RA, Taams LS, Anderton SM. Translational mini-review series on Th17 cells: CD4 T helper cells: functional plasticity and differential sensitivity to regulatory T cell-mediated regulation. Clin Exp Immunol 2010; 159:137-147.
102 Shultz LD, Ishikawa F, Greiner DL. Humanized mice in translational biomedical research. Nat Rev Immunol 2007; 7:118-130.
103 Cao T, Soto A, Zhou W, et al. Ex vivo expanded human CD4+CD25+Foxp3+ regulatory T cells prevent lethal xenogenic graft versus host disease (GVHD). Cell Immunol 2009; 258:65-71.
104 Racki WJ, Covassin L, Brehm M, et al. NOD-scid IL2gamma (null) mouse model of human skin transplantation and allograft rejection. Transplantation 2010; 89:527-536.
105 Thornton AM, Shevach EM. Suppressor effector function of CD4+CD25+ immunoregulatory T cells is antigen nonspecific. J Immunol 2000; 164:183-190.
106 Hsieh CS, Zheng Y, Liang Y, et al. An intersection between the self-reactive regulatory and nonregulatory T cell receptor repertoires. Nat Immunol 2006; 7:401-410.
107 Tarbell KV, Yamazaki S, Olson K, et al. CD25+CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes. J Exp Med 2004; 199:1467-1477.
108 Golshayan D, Jiang S, Tsang J, et al. In vitro-expanded donor alloantigen-specific CD4+CD25+ regulatory T cells promote experimental transplantation tolerance. Blood 2007; 109:827-835.
109 Peters JH, Hilbrands LB, Koenen HJ, Joosten I. Ex vivo generation of human alloantigen-specific regulatory T cells from CD4+CD25+ T cells for immunotherapy. PLoS One 2008; 3:e2233.
110 Jiang S, Tsang J, Game DS, et al. Generation and expansion of human CD4+ CD25+ regulatory T cells with indirect allospecificity: potential reagents to promote donor-specific transplantation tolerance. Transplantation 2006; 82:1738-1743.
111 Jiang S, Camara N, Lombardi G, Lechler RI. Induction of allopeptide-specific human CD4+CD25+ regulatory T cells ex vivo. Blood 2003; 102:2180-2186.
112 Masteller EL, Warner MR, Tang Q, et al. Expansion of functional endogenous antigen-specific CD4+CD25+ regulatory T cells from nonobese diabetic mice. J Immunol 2005; 175:3053-3059.
113 Tsang J, Jiang S, Tanriver Y, et al. In-vitro generation and characterisation of murine CD4+CD25+ regulatory T cells with indirect allospecificity. Int Immunopharmacol 2006; 6:1883-1888.
114 Trenado A, Charlotte F, Fisson S, et al. 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 2003; 112:1688-1696.
115 Trzonkowski P, Bieniaszewska M, Juscinska J, et al. First-in-man clinical results of the treatment of patients with graft versus host disease with human ex vivo expanded CD4+CD25+CD127- T regulatory cells. Clin Immunol 2009; 133:22-26.
|
Language: | English.
|
Document Type: | Tolerance induction: Edited by Alberto Sanchez-Fueyo.
|
Journal Subset: | Clinical Medicine.
|
ISSN: | 1087-2418
|
DOI Number: | https://dx.doi.org/10.1097/MOT.0...- ouverture dans une nouvelle fenêtre
|
Annotation(s) | |
|
|