T亚群Ⅰ、Ⅱ型细胞在造血干细胞移植供、受者中的比例变化研究
详细信息    本馆镜像全文|  推荐本文 |  |   获取CNKI官网全文
摘要
健康人Ⅰ、Ⅱ型T淋巴细胞保持着一定的平衡,Ⅰ、Ⅱ型T淋巴细胞之间的比例失衡决定着免疫和炎症反应的方向,不同的病理过程可以特征化为向Ⅰ型或Ⅱ型免疫反应的极化。通过动物急性移植物抗宿主病(aGVHD)模型,了解到Ⅰ型T细胞及其细胞因子在aGVHD的发生中起关键作用,但是在人类aGVHD发生过程中Ⅰ、Ⅱ型T细胞的确切比例尚未见报道。另外在动物研究中发现G-CSF动员对供者的免疫细胞起调节作用,并影响着移植免疫,但是存在着争议。本研究采用流式细胞术,通过检测造血干细胞移植供者动员前后以及移植早期受者的Ⅰ、Ⅱ型T细胞比例的变化,了解G-CSF对供者免疫细胞功能和对aGVHD的影响,以及Ⅰ、Ⅱ型T细胞比例与aGVHD的相关性。具体工作如下:
     1.健康成人T亚群Ⅰ、Ⅱ型细胞比例以及两种细胞表面抗原标记法对流式检测结果的影响:通过本研究,我们建立了有效的流式检测正常人T亚群Ⅰ、Ⅱ型细胞比例方法。Ⅰ、Ⅱ型细胞因子分泌水平在正常成人中有明显个体差异。正常人的CD4~+T细胞是主要的IL-2产生细胞。以CD3+CD4双标记或以CD3+CD8双标记检测分析T亚群的Ⅰ、Ⅱ型细胞比例结果相近。
     2.G-CSF动员对供者T淋巴细胞亚群功能和急性移植物抗宿主病的影响:本研究发现G-CSF动员使供者外周血的Ⅰ型T细胞比例增加,动员后高Tcl细胞比例与移植早期aGVHD发生相关,Tc2比例与中重度aGVHD
The type I and type II T lymphocytes keep a balance in healthy people. The imbalance of type I and type II T lymphocyte determine the direction of immune response and inflammation. Different pathologic states can be charactered as a polarization to type I or type II response. From the animal aGVHD model, we learned that the type I T cells and its cytokines exert crucial function in aGVHD. While the percent of type I T cells in human aGVHD was not reported so far. Also in research of animals, the function of immune cells in donor was regulated by G-CSF and therefore influenced the immune of transplantation. But there were still controversial about the G-CSF function till now. In this work, we adopt technique of flow cytometry, detct the type I and type II T cell percentage in donor of hematogenic stem cell transplantation (HSCT) befor and after mobilized by G-CSF, and detct the percent change in receptors in the early stage post HSCT. We investigate the influence of G-CSF to the function of donor's immune cells and aGVHD as well as the association of type I and type II T cell percents with aGVHD. The works we have finished were described as below.
    1. The percent of type I and type II lymphocyte subsets in healthy adult and the influence of two different surface markers to the detection with flow cytometry. In this research, We have established effective laboratory technique
引文
1. Braun, J., Z. Yin, I. Spiller, S. Siegert, M. Rudwaleit, L. Liu, A. Radbruch, and J. Sieper. 1999. Low secretion of tumor necrosis factor L, but no other Th 1 or Th2 cytokines, by peripheral blood mononuclear cells correlates with chronicity in reactive arthritis. Arthritis Rheum. 42: 2039-2044.
    2. Crucian, B., P. Dunne, H. Friedman, R. Ragsdale, S. Pross, and R. Widen. 1996. Detection of altered T helper 1 and T helper 2 cytokine production by peripheral blood mononuclear cells in patients with multiple sclerosis utilizing intracellular cytokine detection by flow cytometry and surface marker analysis. Clin. Diagn. Lab. Immunol. 3: 411-416.
    3. Westby, M., J. B. Marriott, M. Guckian, S. Cookson, R Hay, and A. G. Dalgleish. 1998. Abnormal intracellular IL-2 and interferon-gamma(IFN-γ) production as HIV-1-associated markers of immune dysfunction. Clin. Exp. Immunol. 111: 257-263.
    4.Th1细胞在再生障碍性贫血发病机制中的作用。和虹 邵宗鸿 何广胜等。中华血液学杂志,P574,2002 Vol.23 No.11。
    5. Soejima H, Irie A, Miyamoto S, Kajiwara I, Kojima S, Hokamaki J,??Sakamoto T, Tanaka T, Yoshimura M, Nishimura Y, Ogawa H: Preference Toward a T-Helper Type 1 Response in Patients With Coronary Spastic Angina. Circulation 2003 Apr 14; [epub ahead of print]
    
    6. Sacks GP, Redman CW, Sargent IL.Monocytes are primed to produce the Thl type cytokine IL-12 in normal human pregnancy: an intracellular flow cytometric analysis of peripheral blood mononuclear cells. Clin Exp Immunol 2003 Mar;131(3):490-7.
    
    7. Chaouat G.Innately moving away from the Th1/Th2 paradigm in pregnancy. Clin Exp Immunol 2003 Mar;131(3):393-5.
    
    8. van den Berg AP, Twilhaar WN, van Son WJ, van der Bij W, Klompmaker IJ, Slooff MJ, The TH, de Leij LH: Quantification of immunosuppression by flow cytometric measurement of intracellular cytokine-synthesis. Transpl Int: 11 Suppl 1:S318-S321, 1998.
    
    9. Lionel Rostaing, Jean TKaczuk, Martine Durand, Christine Peres, Dominique Durand, Claude de Pr val, Elie Ohayon, and Michel Abbal: Kinetics of intracytoplasmic Thl and Th2 cytokine production assessed by flow cytometry following in vitro activation of peripheral blood mononuclear cells. Cytometry 35:318-328, 1999.
    
    10. E. Chu, J. Elia, D. Sehy, D. Ernst, and C. Shih, Hotlines [Pharmingen] 3:9-10, 1997.
    
    11. Nancy J. O'Neil-Andersen and David A. Lawrence: Differential modulation of surface and intracellular protein expression by T cells after stimulation in the presence of monensin or brefeldin A. Clin. Diagn. Lab. Immunol. 9: 243-250,2002.
    
    12. Sander B, Anderson J, Anderson U. Assessement of cytokines by immunofluorescence and paraformaldehyde saponin procedure. Immunol Rev 1991;119:65-93.
    
    13. Anderson, S. J., and C. Coleclough. 1993. Regulation of CD4 and CD8 expression on mouse T cells. J. Immunol. 151: 5123-5134.
    
    14. Petersen, C. M., E. I. Christensen, B. S. Andresen, and B. K. Moller. 1992. Intemalization, lysosomal degradation and new synthesis of surface membrane CD4 in phorbol ester-activated T-lymphocytes and U-937 cells. Exp. Cell Res. 201:160-173.
    
    15.Ruegg, C. L., S. Rajasekar, B. S. Stein, and E. G. Engleman. 1992. Degradation of CD4 following phorbol-induced intemalization in human T lymphocytes: evidence for distinct endocytic routing of CD4 and CD3. J. Biol. Chem. 267:18837-18843.
    
    16. Bensinger WI, Martin PJ, Storer B, et al. Transplantation of bone marrow as compared with peripherial-blood cells from HLA-identical relatives in patients with hematologic cancers. N Engl J Med. 2001 ;344:175-181.
    17. Abbas AK, Murphy KM, Sher A, et al. Functional diversity of helper T lymphocytes. Nature 1996;383:787-793.
    
    18. Mackall CL, Punt JA, Morgan P et al. Thymic function in young/old chimeras: substantial thymic T cell regenerative capacity despite irreversible age -associated thymic involution. Eur J Immunol 1998; 28: 1886 -1893.
    
    19. Dulude G, Brochu S, Fontaine P et al. Thymic and extrathymic differentiation and expansion of T lymphocytes following bone marrow transplantation in irradiated recipients. Exp Hematol 1997;25: 992-1004.
    
    20. D Prepiorka, D Weisdorf, P Martin et al. Consensus conference on acute GVHD grading. Bone Marrow Transplantation, (1995) 15, 825-828.
    
    21. Lopez A, Nicola N, Burgess A, et al. Activation of granulocyte cytotoxic function by purified mouse colony-stimulating factors. J Immunol 1983; 131: 2983-2988.
    
    22. Singh RK, Ino K, Varney ML et al. Immunoregulatory cytokines in bone marrow and peripherial blood stem cell products. Bone Marrow Translplant 1999;23: 53-62.
    
    23. Varney ML, Ino K, Ageitos AG et al. Expression of IL-10 in isolated CD8+ T cells and monocytes from growth factor mobilized peripheral blood stem cell products: a mechanism of immune dysfunction. J Iterfer Cytok Res 1999; 19:351-360.
    24. Sloand EM, Kim S, Maciejewski JP et al. Pharmacologic doses of granulocyte colony-stimulating factor affect cytokine production by lymphocytes in vitro and in vivo . Blood 2000;95:2269-2274.
    
