环孢霉素A气雾吸入对哮喘小鼠气道炎症及CD4~+CD25~+IL-10~+T细胞的影响
|
摘要
背景和目的支气管哮喘简称哮喘,是世界范围内严重危害公众健康的一种常见病,其病因及发病机制复杂、治疗棘手,难以根除。糖皮质激素(GCs)是治疗哮喘的有效药物,已能有效控制大多数患者的症状,但长期应用可带来严重的副作用。最近发达国家的哮喘普遍增加并成为主要的健康和经济后果令人不安。寻找安全有效的哮喘治疗切入点十分迫切。Th2型细胞源性细胞因子的中心作用表明,治愈或提供长期解除哮喘症状需针对变应原特异性Th2细胞反应。哮喘患者体内存在IL-10含量下降及调节性T细胞(Tregs)功能受损。IL-10的分泌Tregs以IL-10依赖方式抑制变应原特异性Th2细胞细胞因子分泌。一种替代和更具吸引力的策略是通过诱导具有提供安全和长期减轻疾病症状潜力的变应原激活的IL-10的分泌Tregs提供内源性抑制信号。诱导抗原特异性IL-10的分泌Tregs是今后哮喘治疗一个有吸引力的领域。IL-10在IL-10的分泌Tregs的功能活动及抑制Th2反应和过敏反应中发挥重要作用,其强力的抗炎和抑制免疫性质成为一个控制哮喘反应的有吸引力的细胞因子。研究表明,某些免疫方案及钙通道阻滞剂能诱导IL-10的合成,临床上对GCs没有反应的病人在体内同样不能出现GCs诱导的IL-10的合成,诱导IL-10的合成可能有助于GCs治疗哮喘的临床疗效。有可能利用这些影响,通过GCs单独或连同其他药物治疗诱发抗原特异性IL-10的分泌Tregs,诱导IL-10的合成改善哮喘症状。环孢霉素A(CsA)是一个众所周知的通过抑制钙调神经磷酸酶(CaN)活性阻止核因子NF-AT移位到细胞核的免疫抑制剂,能抑制哮喘气道炎症,减少哮喘GCs用量,但其具体作用机制尚未阐明。本研究旨在观察CsA对卵白蛋白(OVA)诱导的小鼠哮喘模型细胞因子IL-10、IL-4、IL-5、IL-2、IFN-γ及炎症细胞、CD4~+CD25~+IL-10~+T细胞的影响,将IL-10、CD4~+CD25~+IL-10~+T细胞联系起来进一步探讨CsA抑制哮喘炎症、免疫的可能机制,为临床综合治疗及开发新药提供理论及实验依据。
方法实验分为对照组,哮喘模型组,CsA组和CsA+IL-10抗体组。用OVA腹腔致敏、雾化激发建立哮喘BALB/c小鼠模型(n=40)。ELISA法检测BALF中IL-4、IL-5、IL-2、IL-10和IFN-γ水平。肺组织病理切片HE、AB/PAS染色观察肺组织炎症情况。流式细胞仪检测肺组织CD4~+CD25~+IL-10~+T细胞百分率。
结果CsA雾化后BALF中炎症细胞细胞数量明显减少,IL-4、IL-5、IL-2水平明显降低(p<0.01),IL-10的含量明显增高(p<0.01)。切片HE、AB/PAS染色显示肺组织及杯状细胞炎症消退明显。同时,肺组织CD4~+CD25~+IL-10~+T细胞百分率明显高于对照组及模型组(p<0.01)。使用IL-10抗体后哮喘炎症较单独使用CsA组加重。
结论1 CsA可以抑制哮喘小鼠气道炎症,该项作用可能通过上调IL-10分泌来实现,CD4~+CD25~+IL-10~+T细胞可能在其中起重要作用。
2 CsA通过诱发CD4~+CD25~+IL-10~+T细胞,诱导IL-10的合成可能有治疗哮喘的潜在理论和实践价值。
Background and Purpose:Bronchial asthma,also named asthma,is a common disease which becomes a severe hazard to public health,affected worldwide.As a result of the unknown etiology and complex mechanism,the therapy of asthma is still an intractable problem.Although inhaled glucocorticoids(GCs) are very effective for the treatment of most patients with asthma,an important subgroup of patients require oral GCs to control their disease at the risk of considerable side effects.The recent disturbing increase in the prevalence of asthma in the developed world has major health and economic consequences.Thus,it is imperative that we should look for a breakthrough in the asthmatic treatment.The central role of Th2-cell-derived cytokines indicates that strategies to cure or provide long-term relief from asthma symptoms need to target this allergen-specific Th2 response.The patients of asthma usually have an impair function of regulatory T cells(Tregs) and a low level of IL-10.allergen-induced cytokine production by allergen-specific Th2 cells was inhibited by allergen-induced IL-10-secreting Tregs in an IL-10-dependent manner.an alternative and more attractive strategy is the local delivery of inhibitory signals through the induction of allergen-activated IL-10-secreting Tregs.Induction of antigen-specific IL-10-secreting Tregs is an appealing future therapeutic area for asthma.IL-10 plays an essential role in the functional activities of