    25. Shantaram S. Joshi, James C. Lynch, Steve Z. Pavletic, Stefano R. Tarantolo, Samuel J. Pirruccello, Anne Kessinger, and Michael R. Bishop. Decreased immune functions of blood cells following mobilization with granulocyte colony-stimulating factor: association with donor characteristics. Blood.2001:98:1963-1970.
    
    26. Clark RE, Hermans J, Madrigal A, et al. HLA-A3 increases and HLA-DR1 decreases the risk of acute graft-versus-host disease after HLA-matched sibling bone marrow transplantation for chronic myelogenous leukemia. Br J Haemato. 2001;114:36-41.
    
    27. Mielcarek M, Graft L, Johnson G, Torok-Storb B. Production of interleukin-10 by granulocyte colony-stimulating factor-mobilized blood products: a mechanism for monocyte-mediated suppression of T-cell proliferation. Blood. 1998;91:215-222.
    
    28. Vasconcelos ZF, Santos BM, Costa ES. T-lymphocyte function from peripheral blood stem-cell donors is inhibited by activated granulocytes. Cytotherapy. 2003;5(4):336-345.
    
    29. Korngold R, Sprent J. Surface markers of T cells causing lethal graft-vs-hostdisease to class I vs class II H-2 differences. J Immunol. 1985; 135:3004-3010.
    
    30. Milica Vukmanovic-Stejic, Beejal Vyas, Patricia Gorak-Stolinska. Human Tc1 and Tc2/0 CD8 T-cell clones display distinct cell surface and functional phenotypes. Blood. 2000,95,231-240.
    
    31. Werner Krenger, Kenneth R. Cooke, James M. Crawford. Transplantation of polarized type 2 doner T cells reduces mortality caused by experimental graft-versus-host disease. Transplantation 1996; 62:1278-1285.
    
    32. S. Arai, G.B. Vogelsang. Management of graft-versus-host disease. Haematological oncology. 2000, 14, 190-214.
    
    33. Rus V, Svetic A, Nguyen P, et al. Kinetics of TH1 and TH2 cytokinge production during the early course of acute and chronic murine graft-versus-host disease: regulatory role of donor CD8+ T cells. J Immunol. 1995, 155:2396-2406.
    
    34. Moore KW, O'Garra AO, De Waal Malefyt R et al. Interleukin-10. Annu Rev Immunol, 1993, 11: 165-190.
    
    35. Werner Krenger, Kurt M. Snyder, John C. H. Byon, et al. Polarized type 2 alloreactive CD4+ and CD8+ donor T cells fail to induce experimental acute graft- versus-host disease. The Journal of Immunology, 1995, 155: 585-593.
    
    36. Fowler, D. H., K. Kurasawa, et al. Cells of the Th2 cytokine phenotype prevent LPS-induced lethality during murine graft-versus-host reaction. J.Immunol., 1994, 152:1004-1013.
    
    37. Krenger W, Hill GR, Ferrara JLM. Cytokine cascades in acute graft-versus-host disease.Transplantation, 1997, 64:553-561.
    
    38. Ferrara JL. Cytokine inhibitors and graft-versus-host disease. Ann N Y Acad Sci, 1995,770:227-236.
    
    39. Gifford GE, Lohmann-Matthes M-L. Gamma interferon priming of mouse and human macrophages for induction of tumor necrosis factor production by bacterial lipopolysaccharide. J Natl Cancer Inst 1987;78:121-124.
    
    40. Huber C, Niederwieser D. Role of cytokines and major histocompatibility complex antigens in graft-versus-host disease: in vitro studies using T cell lines and keratinocytes or hemopoietic targets. Haematol Blood Trans 1990; 33:652-654.
    
    41. Dickinson AM, Sviland L, Dunn J et al. Demonstration of direct involvement of cytokines in graft-versus-host reactions using an in vitro skin explant model. Bone Marrow Transplant 1991;7:209-216.
    
    42. Williams NS, Engelhard VH. Perforin-dependent cytotoxic activity and lymphokine serection by CD4+ T cells are regulated by CD8+ T cells. J Immunol. 1997; 159:2091-2099
    
    43. Sad S, Mosmann TR. Interleukin (IL)4, in the absence of antigen stimulation, induces an anergy like state in differentiated CD8+ Tc1 cells: loss of IL-2
    synthesis and autonomous proliferation but retention of cytotoxicity and synthesis of other cytokines. J Exp Med. 1995;182:1505-1515
    
    44. Sad S, Li L, Mosmann TR. Cytokine-deficient CD8+ Tc1 cells induced by IL-4: retained inflammation and perform and Fas cytotoxicity but compromised long term killing of tumor cells. J Immunol. 1997;159:606-613
    
    45. Goker H, Haznedaroglu IC, Chao NJ. Acute graft-vs-host disease: pathobiology and management. Exp Hematol, 2001, 29:259-277
    
    46. Hill G, Krenger W, Ferrara J. Cytokine dysregulation in acute graft-versus-host disease. Hematology, 1998, 2: 423-431
    
    47. Via CS, Finkelman FD. Critical role of interleukin-2 in the development of acute graft-versus-host disease. Int Immunol, 1993, 5: 565-572
    
    48. Mosmann TR, Li L, Sad S. Function of CD8 T-cell subsets secreting different cytokine patterns. Semin Immunol. 1997, 9(2): 87-92
    
    49. Li L, Sad S, Kagi D, Mosmann TR. CD8Tcl and Tc2 cells secrete distinct cytokine patterns in vitro and in vivo but induce similar inflammatory reactions. J Immunol. 1997, 158(9): 4252-61
    
    50. Milica Vukmanovic-Stejic, Beejal Vyas, Patricia Gorak-Stolinska. Human Tc1 and Tc2/0 CD8 T-cell clones display distinct cell surface and functional phenotypes. Blood. 2000,95,231-240.
    51. Boris Nikolic, Seika Lee, Roderick T, et al. Th1 and Th2 mediated acute graft-versus-host disease, each with distinct end-organ targets. J. Clin. Invest. 2000. 105:1289-1298.
    1. James L. M. Ferrara, Kenneth R. Cooke, Luying Pan, Werner Krenger. The Immunopatho- physiology of acute graft-versus-host-disease. Stem cells. 1996; 14: 473-489.
    2. Reddy P. Pathophysiology of acute graft-versus-host disease. Hematol Oncol. 2003 Dec; 21(4): 149-161.
    3.居小萍,王建民,章卫平等.可溶性白细胞介素一2受体、CD_(25)~+细胞与急性移值物抗宿主病关系的研究.中华内科杂志,2001:40(4):222-225.
    4. Grimm J, Zeller W, Zander AR. Soluble interleukin-2 receptor serum levels after allogeneic bone marrow transplantations as a marker for GVHD. Bone Marrow Transplant. 1998 Jan; 21(1): 29-32.5. Fujimori Y, Takatsuka H, Takemoto Y, Hara H, Okamura H, Nakanishi K, Kakishita E. Elevated interleukin (IL) —18 levels during acute graft-versus-host disease after allogeneic bone marrow transplantation. Br J Haematol. 2000 Jun;109(3):652-7.
    
    6. Nakamura H, Komatsu K, Ayaki M, Kawamoto S, Murakami M, Uoshima N, Yagi T, Hasegawa T, Yasumi M, Karasuno T, Teshima H, Hiraoka A, Masaoka T. Serum levels of soluble IL-2 receptor, IL—12, IL—18, and IFN-gamma in patients with acute graft-versus-host disease after allogeneic bone marrow transplantation. J Allergy Clin Immunol. 2000 Jul; 106(1 Pt 2):S45-50.
    
    7. Nagler A, Bishara A, Brautbar C, Barak V. Dysregulation of inflammatory cytokines in unrelated bone marrow transplantation. Cytokines Cell Mol Ther. 1998 Sep;4(3):161-167.
    
    8. Ferra C, de Sanjose S, Gallardo D, Berlanga JJ, Rueda F, Mar in D, de la Banda E, Ancin I, Peris J, Garcia J, Granena A. IL-6 and IL-8 levels in plasma during hematopoietic progenitor transplantation. Haematologica. 1998 Dec;83(12):1082-1087.
    
    9. Kumaki S, Minegishi M, Fujie H, Sasahara Y, Ohashi Y, Tsuchiya S, Konno T. Prolonged secretion of IL-15 in patients with severe forms of acute graft-versus-host disease after allogeneic bone marrowtransplantation in children. Int J Hematol. 1998 Apr;67(3): 307 -312.
    
    10. Chik KW, Li K, Pong H, Shing MM, Li CK, Yuen PM. Elevated serum interleukin-15 level in acute graft-versus -host disease after hematopoietic cell transplantation. J Pediatr Hematol Oncol. 2003 Dec; 25 (12): 960-964.
    
    11. Imamura M, Tsutsumi Y, Miura Y, Toubai T, Tanaka J. Immune reconstitution and tolerance after allogeneic hematopoietic stem cell transplantation. Hematology. 2003 Feb;8(1):19-26.
    
    12. Ju X, Wang J, Xu B, Cao Y, Lu S. Roles of interleukin-10 in acute graft-versus-host disease and graft rejection. Chin Med J (Engl). 2003 Apr; 116 (4): 534-537.
    
    13. Sakata N, Yasui M, Okamura T, Inoue M, Yumura-Yagi K, Kawa K。 Kinetics of plasma cytokines after hematopoietic stem cell transplantation from unrelated donors: the ratio of plasma IL-10/sTNFR level as a potential prognostic marker in severe acute graft-versus-host disease. Bone Marrow Transplant. 2001 Jun;27(11):1153-1161.
    
    14. Visentainer JE, Lieber SR, Persoli LB, Vigorito AC, Aranha FJ, de Brito Eid KA, Oliveira GB, Miranda EC, de Souza CA. Serumcytokine levels and acute graft-versus-host disease after HLA-identical hematopoietic stem cell transplantation. Exp Hematol. 2003 Nov;31(11):1044-1050.
    
    15. Miura Y, Thoburn CJ, Bright EC, Chen W, Nakao S, Hess AD. Cytokine and chemokine profiles in autologous graft-versus-host disease (GVHD): interleukin 10 and interferon gamma may be critical mediators for the development of autologous GVHD. Blood. 2002 Oct 1;100 (7):2650-2658.
    
    16. CorreiaO, Delgado L, Barbosa IL, Campilho F, Fleming-Torrinha J. Increased interleukin 10, tumor necrosis factor alpha, and interleukin 6 levels in blister fluid of toxic epidermal necrolysis. J Am Acad Dermatol. 2002 Jul;47(1):58-62.
    
    17. Imoto S, Oomoto Y, Murata K, Das H, Murayama T, Kajimoto K, Sugimoto T, Gomyo H, Nakagawa T, Nishimura R, Koizumi T. Kinetics of serum cytokines after allogeneic bone marrow transplantation: interleukin-5 as a potential marker of acute graft-versus-host disease. Int J Hematol. 2000 Jul;72(1):92-97.
    
    18. Jordan WJ, Brookes PA, Szydlo RM, Goldman JM, Lechler RI, Ritter MA. IL-13 production by donor T cells is prognostic of acute graft-versus-host disease following unrelated donor stem celltransplantation. Blood. 2004 Jan 15;103(2):717-24. Epub 2003 Sep 25.
    
    19. Nikolic B, Lee S, Bronson RT, Grusby MJ, Sykes M. Th1 and Th2 mediate acute graft-versus -host disease, each with distinct end-organ targets. J Clin Invest. 2000 May;105(9):1289-1298.
    
    20. Brouwer RE, van der HM, Kluin-Nelemans HC, Zelderen-Bhola S, Willemze R, Falkenburg JH. The generation of dendritic-like cells with increased allostimulatory function from acute myeloid leukemia cells of various FAB subclasses. Hum Immunol. 2000:61:565-574.
    
    21. Marsh SG, Parham P, Dupont B, et al. Killer-cell immunoglobulin-1 ike receptor (KIR) Nomenclature Report, 2002. Hum Immunol. 2003:64:648-654.
    
    22. Nordlander A, Uzunel M, Mattsson J, Remberger M. The TNFd4 allele is correlated to moderate-to-severe acute graft-versus-host disease after allogeneic stem cell transplantation. Br J Haematol. 2002 Dec;119(4):1133-1136.
    
    23. Ishikawa Y, Kashiwase K, Akaza T, et al. Polymorphisms in TNFA and TNFR2 affect outcome of unrelated bone marrow transplantation. Bone Marrow Transplant. 2002;29:569- 575.
    24. Stark GL, Dickinson AM, Jackson GH, Taylor PRA, Proctor SJ, Middleton PG. Tumour necrosis factor receptor type II 196M/R genotype correlates with circulating soluble receptor levels in normal subjects and with graft- versus-host disease after sibling allogeneic bone marrow transplantation. Transplantation. In Press.
    
    25. Turner DM, Williams DM, Sankaran D, Lazarus M, Sinnott PJ, Hutchinson IV. An investigation of polymorphism in the interleukin-10 gene promoter. Eur J Immunogenet. 1997;24:1-8.
    
    26. Edwards-Smith CJ, Jonsson JR, Purdie DM, Bansal A, Shorthouse C, Powell EE. Interleukin- 10 promotor polymorphism predicts initial response of hepatitis C to interferon alfa. Hepat- ology. 1999:30:526-530.
    
    27. Marijt WA, Heemskerk MH, Kloosterboer FM, et al. Hematopoiesis-restricted minor histocompatibility antigens HA-1-or HA-2-specific T cells can induce complete remissions of relapsed leukemia. Proc Natl Acad Sci U S A. 2003; 100:2742-2747.
    
    28. Davies SM, Ruggieri L, DeFor T, et al. Evaluation of KIR ligand incompatibility in mismatched unrelated donor hematopoietic transplants. Killer immunoglobulin-like 368 American Society ofHematology receptor. Blood. 2002;100:3825-3827.
    
    29. Middleton PG, Cullup H, Dickinson AM, Norden J, Jackson GH, Taylor PR, Cavet J. Vitamin D receptor gene polymorphism associates with graft-versus-host disease and survival in HLA-matched sibling allogeneic bone marrow transplantation. Bone Marrow Transplant. 2002 Aug; 30 (4):223-228.
    
    30. Cavet J, Dickinson AM, Norden J, Taylor PR, Jackson GH, Middleton PG. Interferon-gamma and interleukin-6 gene polymorphisms associate with graft-versus-host disease in HLA-matched sibling bone marrow transplantation. Blood. 2001 Sep 1; 98 (5): 1594-1600.
    
    31. Lin MT, Storer B, Martin PJ, Tseng LH, Gooley T, Chen PJ, Hansen JA. Relation of an interleukin-10 promoter polymorphism to graft-versus-host disease and survival after hematopoietic-cell transplantation. N Engl J Med. 2003 Dec 4;349 (23):2183-2184.
    
    32. Rocha V, Franco RF, Porcher R, Bittencourt H, Silva WA Jr, Latouche A, Devergie A, Esperou H, Ribaud P, Socie G, Zago MA, Gluckman E. Host defense and inflammatory gene polymorphisms are associated with outcomes after HLA-identical sibling bone marrow transplantation. Blood. 2002 Dec 1; 100(12): 3908-18. Epub 2002 Jul25.
    
    33. Socie G, Loiseau P, Tamouza R, et al. Both genetic and clinical factors predict the development of graft-versus -host disease after allogeneic hematopoietic stem cell transplantation. Transplantation. 2001;72:699-705.
    
    34. Molldrem JJ, Komanduri K, Wieder E. Overexpressed differentiation antigens as targets of graft-versus- leukemia reactions. Curr Opin Hematol. 2002;9:503-508.
    
    35. Cullup H, Dickinson AM, Jackson GH, Taylor PR, Cavet J, Middleton PG. Donor interleukin 1 receptor antagonist genotype associated with acute graft-versus-host disease in human leucocyte antigen-matched sibling allogeneic transplants. Br J Haematol. 2001 Jun;113(3): 807-813.
    
    36. Mutis T, Gillespie G, Schrama E, Falkenburg JH, Moss P, Goulmy E. Tetrameric HLA class I minor histocom- patibility antigen peptide complexes demonstrate minor histocompatibility antigen-specific cytotoxic T lympho- cytes in patients with graft-versus-host disease. Nat Med. 1999;5:839-842.
    
    37. MacMillan ML, Radloff GA, DeFor TE, Weisdorf DJ, Davies SM. Interleukin-1 genotype and outcome of unrelated donor bone marrowtransplantation. Br J Haematol. 2003 May;121 (4):597-604.
    
    38. Dickinson AM, Wang XN, Sviland L, et al. In situ dissection of the graft-versus-host activities of cytotoxic T cells specific for minor histocompatibility antigens. Nat Med. 2002;8:410-414.
    
    39. Hattori H, Matsuzaki A, Suminoe A, et al. Polymorphisms of transforming growth factor-beta 1 and trans- forming growth factor-beta 1 type 2 receptor genes are associated with acute graft- versus-host disease in children with HLA-matched sibling bone marrow transplantation. Bone Marrow Transplant. 2002:30:665-671.
    
    40. MacMillan ML, Radloff GA, Kiffmeyer WR, DeFor TE, Weisdorf DJ, Davies SM. High-producer interleukin-2 genotype increases risk for acute graft-versus-host disease after unrelated donor bone marrow transplantation. Transplantation. 2003 Dec 27:76(12): 1758-1762.
    
    41. Murphy WJ, Welniak LA, Taub DD, Wiltrout RH, Taylor PA, Vallera DA, Kopf M, Young H, Longo DL, Blazar BR. Differential effects of the absence of interferon- γ and IL-4 in acute graft-versus-host disease after allogeneic bone marrow transplantation in mice. J Clin Invest 1998; 102: 1742-1748.
    42. Ellison CA, Fischer JMM, HayGlass KT, Gartner GJ. Murine graft-versus-host disease in a FI-hybrid model using IFN-γ gene knockout donors. The Journal of Immunology 1998; 161: 631-640.
    
    43. Welniak LA, Blazar BR, Wiltrout RH, Anver MR, Murphy WJ. Role of interleukin-12 in acute graft-versus-host disease(1). Transpl Proc 2001; 33: 1752-1753.
    