IL-10-secreting Tregs and in the regulation of Th2 responses and allergic responses.The anti-inflammatory and immunological properties of IL-10 make it an attractive cytokine for the control of asthmatic responses.Several immunomodulatory regimens and calcium channels blocker have been shown to increase IL-10 synthesis.Induction of IL-10 synthesis may contribute to the clinical efficacy of GCs therapy in asthma since patients who fail to respond clinically to GCs also fail to respond ex vivo to GCs for induction of IL-10 synthesis.it might be possible to harness these effects to promote the induction of antigen-specific IL-10- secreting Tregs,either by treatment with GCs alone or together with other drugs,induction of IL-10 synthesis is associated with amelioration of disease symptoms.Cyclosporine A(CsA) is a well-known immunosuppressant that blocks NF-AT translocation into the nucleus by inhibition calcineurin phosphatease activity.It was proved that can inhibit airway inflammation and decrease the dosage of GCs,but the mechanism of its anti-inflammatory function is still unclear.The purpose of our study is to observe the influence of CsA on the level of IL-10、IL-4、IL-5、IL-2、IFN-γand inflammatory cells in ovalbumin(OVA) -induced mouse model and detect the relationship between IL-10 and CD4~+CD25~+IL-10~+T cells,consequently,investigate the mechanism of resolution in asthmatic inflammation and provide the oretical basis for the clinical therapy and development of new drugs in asthma.
Material and methods:BALB/c mice(n=40) were divide into four groups:control group,model group,CsA group and CsA +anti-IL-10 antibody group(n=40).Mice were sensitized to OVA by intraperitoneal injection and challenged with OVA aerosol for 7 consecutive days.The concentration of cytokines including IL-4、IL-5、IL-2、IL-10 and IFN-γin BALF were measured by using ELISA Kits.Lung tissue sections were stained with hematoxylin-eosin(HE) and Alcian blue /periodic acid Schiff(AB/PAS) to observe general morphology and goblet cells.Flow cytometry were used to detect the percentage of CD4~+CD25~+IL-10~+T cells.
Results:Treated by CsA aerosol significantly reduced the numbers of inflammatory cells and the level of IL-4JL-5 and IL-2,also,resolved pulmonary infiltration of inflammatory and goblet cells hyperplasia,with a high level of IL-10 in BALF (p<0.01).Further,the percentage of CD4~+CD25~+IL-10~+T cells presented negative correlations with the numbers of inflammatory cells,goblet cells hyperplasia and the levels of Th2 cytokines(p<0.01).
Conclusions:1.CsA can inhibit airway inflammation in asthmatic mouse,as a result of the up-regulation in the level of IL-10 probably.CD4+CD25+IL-10+T cells may play an important role during the process.
2.CsA-induced increase of CD4~+CD25~+IL-10~+ T cells to up-regulate the level of IL-10 may provide theoretical basis and practical value.