    44. Blazar BR, Taylor PA, Smith S, Vallera DA. Interleukin-10 administration decrease survival in murine recipients of major histocompatibility complex disparate donor bone marrow grafts. Blood 1995; 85: 842-851.
    
    45. Ushiyama C, Hirano T, Miyajima H, Okumura K, Ovary Z, Hashimoto H. Anti-IL-4 antibody prevents graft-versus-host disease in mice after bone marrow transplantation. J Immunol 1995; 154: 2687-2696.
    
    46. Liu J, Anderson BE, Robert ME, McNiff JM, Emerson SG, Shlomchik WD, Shlomchik MJ. Selective T-cell subset ablation demonstrates a role for T1 and T2 cells in ongoing acute graft-versus-host disease: a model system for the reversal of disease. Blood 2001; 98: 3367-3375.
    
    47. Fowler DH, Gress RE. Th2 and Tc2 cells in the regulation of GVHD, GVL, and graft rejection: considerations for the allogeneic
    transplantation therapy of leukemia and lymphoma. Leuk lymphoma 2000; 38: 221-234.
    
    48. Reddy P, Teshima T, Hildebrandt G, Williams DL, Liu C, Cooke KR, Ferrara JL. Pretreatment of donors with interleukin-18 attenuates acute graft-versus-host disease via STAT6 and preserves graft-versus-leukemia effects. Blood. 2003 Apr 1; 101 (7): 2877-2885.
    
    49. Hill GR, Cooke KR, Teshima T, Crawford JM, Keith JC, Brinson YS, Bungard D, Ferrara JLM. Interleukin-11 promotes T cell polarization and prevents acute graft-versus-host disease after allogeneic bone marrow transplantation. J Clin Invest 1998; 102: 115-123.
    
    50. Zeng D, Lewis, Dejbakhsh-jones S, Lan F, Garcia-Ojeda M, Sibley R, Strober S. Bone marrow NK1.1- and NK1. 1+ T cells reciprocally regulate acute graft versus host disease. J Exp Med 1999; 189: 1073-1081.
    
    51. Reddy P, Teshima T, Kukuruga M, Ordemann R, Liu C, Lowler K, Ferrara JL. Interleukin-18 regulates acute graft-versus-host disease by enhancing Fas-mediated donor T cell apoptosis. J Exp Med 2001;194: 1433-1440.
    52. Brok HPM, Heidt PJ, van der Meide PH, Zurcher C, Vossen JM. Interferon-γ prevents graft-versus-host disease after allogeneic bone marrow transplantation in mice. J Immunol 1993; 151:6451-6459.
    
    53. Sykes M, Romick ML, Sachs DH. Interleukin 2 prevents graft-versus-host disease while preserving the graftversus-leukemia effect of allogeneic T cells. Pro Nad Acad Sci USA 1990;87:5633-5637.
    
    54. Sykes M, Szot GL, Nguyen PL, Pearson DA. Interleukin-12 inhibits murine graft-versus-host disease. Blood 1995; 86: 2429-2438.
    
    55. Antin JH, Weisdorf D, Neuberg D, Nicklow R, Clouthier S, Lee SJ, Alyea E, McGarigle C, Blazar BR, Sonis S, Soiffer RJ, Ferrara JL. Interleukin-1 blockade does not prevent acute graft-versus-host disease: results of a randomized, double-blind, placebo-controlled trial of interleukin-1 receptor antagonist in allogeneic bone marrow transplantation. Blood. 2002 Nov 15; 100 (10): 3479-82. Epub 2002 Jul 18.
    
    56. Arnold D, Wasem C, Juillard P, Graber P, Cima I, Frutschi C, Herren S, Jakob S, Alouani S, Mueller C, Chvatchko Y, Brunner T.IL-18-independent cytotoxic T lymphocyte activation and IFN-gamma production during experimental acute graft-versus-host disease. Int Immunol. 2002 May; 14(5):503-511.
    
    57. Nakanishi K, Yoshimoto T, Tsutsui H, Okamura H. Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu. Cytokine Growth Factor Rev. 2001 Mar; 12(1): 53-72.
    
    58. Stuber E, Schlenger P, Von Freier A, Arendt T, Folsch UR. Interferon-gamma is not involved in the intestinal manifestations of the acute murine semiallogenic graft-versus-host disease. Int J Colorectal Dis. 2001 Sep; 16(5): 346-351.
    
    59. Williamson E, Garside P, Bradley JA, More IA, Mowat AM. Neutralizing IL-12 during induction of murine acute graft-versus-host disease polarizes the cytokine profile toward a Th2-type alloimmune response and confers long term protection from disease. J Immunol. 1997 Aug 1; 159(3):1208-1215.
    
    60. Yang YG. The role of interleukin-12 and interferon-gamma in GVHD and GVL. Cytokines Cell Mol Ther. 2000 Mar;6(1):41-46.
    
    61. Yang YG, Sykes M. The role of interleukin-12 in preserving the graft-versus-leukemia effect of allogeneic CD8 T cellsindependently of GVHD. Leuk Lymphoma. 1999 May;33(5-6): 409-420.
    
    62. Sykes M, Pearson DA, Taylor PA, Szot GL, Goldman SJ, Blazar BR. Dose and timing of interleukin (IL) —12 and timing and type of total-body irradiation: effects on graft-vs. -host disease inhibition and toxicity of exogenous IL—12 in murine bone marrow transplant recipients. Biol Blood Marrow Transplant. 1999:5(5): 277-284.
    
    63. Alpdogan O, Muriglan SJ, Eng JM, Willis LM, Greenberg AS, Kappel BJ, van den Brink MR. IL-7 enhances peripheral T cell reconstitution after allogeneic hematopoietic stem cell transplantation. J Clin Invest. 2003 Oct; 112(7):1095-1107.
    
    64. Gendelman M, Hecht T, Logan B, Vodanovic-Jankovic S, Komorowski R, Drobyski WR. Host conditioning is a primary determinant in modulating the effect of IL-7 on murine graft-versus-host disease. J Immunol. 2004 Mar 1;172 (5):3328-3336.
    
    65. Teshima T, Hill GR, Pan L, Brinson YS, van den Brink MR, Cooke KR, Ferrara JL. IL—11 separates graft- versus-leukemia effects from graft-versus-host disease after bone marrow transplantation. J Clin Invest. 1999 Aug; 104(3):317-25.
    66. Panoskaltsis-Mortari A, Lacey DL, Vallera DA, Blazar BR. Keratinocyte growth factor administered before conditioning ameliorates graft-versus-host disease after allogeneic bone marrow transplantation in mice. Blood. 1998 Nov 15; 92 (10) : 3960-7.
    
    67. Panoskaltsis-Mortari A, Taylor PA, Rubin JS, Uren A, Welniak LA, Murphy WJ, Farrell CL, Lacey DL, Blazar BR. Keratinocyte growth factor facilitates alloengraftment and ameliorates graft-versus-host disease in mice by a mechanism independent of repair of conditioning induced tissue injury. Blood. 2000 Dec 15;96(13): 4350-6.
    
    68. Rossi S, Blazar BR, Farrell CL, Danilenko DM, Lacey DL, Weinberg KI, Krenger W, Hollander GA. Keratinocyte growth factor preserves normal thymopoiesis and thymic microenvironment during experimental graft-versus-host disease. Blood. 2002 Jul 15; 100(2):682-91.
    
    69. Ziegler TR, Panoskaltsus-Mortari A, Gu LH, Jonas CR, Farrell CL, Lacey DL, Jones DP, Blazar BR. Regulation of glutathione redox status in lung and liver by conditioning regimens and keratinocyte growth factor in murine allogeneic bone marrow transplantation. Transplantation. 2001 Oct 27;72(8):1354-62.
    70. Krijanovski OI, Hill GR, Cooke KR, Teshima T, Crawford JM, Brinson YS, Ferrara JL. Keratinocyte growth factor separates graft-versus-leukemia effects from graft-versus-host disease. Blood. 1999 Jul 15; 94(2): 825-31.
    71.路瑾,许兰平,黄晓军等.CD_(25)单克隆抗体治疗皮质激素耐药的重度移植物抗宿主病.中华医学杂志.2003:83(3):216-219.
    72. Massenkeil G, Rackwitz S, Genvresse I, Rosen O, Dorken B, Arnold R. Basiliximab is well tolerated and effective in the treatment of steroid-refractory acute graft-versus-host disease after allogeneic stem cell transplantation. Bone Marrow Transplant. 2002 Dec; 30(12): 899-903.
    73. Jacobsohn DA, Hallick J, Anders V, McMillan S, Morris L, Vogelsang GB. Infliximab for steroid-refractory acute GVHD: a case series. Am J Hematol. 2003 Oct; 74(2): 119-124.
    74. Korngold R, Marini JC, de Baca ME, Murphy GF, Giles-Komar J. Role of tumor necrosis factor-alpha in graft-versus-host disease and graft-versus-leukemia responses. Biol Blood Marrow Transplant. 2003 May; 9(5): 292-303.1. Mosmann TR, Coffman RL: THI and TH2 cells: Different patterns of lymphokine secretion lead to different functional properties. Annu Rev Immunol 1989; 7: 145.
    2. Swain SL, Bradley LM, Croft M et al: Helper T-cell subsets: Phenotype, function and the role of lymphokines in regulating their development. Immunol Rev 1991; 123: 115.
    3. Salgame P, Abrams JS, Clayberger C et al: Differing lymphokine profiles of functional subsets of human CD4 and CD8 T cell clones. Science 1991; 254: 279-282.
    4. Finkelman FD: Relationships among antigen presentation, cytokines, immune deviation, and autoimmune disease. J Exp Med 1995; 18: 2279.
    5. Seder RA, Le Gros G G. The functional role of CD8+ T helper type 2 cells. J Exp Med 1995; 18: 15.
    6. Croft M, Carter L, Swain SL, et al: Generation of polarized antigen-specific CD8 effector populations: reciprocal action of interleukin(IL)-4 and IL-12??in promoting type 2 versus type 1 cytokine profiles. J Exp Med 1994;180:1715.
    
    7. Lafaille JJ. The role of helper T cell subsets in autoimmune diseases. Cytokine Growth Factor Rev. 1998;9:139-151.
    
    8. Rocken M, Biedermann T, Ogilvie A. The role of TH1 and Th2 dichotomy: implications for autoimmunity. Rev Rhum Engl Ed. 1997;64:131S-137S.
    
    9. Gately MK, Renzetti LM, Magram J et al. The interleukin-12-receptor system: role in normal and pathologic immune responses. Annu Rev Immunol. 1998;16:495-521.
    
    10. Pan L, Bressler S, Cooke KR et al. Long-term engraftment, graft-vs.-host disease, and immunologic reconstitution after experimental transplantation of allogeneic peripheral blood cells from G-CSF-treated donors. Biol Blood Marrow Transplant. 1996;2:126-133.
    
    11. Mielcarek M, Torok-Storb B. Phenotype and engraftment potential of cytokine-mobilized peripheral blood mononuclear cells. Curr Opin Hematol.l997;4:176-182.
    
    12. Korbing M, Huh YO, Durett A et al.Allogeneic blood stem cell transplantation: peripherialization and yield of donor derived primitive hematopoietic progenitor cells (CD34+ Thy-1 dim) and lymphoid subsets,and possible predictors of engraftment and graft-versus-host disease. Blood,1995,86:2842-2848.
    13. Singhal S, Powles R, Kulkarni S et al. Comparison of marrow and blood cell yields from the same donors in a double-blind, randomized study of allogeneic marrow vs blood stem cell transplantation. Bone marrow transplant 2000; 25: 501.
    
    14. Weaver CH, Longin K, Buckner CD et al. Lymphocyte content in peripheral blood mononuclear cells collected after the administration of recombinant human granulocyte colony-stimulating factor. Bone marrow transplant 1994; 12:411.
    
    15. Dreger P, Haferlach T, Eckstein V et al. G-CSF-mobilized peripheral blood progenitor cells for allogeneic transplantation: safty, kinetics of mobilization, and composition of the graft. Brit J Haematol 1994; 87: 609.
    
    16. Bensinger WI, Weaver CH, Appelbaum FR et al. Transplantation of allogeneic peripheral blood stem cells mobilized by recombinant human granulocyte colony-stimulating factor. Blood 1995; 85: 1655-1658,
    
    17. Bensinger WI, Clift RA, Anasetti C et al. Transplantation of allogeneic peripheral blood stem cells mobilized by recombinant human granulocyte colony stimulating factor. Stem Cells. 1996; 14:90-105.
    
    18. Schmitz N, Dreger P, Suttorp M et al. Primary transplantation of allogeneic peripheral blood progenitor cells mobilized by filgrastim (granulocyte colony-stimulating factor). Blood 1995; 85: 1666-1672.
    19. Schmitz N, Bacigalupo A, Hasenclever D et al. Allogeneic bone marrow transplantation vs filgrastim-mobilised peripheral blood porgenitor cell transplantation in patients with early leukemia:first results of a randomized multicentre trial of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant, 1998,21:995-1003.
    
    20. Bensinger W, Martin P, Clift R et al. A prospective,randomized trial of peripheral blood stem cells(PBSC) or marrow(BM) for patients undergoing allogeneic transplantation for hematologic malignancies.Blood, 1999,94 Suppl 1:10a.
    
    21. Russell JA, Luider J, Weaver M et al. Collection of progenitor cells for allogeneic transplantation from peripheral blood from normal donors. Bone Marrow Transplant 1995; 15: 111-115.
    
    22. Azevedo WM, Aranha FJ, Gouvea JV et al. Allogeneic transplantation with blood stem cells mobilized by rhG-GSF for hematological malignancies. Bone Marrow Transplant 1995; 16: 647-653.
    
    23. Kusnierz-Glaz CR, Still BJ, Amano M, et al. Granulocyte colony-stimulating factor-induced comobilization of CD4- CD8- T cells and hematopoietic progenitor cells (CD34+) in the blood of normal donors. Blood. 1997;89;2586-2595.
    
    24. Strober S, Cheng L, Zeng D, et al. Double negative (CD4-CD8-alpha beta1)T cells which promote tolerance induction and regulate autoimmunity. Immunol Rev. 1996; 149;217-230.
    
    25. Palathumpat V, Dejbakhsh-Jones, Holm B et al. Different subsets of T cells in the adult mouse bone marrow and spleen induce or suppress acute graft-versus-host disease. J Immunol 1992; 149: 808-817.
    
    26. Palathumpat V, Dejbakhsh-Jones, Holm B et al. Studies of CD4-CD8- bone marrow T cells with suppressor activity. J Immunol 1992; 148: 373-380.
    
    27. Schmidt-Wolf IGH, Dejbakhsh-Jones S, Ginzton N et al. T cell subsets and suppressor cells in human bone marrow. Blood 1993; 80: 3242-3250.
    
    28. Mielcarek M,Graf L,Johnson G,et al.Production of interleukin-10 by granulocyte colony stimulating factor mobilized blood products:a mechanism for monocyte mediated suppression of T cell proliferation. Blood, 1998,92:215-222.
    
    29. Mielcarek M, Martin PJ, Torok-Storb B. Suppression of alloantigen-induced T-cell proliferation by CD141 cells derived from granulocyte colonystimulating factor-mobilized peripheral blood mononuclear cells. Blood. 1997;89:1629-1634.
    
    30. Pan L, Delmonte J Jr, Jalonen CK, Ferrara JLM. Pretreatment of donor mice with granulocyte colony-stimulating factor polarizes donor T-lymphocytes toward type-2 cytokine production and reduces severity of experimental graft-versus-host disease. Blood. 1995;86:4422-4429.
    31.Zeng D, Dejbakhsh-Jones S, Strober S. Granulocyte colony-stimulating factor reduces the capacity of blood mononuclear cells to induce graft-versus-host disease: impact on blood progenitor cell transplantation. Blood 1997; 90:453-463.
    
    32. Fowler DH, Kurasawa K, Smith R et al. Donor CD4-enriched cells of Th2 cytokine phenotype regulate graft-versus-host disease without impairing allogeneic engraftment in sublethally irradiated mice. Blood 1994; 84: 3540-3549.
    
    33. Krenger W, Snyder KM, Byon JCH et al. Polarized type 2 alloreactive CD4+ and CD8+ donor T cells fail to induce experimental acute graft-versus-host disease. J Immunol 1995; 155: 585-593.
    
    34. Ageitos AG, Varney ML, Bierman PJ et al. Comparison of monocyte-dependent T cell inhibitory activity in GM-CSF vs G-CSF mobilized PSC products. Bone marrow Transplantation 1999; 23: 63-69.
    
    35. Korneich A, Lambermont M, Feremans W et al. Decreased IFN-γ secretion by T lymphocytes in leukapheresis after G-CSF mobilization of healthy donors. Blood 1997; 90 (Suppl. 1): (Abstr. 564a).
    
    36. Zeng D, Lewis D, Dejhakhsh-Jones S, et al. Bone marrow NK1.1- and NK1.1+ T cells reciprocally regulate acute graft versus host disease. J Exp Med 1999; 189: 1073.
    37. Dreger P, Oberboster K, Schmitz N. PBSC grafts from healthy donors: analysis of CD34+ and CD3+ subpopulations. Bone marrow transplant 1996; 17(Suppl 2):S22.
    
    38. Hakim Tayebi, Fabien Kuttler, Philippe Saas et al. Effect of granulocyte colony-stimulating factor mobilization on phenotypical and functional properties of immune cells. Experimental Hematology 2001; 29: 458-470.
    
    39. Exley M, Garcia J, Balk SP et al. Requirements for CD1d recognition by human invariant Vα24CD4-CD8- T cells. J Exp Med 1997; 186:109.
    
    40. Sakamoto A, Oishi Y, Kurasawa K et al. Characteristics of T-cell receptor Vα24JαQ T cells, a human counter part of murine NK1 T cells, from normal subjects. J Allergy Clin Immunol 1999; 103: S445.
    
    41. Wang EC, Taylor-Wiedeman J, Perera P et al. Subsets of CD8+, CD57+ cells in normal, healthy individuals with human cytomegalovirus (HCMV) carrier status, phenotypic and functional analyses. Clin Exp Immunol 1993; 94: 297.
    
    42. Nicol A, Nieda M, Koezuka Y et al. Dendritic cells are targets for human invariant Va24+ natural killer T-cell cytotoxic activity: an important immune regulatory function. Exp Hematol 2000; 28: 276.
    