方法实验分为对照组,哮喘模型组,CsA组和CsA+IL-10抗体组。用OVA腹腔致敏、雾化激发建立哮喘BALB/c小鼠模型(n=40)。ELISA法检测BALF中IL-4、IL-5、IL-2、IL-10和IFN-γ水平。肺组织病理切片HE、AB/PAS染色观察肺组织炎症情况。流式细胞仪检测肺组织CD4~+CD25~+IL-10~+T细胞百分率。
结果CsA雾化后BALF中炎症细胞细胞数量明显减少,IL-4、IL-5、IL-2水平明显降低(p<0.01),IL-10的含量明显增高(p<0.01)。切片HE、AB/PAS染色显示肺组织及杯状细胞炎症消退明显。同时,肺组织CD4~+CD25~+IL-10~+T细胞百分率明显高于对照组及模型组(p<0.01)。使用IL-10抗体后哮喘炎症较单独使用CsA组加重。
结论1 CsA可以抑制哮喘小鼠气道炎症,该项作用可能通过上调IL-10分泌来实现,CD4~+CD25~+IL-10~+T细胞可能在其中起重要作用。
2 CsA通过诱发CD4~+CD25~+IL-10~+T细胞,诱导IL-10的合成可能有治疗哮喘的潜在理论和实践价值。
Background and Purpose:Bronchial asthma,also named asthma,is a common disease which becomes a severe hazard to public health,affected worldwide.As a result of the unknown etiology and complex mechanism,the therapy of asthma is still an intractable problem.Although inhaled glucocorticoids(GCs) are very effective for the treatment of most patients with asthma,an important subgroup of patients require oral GCs to control their disease at the risk of considerable side effects.The recent disturbing increase in the prevalence of asthma in the developed world has major health and economic consequences.Thus,it is imperative that we should look for a breakthrough in the asthmatic treatment.The central role of Th2-cell-derived cytokines indicates that strategies to cure or provide long-term relief from asthma symptoms need to target this allergen-specific Th2 response.The patients of asthma usually have an impair function of regulatory T cells(Tregs) and a low level of IL-10.allergen-induced cytokine production by allergen-specific Th2 cells was inhibited by allergen-induced IL-10-secreting Tregs in an IL-10-dependent manner.an alternative and more attractive strategy is the local delivery of inhibitory signals through the induction of allergen-activated IL-10-secreting Tregs.Induction of antigen-specific IL-10-secreting Tregs is an appealing future therapeutic area for asthma.IL-10 plays an essential role in the functional activities of IL-10-secreting Tregs and in the regulation of Th2 responses and allergic responses.The anti-inflammatory and immunological properties of IL-10 make it an attractive cytokine for the control of asthmatic responses.Several immunomodulatory regimens and calcium channels blocker have been shown to increase IL-10 synthesis.Induction of IL-10 synthesis may contribute to the clinical efficacy of GCs therapy in asthma since patients who fail to respond clinically to GCs also fail to respond ex vivo to GCs for induction of IL-10 synthesis.it might be possible to harness these effects to promote the induction of antigen-specific IL-10- secreting Tregs,either by treatment with GCs alone or together with other drugs,induction of IL-10 synthesis is associated with amelioration of disease symptoms.Cyclosporine A(CsA) is a well-known immunosuppressant that blocks NF-AT translocation into the nucleus by inhibition calcineurin phosphatease activity.It was proved that can inhibit airway inflammation and decrease the dosage of GCs,but the mechanism of its anti-inflammatory function is still unclear.The purpose of our study is to observe the influence of CsA on the level of IL-10、IL-4、IL-5、IL-2、IFN-γand inflammatory cells in ovalbumin(OVA) -induced mouse model and detect the relationship between IL-10 and CD4~+CD25~+IL-10~+T cells,consequently,investigate the mechanism of resolution in asthmatic inflammation and provide the oretical basis for the clinical therapy and development of new drugs in asthma.
Material and methods:BALB/c mice(n=40) were divide into four groups:control group,model group,CsA group and CsA +anti-IL-10 antibody group(n=40).Mice were sensitized to OVA by intraperitoneal injection and challenged with OVA aerosol for 7 consecutive days.The concentration of cytokines including IL-4、IL-5、IL-2、IL-10 and IFN-γin BALF were measured by using ELISA Kits.Lung tissue sections were stained with hematoxylin-eosin(HE) and Alcian blue /periodic acid Schiff(AB/PAS) to observe general morphology and goblet cells.Flow cytometry were used to detect the percentage of CD4~+CD25~+IL-10~+T cells.
Results:Treated by CsA aerosol significantly reduced the numbers of inflammatory cells and the level of IL-4JL-5 and IL-2,also,resolved pulmonary infiltration of inflammatory and goblet cells hyperplasia,with a high level of IL-10 in BALF (p<0.01).Further,the percentage of CD4~+CD25~+IL-10~+T cells presented negative correlations with the numbers of inflammatory cells,goblet cells hyperplasia and the levels of Th2 cytokines(p<0.01).
Conclusions:1.CsA can inhibit airway inflammation in asthmatic mouse,as a result of the up-regulation in the level of IL-10 probably.CD4+CD25+IL-10+T cells may play an important role during the process.
2.CsA-induced increase of CD4~+CD25~+IL-10~+ T cells to up-regulate the level of IL-10 may provide theoretical basis and practical value.