    43. Elaine M. Sloand, Sonnie Kim, Jaroslaw P. Maciejewski et al. Pharmacologic doses of granulocyte colony-stimulating factor affectcytokine production by lymphocytes in vitro and vivo. Blood 2000; 95: 2269-2274.
    
    44. Bachetta R, Panina-Bordignon P, Zappone E, et al. Suppression of alloreactive T-cell responses, after in vivo G-CSF treatment, is mediated by IL-10 and TGF-β and it is associated with a switch toward a Th2 phenotype. Blood 1998; 92 (Suppl 1): 641a.
    
    45. Tarantolo SR, Bishop MR, Lynch JC et al. Effect of G-CSF mobilization on type 1 and type 2 T cells and correlation to acute graft-versus-host disease (GVHD). Blood 1998; 92(Suppl 1): 722a.
    
    46. Nawa Y, Teshima T, Sunami K et al. G-CSF reduces IFN-γ and IL-4 production by T cells after allogeneic stimulation by indirectly modulating monocyte function. Bone marrow transplant 2000; 25: 1035.
    
    47. ZFM Vasconcelos, BM Santos, ES Costa et al. T-lymphocyte function from peripherial blood stem-cell donors is inhibited by activated granulocytes. Cytotherapy 2003; 5(4): 336-345.
    
    48. D Prepiorka, D Weisdorf, P Martin, H-G Klingemann, P Beatty, J Hows and ED Thomas. Consensus conference on acute GVHD grading. Bone Marrow Transplantation, (1995) 15, 825-828.
    
    49. Shirafuji N, Matsuda S, Ogura H, et al. Granulocyte colony-stimulating factor stimulates human mature neutrophilic granulocytes to produceinterferon-alpha. Blood 1990; 75: 17-19.
    
    50. Singh RK, Ino K, Varney ML et al. Immunoregulatory cytokines in bone marrow and peripherial blood stem cell products. Bone Marrow Translplant 1999;23: 53-62.
    
    51. Varney ML, Ino K, Ageitos AG et al. Expression of IL-10 in isolated CD8+ T cells and monocytes from growth factor mobilized peripheral blood stem cell products: a mechanism of immune dysfunction. J Iterfer Cytok Res 1999; 19:351-360.
    
    52. Shantaram S. Joshi, James C. Lynch, Steve Z. Pavletic, Stefano R. Tarantolo, Samuel J. Pirruccello, Anne Kessinger, and Michael R. Bishop. Decreased immune functions of blood cells following mobilization with granulocyte colony-stimulating factor: association with donor characteristics. Blood.2001:98:1963-1970.
    
    53. Ringden O, Labopin M, Gorin NC et al. Treatment with granulocyte colony-stimulating factor after allogeneic bone marrow transplantation for acute leukemia increases the risk of graft-versus-host disease and death: a study from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. J Clin Oncol. 2004 1 ;22(3):416-423.
    
    54. Fowler DH, Kurasawa K, Husebekk A et al. Cells of the Th2 cytokine phenotype prevent LPS-induced murine graft-versus-host reaction. JImmunol 1994; 152: 1004.
    
    55. Kichian K, Nestel FP, Kim D et al. IL-12 P40 messenger RNA expression in target organs during acute graft-versus-host disease. J Immunol 1996; 153: 2851.
    
    56. Via CS, Rus V, Gately MK et al. IL-12 stimulates the development of acute graft-versus-host disease in mice that would normally develop chronic, autoimmune graft-versus-host disease. J Immunol 1994; 153: 4040.
    
    57. Anasetti C, Hansen JA, Waldmann TA et al. Treatment of acute graft-versus-host disease with humanized anti-Tac: An antibody that binds to the interleukin-2 receptor. Blood 1994; 84: 1320.
    
    58. Ferrara JLM, Marion A, McIntyre JF et al. Amelioration of acute graft-versus-host disease due to minor histocompatibility antigens by in vivo administration of anti-interleukin 2 receptor antibody. J Immunol 1986; 137: 1874.
    
    59. Allen RD, Staley TA, Sidman CL. Differential cytokine expression in acute and chronic murine graft-versus-host disease. Eur J Immunol 1993; 23:333.
    
    60. Kelso A. Frequency analysis of lymphokine-secreting CD4+ and CD8+ T cells activatied in a graft-versus-host reaction. J Immunol 1990; 145: 2167.
    
    61. Rus V, Svetic A, Nguyen P et al. Kinetics of Th1 and Th2 cytokine production during the early course of acute and chronic murinegraft-versus-host disease. J Immunol 1995; 155: 2396.
    
    62. Blazar BR, Taylor PA, Panoskaltsis-Mortai A et al. Interleukin-10 dose-dependent regulation of CD4+ and CD8+ T cell-mediated graft-versus-host disease. Transplantation 1998; 66: 1220.
    
    63. Goker H, Haznedaroglu IC, Chao NJ. Acute graft-vs-host disease: pathobiology and management. Exp Hematol 2001; 29: 259-277.
    
    64. Hill G, Ferrara J. The primacy of the gastrointestinal tract as a target organ of acute graft-versus-host disease: rationale for the use of cytokine shields in allogeneic bone marrow transplantation. Blood 2000; 95: 2754-2759.
    
    65. Hill G, Krenger W, Ferrara J. Cytokine dysregulation in acute graft-versus-host disease. Hematology 1998; 2: 423.
    
    66. Via CS, Finkelman FD. Critical role of interleukin-2 in the development of acute graft-versus-host disease. Int Immunol 1998; 5: 565-572.
    
    67. Jadus MR, Peck AB. Lethal murine graft-versus-host disease in absence of detectable cytotoxic T lymphocytes. Transplantation 1983; 36: 281-289.
    
    68. Sykes M, Rommick ML, Hoyles KA et al. In vivo administration of interleukin 2 plus T-cell depleted syngeneic marrow prevents graft-versus-host disease and permits alloengraftment. J Exp Med 1990; 171: 645-658.
    
    69. Sykes M, Abraham VS, Harty MW et al. IL-2 reduces graft-vs-host diseaseand preserves a graft-vs-leukemia effect by selectively inhibiting CD4T cell activity. J Immunol 1993; 150: 197-205.
    
    70. Szebeni J, Wang MG, Pearson DA et al. IL-2 inhibits early increases in serum gamma interferon levels associated with graft-versus-host disease. Transplantation 1995; 58: 1385-1393.
    
    71. Soiffer RJ, Murray C, Cochran K et al. Clinical and immunologic effects of prolonged infusion of low-dose recombinant interleukin-2 after autologous and T-cell-depleted bone marrow transplantation. Blood 1992; 79: 517-526.
    
    72. Belanger C, Esperou-Bourdeau H, Bordigoni P et al. Use of an anti-interleukin-2 receptor mononuclonal antibody for GVHD pophylaxis in unrelated donor BMT. Bone Marrow Transplant 1993; 11: 293-297.
    
    73. Anasetti C, Martin PM, Hansen JA et al. A Phase I-II study evaluating the murine anti-IL-2 receptor antibody 2A3 for treatment of acute graft-versus-host disease. Transplantation 1990; 50: 49-54.
    
    74. Herve P, Wijdenes J, Bergerat JP et al. Treatment of corticosteroid resistant acute graft-versus-host disease by in vivo administration of anti-interleukin-2 receptor monoclonal antibody (B-B10). Blood 1990; 75: 1017-1023.
    
    75. Kumaki S, Minegishi M, Fujie H et al. Prolonged serection of IL-15 in patients with severe forms of acute graft-versus-host disease after allogeneicbone marrow transplantation in children. Int J Hematol 1998; 67:307-312.
    
    76. Imamura M, Tanaka J, Hashino S et al. Cytokines involved in graft-versus-host disease. Hokkaido Igaku Zasshi 1994; 69: 1348-1353.
    
    77. N Sakata, M Yasui, T Okamura, M Inoue, K Yumura-Yagi and K Kawa. Kinetics of plasma cytokines after hematopoietic stem cell transplantation from unrelated donors: the ratio of plasma IL-10/sTNFR level as a potential prognostic marker in severe acute graft-versus-host disease. Bone Marrow Transplantation.(2001) 27, 1153-1161.
    
    78. Wolf SF, Temple PA, Kobayashi M et al. Cloning of cDNA for natural killer cell stimulatory factor, a heterodimeric cytokine with multiple biologic effects on T and natural killer cells. J Immmunol 1991; 146: 3074-3081.
    
    79. Manetti R, Parronchi P, Giudizi M et al. Natural killer cell stimulatory factor (interleukin 12 (IL-12)) induces T helper type (Thl)-specific immune responses and inhibits the development of IL-4 producing Th cells. J Exp Med 1993; 177:1199-1204.
    
    80. Trinchieri G. Interleukin-12: a cytokine produced by antigen-presenting cells with immunoregulatory functions in the generation of T-helper cells type 1 and cytotoxic lymphocytes. Blood 1994; 84: 4008-4027.
    