引文
[1]McFadden ER Jr.A century of asthma[J].Am J Respri Crit Care Med,2004,170(3):215-221.
[2]Eagan TM,Brogger JC,Eide GE,et al.The incidence of adult asthma:a review[J].Int J Tuberc Lung Dis,2005,9(6):603-612.
[3]Masoli MFD,Holt S,Beasley R.Global Initiative for Asthma(GNIA) Porgram The global burden of asthma:executive summary of the GINA Dissemination Committee report[J].Allergy,2004,59(5):469-478.
[4]Hawrylowicz CM,O'Garra A.Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma[J].Immunology,2005,5(4):271-283.
[5]Ling E M,Smith T,Nguyen X D,et al.Relation of CD4~+CD25~+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease[J].Lancet,2004,363(9409):608-615.
[6]Akbari O,Freeman GJ,Meyer EH,et al.Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergeninduced airway hyperreactivity[J].Nature Med,2002,8(9):1024-1032.
[7]Hawrylowicz CM.Correction of the defect in glucocorticoid induced IL-10synthesis in T cells from glucocorticoid resistant asthmatic patients[J].J Allergy Clin Immunol,2004,113(Suppl),A735.
[8]Akdis M,Verhagen J.Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells[J].J Exp Med,2004,199(11):1567-1575.
[9]Borish L,Aarons A,Rumbyrt J,et al.Interleukin-10 regulation in normal subjects and patients with asthma[J].J Allergy Clin Immunol,1996,97(6):1288-1296.
[10]van Oosterhout AJM,Bloksma N.Regulatory T-lymphocytes in asthma[J].Eur Respir J.2005;26(5):918-932.
[11]Akdis M.Healthy immune response to allergens:T regulatory cells and more[J].Curr Opin Immunol,2006,18(6):738-744.
[12]Jutel M,Akdis M,Blaser K,et al.Mechanisms of allergen specific immunotherapy-T-cell tolerance and more[J].Allergy,2006,61(7):796-807.
[13]Xystrakis E,Kusumakar S,Boswell S,et al.Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid- resistant asthma patients[J].J Clin Invest,2006,116(1):146-155.
[14]Moore KW,de Waal Malefyt R,Coffman RL,et al.Interleukin-10 and the interleukin-10 receptor[J].Annu Rev Immunol,2001,19:683-765.
[15]Peek EJ,Richards DF,Faith A,et al.Interleukin-10-secreting"regulatory" T cells induced by glucocorticoids and beta2-agonists[J].Am J Respir Cell Mol Biol,
2005,33(1):105-111.
[16]Akdis M,Akdis CA.Mechanisms of allergen-specific immunotherapy[J].J Allergy Clin Immunol,2007,119(4):780-789.
[17]Appleman L J,Boussiotis V A.T cell anergy and costimulation[J].Immunol Rev,2003,192(2):161-180.
[18]Asadullah K,Sterry W,Volk HD.Interleukin-10 therapy- review of a new approach [J].Pharmacol Rev,2003,55(2):241-269.
[19]Cobbold S P,Castejon R,Adams E,et al.Induction of Foxp3~+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants[J].J Immunol,2004,172(10):6003-6010
[20]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].J Exp Med,2002,195(5):603-616.
[21]Hawrylowicz C,Richards D,Loke T K,et al.A defect in corticosteroid-induced IL-10 production in T lymphocytes from corticosteroid-resistant asthmatic patients [J].J Allergy Clin Immunol,2002,109(2):369-370.
[22]Vieira PL,Christensen JR,Minaee S,et al.IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4~+CD25~+ regulatory T cells[J].J Immunol,2004,172(10):5986-5993.
[23]Karagiannidis C,Akdis M,Holopainen P,et al.Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma[J].J Allergy Clin Immunol,2004,114 (6):1425-1433.
[24]Dunn C J,Wagstaff A J,Perry CM,et al.Cyclosporin:an updated review of the pharmacokinetic properties,clinical efficacy and tolerability of a microemulsionbased formulation (neoral)1 in organ transplantation[J].Drugs,2001,61(13):1957-2016.
[25]Lock SH,Kay AB,Barnes NC.Double-blind,placebo-controlled study of cyclosporin A as a corticosteroid-sparing agent in corticosteroid-dependent asthma[J].Am J Respir Crit Care Med,1996,153(2):509-514.