    81. Granelli-Piperno A. Lymphokine gene expression in vivo is inhibited by cyclosporin A. J Exp Med 1990; 171: 533-544.
    
    82. Mehrotra PT, Wu D, Crim JM et al. Effects of IL-12 on the generation of cytotoxic activity in human CD8+ T lymphocytes. J Immunol 1993; 151: 2444-2452.
    
    83. Sykes M, Szot GL, Nguyen PL, Pearson DA. Interleukin-12 inhibits murine graft-versus-host disease. Blood 1995; 86: 2429-2438.
    
    84. Teshima T, Ferrara JL. Understanding the alloresponse: new approaches to graft-versus-host disease prevention. Semin Hematol 2002; 39: 15-22.
    
    85. Hill GR, Crawford JM, Cooke KJ et al. Total body irradiation and acute graft versus host disease. The role of gastrointestinal damage and inflammatory cytokines. Blood 1997; 90: 3204-3213.
    
    86. Velardi A, Varese P, Terenzi A et al. Lymphokine production by T-cell clones after human bone marrow transplantation. Blood 1989; 74: 1665-1672.
    
    87. Niederwiseser D, Herold M, Woloszczuk W et al. Endogenous IFN-γ during human bone marrow transplantation. Transplantation 1990; 50: 620-625.
    
    88. Mowat A. Antibodies to IFN-y prevent immunological mediated intestinal damage in murine graft-versus-host reactions. Immunology 1989; 86: 18-24.
    
    89. Dickinson AM, Sviland L, Dunn J et al. Demonstration of direct involvement of cytokines in graft-versus-host reactions using an in vitro skin explant model. Bone Marrow Transpl 1991; 7: 209-216.
    
    90. Klimpel GR, Annable CR, Cleveland MG et al. Immunosuppression andlymphoid hypoplasia associated with chronic graft-versus-host disease is dependent upon IFN-g production. J Immunol 1990; 144; 84-93.
    91. Wall DA, Sheehan KC. The role of tumor necrosis factor-αand interferon γ, in graft-versus-host disease and related immunodeficiency. Transplantation 1994; 57: 273-279.
    92. Brochu S, Rioux-Masse B, Roy J et al. Massive activation-induced cell death of alloreactive T cells with apoptosis of bystander postthymic T cells prevents immne reconstitution in mice with graft-versus-host disease. Blood 1999; 94: 390-400.
    93. Reddy P, Teshima T, Kukuruga Met al. Interleukin-18 regulates acute graft-versus-host disease by enhancing Fas-mediated donor T cell apoptosis. J Exp Med 2001; 194: 1433-1440.
    94. Refaeli Y, Van Parijis L, Alexander SI et al. Interferon-7 is required for activation-induced death ofT lymphocytes. J Exp Med 2002; 196: 999-1005.
    95. Brok HPM, Heidt PJ, van der Meide PH et al. Interferon-Tprevents graft-versus-host disease after allogeneic bone marrow transplantation in mice. J Immunol 1993; 151: 6451-6459.
    96. Brok HPM, Vossen JM, Heidt PJ. Interferon-g-mediated prevention of graft-versus-host disease: development of immune competent and allo-tolerant T cells in chimeric mice. Bone Marrow Transplantation,(1997)??19,601-606.
    
    97. Heremans H, Dijkmans R, Sobis H et al. Regulation by interferons of the local inflammatory response to lipopolysaccharide. J Immunol 1987; 138: 4157-4179.
    
    98. Wang MG, Szebeni J, Pearson DA et al. Inhibition of graft-versus-host disease by interleukin-2 treatment is associated with altered cytokine production by expanded graft-versus-host-reactive CD4+ helper cells. Transplantation 1995; 60: 481-490.
    
    99. Belardelli F. Role of interferons and other cytokines in the regulation of the immune response. APMIS 1995; 103: 161-169.
    
    100. Trinchieri G. Interleukin-12 and its role in the generation of TH1 cells. Immunol Today 1993; 14: 335-338.
    
    101. Gajewski TF, Goldwasser E, Fitch FW. Anti-proliferative effect of IFN-gamma in immune regulation. II. IFN-gamma inhibits the proliferation of murine bone marrow cells stimulated with IL-3, IL-4 or granulocyte-macrophage colony stimulating factor. J Immunol 1988; 141: 2635-2642.
    
    102. Gajewski TF, Fitch FW. Anti-proliferative effect of IFN- gamma in immune regulation. I. IFN-gamma inhibits the proliferation of Th2 but not Th1 murine T lymphocyte clones. J Immunol 1988; 140: 4245-4252.
    103. Tare NS, Bowen S, Warrier RR et al. Administration of recombinant interleukin-12 to mice suppresses hematopoiesis in the bone marrow but enhances hematopoiesis in the spleen. J Interferon Cytokine Res 1995; 15: 377-383.
    
    104. Godfrey, DI, Gately MK, Hakimi J et al. IL-12 influences intrathymic T cell development. J Immunol 1994; 152:2729-2735.
    
    105. Krenger, W Falzarano G, Delmonte J Jr et al. Interferon-gamma suppresses T-cell proliferation to mitogen via the nitric oxide pathway during experimental acute graft-versus-host disease. Blood 1996; 88: 1113-1121.
    
    106. Hilton DJ. Negative regulators of cytokine signal transduction. Cell Mol Life Sci 1999; 55: 1568-1577.
    
    107. Irie-Sasaki J, Sasaki T, Matsumoto W et al. CD45 is a JAK phosphatase and negatively regulates cytokine receptor signaling. Nature 2001; 409: 349-354.
    
    108. Danielle L. Kerbs, Douglas J. Hilton. SOCS proteins: Negative regulators of cytokine signaling. Stem cell 2001; 19: 378-387.
    
    109. Ushiyama, C, et al. Anti-IL-4 antibody prevents graft-versus-host disease in mice after allogeneic bone marrow transplantation. The IgE allotype is an important marker of graft-versus-host disease. J Immunol1995; 154:2687-2696.
    
    110. Williamson, E., Garside, P., Bradley, J.A. et al. Neutralizing IL-12 during induction of murine acute graft-versus-host disease polarizes the cytokine profile toward a Th2-type alloimmune response and confers long term protection from disease. J. Immunol 1997; 159: 1208-1215.
    
    111. Dey, B., Yang, Y.-G, Szot, G.L. et al. IL-12 inhibits GVHD through a Fas-mediated mechanism associated with alteration in donor T cell activation and expansion. Blood 1998; 91: 3315-3322.
    
    112. Sykes, M., Abraham, V.S., Harty, M.W. et al. Selective inhibition of CD4 graft-versus-host activity in IL-2-treated mice. Transplant. Proc 1992; 25: 1225-1226.
    
    113. Sykes, M., Abraham, V.S.. Mechanism of IL-2 mediated protection against GVHD in mice. II. Protection occurs independently of NK/LAK cells. Transplantation 1992; 53: 1063-0170.
    
    114. Sykes, M., Harry, M.W., Szot, G.L.. Interleukin-2 inhibits graft-versus-host disease-promoting activity of CD4+ cells while preserving CD4- and CD8-mediated graft-versus-leukemia effects. Blood 1994; 83: 2560-2569.
    
    115. Hsieh CS, Macatonia SE, O'Garra A et al. Pathogen-induced Th1 phenotype development in CD4+ alphabeta-TCR transgenic T cells ismacrophage dependent. Int Immunol 1993; 5:371-382.
    
    116. Hsieh CS, Macatonia SE, Tripp CS et al. Development of Th1 CD4+ T cells through IL-12 produced by listeria-induced macrophages. Science 1993; 260: 547-549.
    
    117. de Waal Malefyt R, Yessel H, Roncarolo MG. Interleukin 10. Curr Opin Immunol 1992; 4: 314-320.
    
    118. Willems F, Marchant A, Deville JP. Interleukin 10 inhibits B7 and intercellular adhesion molecule-1 expression on human monocytes. Eur J Immunol 1994; 24: 1007-1009.
    
    119. Groux H, Bigler M, de Vries JE et al. Interleukin-10 induces a long term antigen specific anergic state in human CD4+ T cells. J Exp Med 1996; 184: 19-29.
    
    120. Enk AH, Saloga J, Becker D et al. Induction of hapten-specific tolerance by interleukin 10 in vivo. J Exp Med 1994; 179: 1397-1402.
    
    121. Bacetta R, Bigler M, Touraine JL et al. High levels of interleukin 10 production in vivo are associated with tolerance in SCID patients transplanted with HLA mismatched hemotopoietic stem cells. J Exp Med 1994; 179:493-502.
    
    122. Becker JC, Czerny C, Brocker EB. Maintenance of clonal anergy by endogenously produced IL-10. Int Immunol 1994; 6: 1605-1612. 123. Akdis CA, Blesken T, Akdis M et al. Role of interleukin 10 in specific immunity. J Clin Invest 1998; 102: 98-106.
    
    124. Tanasaki S, Nonaka R, Xing Z. Interleukin 10 inhibits lipopolysaccharide-induced survival and cytokine production by human peripheral blood eosinophils. J Exp Med 1994; 180: 711-715.
    
    125. Ralph P, Nakoinz I, Sampson-Johannes A. IL-10, T lymphocyte inhibitor of human blood cell production of IL-1 and tumor necrosis factor. J Immunol 1992; 148:808-814.
    
    126. de Waal Malefyt R, Yessel H, de Vries JE. Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. J Immunol 1993; 150: 4754-4765.
    
    127. de Waal Malefyt R, Abrams J, Benntt B. Interleukin 10 (IL-10) inhibit cytokine synthesis by human monocytes: an autoregulatory role of IL-10 produced by monocytes. J Exp Med 1991; 174: 1209-1220.
    
    128. Fiorentino DF, Zlotnik A, Vieira P et al. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J Immunol 1991; 146: 3444-3451.
    
    129. Buelens C, Verhasselt V, De Groote D et al. Human dendritic cell responses to lipopolysaccharide and CD40 ligation are differentially regulated by IL-10. Eur J Immunol 1997; 27: 1848-1854.
    130. Baker KS, Roncarolo M-G, Peters C et al. High spontaneous IL-10 production in unrelated bone marrow transplantation recipients is associated with fewer transplant-related complications and early deaths. Bone Marrow transplant 1999; 23:1123-1129.
    
    131. Takatsuka H, Takamoto Y, Okamoto T et al. Predicting the severity of graft-versus-host disease from interleukin-10 levels after bone marrow transplantation. Bone Marrow Transplant 1999; 24: 1005-1007.
    
    132. Krenger W, Snyder K, Smith S et al. Effects of exogenous interleukin-10 in a murine model of graft-versus-host disease to minor histocompatibility antigens. Transplantation 1994; 58: 1251.
    
    133. Atkinson, K., C. Matias, A. Guiffre et al. In vivo administration of granulocyte colony-stimulating (G-CSF), granulocyte-macrophage CSF, interleukin-1 (IL-1), and IL-4, alone and in combination, after allogeneic murine hematopoietic stem cell transplantation. Blood 1991; 77: 1376.
    
    134. Blazar, B.R., Taylor, P.A., Smith S. et al. Interleukin 10 administration decreases survival in murine recipients of major histocompatibility complex disparate donor bone marrow cells. Blood 1994; 85: 842-851.
    
    135. Hakim FT, Mackall CL. The immune system: effector and target of graft-versus-host disease. In: JLM Ferrara, HJ Deeg. SJ Burakoff (eds). Graft-vs-host Disease, 2nd edn. Marcel Dekker: New York, 1997; 257-289.
    136. Visentainer JE, Lieber SR, Persoli LB et al. Serum cytokine levels and acute graft-versus-host disease after HLA-identical hematopoietic stem cell transplantation. Exp Hematol. 2003 Nov;31(11): 1044-1050.
    
    137. Hempel L, Korholz D, Nussubaum P et al. High interleukin-10 serum levels are associated with fatal out come in patients after bone marrow transplantation. Bone Marrow Transplant 1997; 20: 365-385.
    
    138. Miura Y, Thoburn CJ, Bright EC, Chen W, Nakao S, Hess AD. Cytokine and chemokine profiles in autologous graft-versus-host disease (GVHD): interleukin 10 and interferon gamma may be critical mediators for the development of autologous GVHD. Blood. 2002 Oct 1;100(7):2650-2658.
    
    139. Correia O, Delgado L, Barbosa IL, Campilho F, Fleming-Torrinha J. Increased interleukin 10, tumor necrosis factor alpha, and interleukin 6 levels in blister fluid of toxic epidermal necrolysis. J Am Acad Dermatol. 2002 Jul;47(1):58-62.
    
    140. Imoto S, Oomoto Y, Murata K, Das H, Murayama T, Kajimoto K, Sugimoto T, Gomyo H, Nakagawa T, Nishimura R, Koizumi T. Kinetics of serum cytokines after allogeneic bone marrow transplantation: interleukin-5 as a potential marker of acute graft-versus-host disease. Int J Hematol. 2000 Jul;72(1):92-97.
    
    141. Jordan WJ, Brookes PA, Szydlo RM, Goldman JM, Lechler RI, RitterMA. IL-13 production by donor T cells is prognostic of acute graft-versus-host disease following unrelated donor stem cell transplantation. Blood. 2004 Jan 15;103(2):717-24. Epub 2003 Sep 25.
    
    142. Xian, L.C., Zand, M.S., Li, Y.. On histocompatiblity barriers, Th1 to Th2 immune deviation, and the nature of the allograft responses. J Immunol 1998; 161:2241-2247.
    
    143. Krenger, W., et al. Transplantation of polarized type 2 donor T cells reduces mortality caused by experimental graft-versus-host disease. Transplantation 1996; 62: 1278-1285.
    
    144. Murphy, W.J., et al. Differential effects of the absence of interferon-γ and IL-4 in acute graft-versus-host disease after allogeneic bone marrow transplantation in mice. J Clin Invest 1998; 102: 1742-1748.
    
    145. Takai, S., et al. Increased IgE level as a marker of host-versus-graft disease inhibition of this HVGD with a monoclonal antibody to IL-4. Cell Immunol 1993; 149: 1-10.
    
    146. Heyd, J., Doonenberg, A.D., Burns, W.H., et al. Immunoglobulin E levels following allogeneic, autologous and syngeneic bone marrow transplantation: an indirect association between hyperproduction and acute GVHD in allogeneic bone marrow transplantation. Blood 1998; 72: 442-446.
    
    147. Sad S, Marcotte R, Mosmann TR. Cytokine-induced differentiation ofprecursor mouse CD8+ T cells into cytotoxic CD8+ T cells secreting Th1 or Th2 cytokines. Immunity 1995; 2: 271-279.
    
    148. Cronin DN, Stack R, Fitch FW. IL-4 producing CD8+ T cell clones can provide B cell help. J Immunol 1995; 154: 3118-3127.
    
    149. Noble A, Macary PA, Kemeny DM. IFN-gamma and IL-4 regulate the growth and differentitiation of CD8+ T cells into subpopulations with distinct cytokine profiles. J Immunol 1995; 155: 2928-2937.
    
    150. Macary PA, Holmes BJ, Kemeny DM. Ovalbumin-specific MHC class-I restricted alpha beta-positive rat Tc1 and Tc0 CD8+ T cell clones mediate the in vivo inhibition of rat IgE. J Immunol 1998; 160: 580-587.
    
    151. Maggi E, Giudizi MG, Biagiotti R, et al. Th2-like CD8+ T cells showing B cell helper function and reduced cytolytic activity in human immunodeficiency virus type 1 infection. J Exp Med 1994; 180: 489-495.
    
    152. Kennedy MK, Picha KS, Fanslow WC et al. CD40/CD40L ligand interactions are required for T cell-dependent production of interleukin-12 by mouse macrophages. Eur J Immunol 1996; 26: 370-378.
    
    153. McDyer JF, Goletz TJ, Thomas E et al. CD401igand/CD40 stimulation regulates the production of IFN-gamma from human peripheral blood mononuclear cells in an IL-12 and/or CD28-dependent manner. J Immunol 1998; 160: 1701-1701.
    154. Fowler DH, Breglio J, Nagel G et al. Allospecific CD8+ Tc1 and Tc2 populations in graft-versus-leukemia effect and graft-versus-host disease. J Immunol 1996; 157: 4811-4821.
    
    155. Carter LL, Dutton RW. Relative perforin- and Fas- mediated lysis in T1 and T2 CD8 effector populations. J Immunol 1995; 155: 1028-1031.
    
    156. Milica Vukmanovic-Stejic, Beejal Vyas, Patricia Gorak-Stolinska et al. Human Tc1 and Tc2/Tc0 CD8 T-cell clones display distint cell surface and functional phenotypes. Blood 2000; 95: 231-240.
    
    157. Li L, Sad S, Kagi D et al. CD8Tc1 and Tc2 cells secrete distinct cytokine patterns in vitro and in vivo but induce similar inflammatory reactions. J Immunol 1997; 1: 4152-4161.
    
    158. Tsukada, N., Kobata, T., Aizawa, Y., et al. Graft-versus-leukemia effect and graft-versus-host disease can be differentiated by cytotoxic mechanisms in a murine model of allogeneic bone marrow transplantation. Blood 1999; 93:2738-2747.
    
    159. Miwa, K., et al. Therapeutic effect of an anti-Fas ligand mAb on lethal graft-versus-host disease. Int Immunol 1999; 11: 925-931.
    
    160. Boris Nikolic, Seika Lee, Roderick T et al. Th1 and Th2 mediate acute graft-versus-host disease, each with distinct end-organ targets. J Clin Invest 2000; 105: 1289-1298.
    161. Fowler DH, Whitfield B, Liveingston M et al. Non-host-reactive donor CD8+ T cells of Tc2 phenotype potently inhibit marrow graft rejection. Blood 1998; 91: 4045-4050.
    
    162. Fowler DH, Gress RE. Th2 and Tc2 cells in the regulation of GVHD, GVL, and graft rejection: considerations for the allogeneic transplantation therapy of leukemia and lymphoma. Leuk Lymphoma 2000; 38: 221-234.
    
    163. Hiruma K, Nakamura H, Henkart PA et al. Clonal deletion of postthymic T cells: Veto cells kill precursor cytotoxic T lymphocytes. J Exp Med 1992; 175: 863.

© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号

地址:北京市海淀区学院路29号 邮编:100083

电话:办公室:(+86 10)66554848;文献借阅、咨询服务、科技查新:66554700