[26]Mantel PY,Ouaked N,Ruckert B,et al.Molecular mechanisms underlying FOXP3 induction in human T cells[J].J Immunol,2006,176(6):3593-3602.
[27]Corrigan CJ,Brown PH,Barnes NC,et al.Glucocorticoid resistance in chronic asthma.Peripheral blood T lymphocyte activation and comparison of the T lymphocyte inhibitory effects of glucocorticoids and cyclosporin A [J].Am Rev Respir Dis,1991,144(5):1026-1032.
[28]Windt LJ,Lim HW,Haq S,etal.Caleineurin promotes protein kinase C and c-Jun NH2-terminal kinase activation in the heart[J].J Biol Chem,2000,275(8):13571-13579.
[29]Wassim Y,Almawi,Ohaaes K,et al.Clinical and mechanistic differences between FK506(tacrolimus) and cyclosporin A[J].Nephrol Dial Transplant,2000,15(12):1916-1918.
[30]Feske S,Giltuane J,Dolmetsh R,et al.Gene regulation mediated by calcium signals in T lymphocytes[J].Nat Immunol,2001,(4)2:316-324.
[31]Sigal NH,Dumont FJ.Cyclosporin A,FK-506,and rapamycin:pharmacologic probes of lymphocyte signal transduction[J].Annu Rev Immunol,1992,10(4):519-560.
[32]Tajjma K,Amakawa R,Ito T et al.Immunomodulatory effect of cyclosporin A on humanperipheral blood dentritic cell subsets[J].Immunology,2003,108(3):321-328.
[33]Dao Nguyen X,ORbinson DS.Fluticasone propionate increases CD4~+CD25~+ T Regulatory cell suppression of allergen stimulated CD4~+CD25~- T cells by an IL-10-dependent mechanism[J].J Allergy Clin Immunol,2004,114(2):296-301.
[34]Zhou J,Liu DF,Liu C,et al.Glucocorticoids inhibit degranulation of mast cells in allergic asthma via nongenomic mechanism[J].AUergy,2008,63(9):1177-1185.
[35]Taylor A,Verhagen J,Blaser K,et al.Mechanisms of immune suppression by interleukin-10 and transforming growth factor-p:the role of T regulatory cells [J].Immunology,2006,117(4):433-442.
[36]Zheng SG,Wang JH,Gray JD,et al.Natural and induced CD4~+CD25~+ cells educate CD4~+ CD25~- cells to develop suppressive activity:the role of IL-2,TGF-β,and IL-10[J].J Immunol,2004,172(9):5213-5221.
[37]Murray PJ.STAT3-mediated anti-inflammatory signalling[J].Biochem Soc Trans,2006,34(Pt 6):1028-1031.
[38]Finbloom DS,Winestock KD.IL-10 induces the tyrosine phosphorylation of tyk2 and Jak 1 and the differential assembly of STAT1 alpha and STAT3complexes in human T cells and monocytes[J].J Immunol,1995,155(3):1079-1090.
[39]Tsuji-Takayama K,Suzuki M,Yamamoto M,et al.IL-2 activation of STAT5enhances production of IL-10 from human cytotoxic regulatory T cells[J].Exp Hematol,2008,36(2):181-192.
[40]Sheng KC,Pietersz GA,Wright MD,et al.Dendritic cells:activation and maturation-applications for cancer immunotherapy[J].Curr Med Chem,2005,12(15):1783-1800.
[41]Venet F,Pachot A,Debard AL,et al.Human CD4~+CD25~+ regulatory T lymphocytes inhibit lipopolysaccharide-induced monocyte survival through a Fas/Fas ligand-dependent mechanism[J].J Immunol,2006,177(9):6540-6547
[42]Dieckmann D,Bruett CH,Ploettner H,et al.Human CD4~+CD25~+ regulatory,contact-dependent T cells induce interleukin 10-producing,contact-independent type 1-like regulatory T cells[J].J Exp Med,2002,196(2):247-253.
[43]Xia ZW,Zhong WW,Xu LQ,et al.Heme oxygenase-1-mediated CD4~+CD25~(high)regulatory T cells suppress allergic airway inflammation[J].J Immunol,2006,177(9):5936-5945.
[44]Levings MK,Sangregorio R,Galbiati F,et al.IFN- alpha and IL-10 induce the differentiation of human type 1 T regulatory cells[J].J Immunol,2001,166(9):5530-5539.
[45]Ding Q,Lu L,Wang B,et al.B7H1-Ig fusion protein activates the CD4~+ IFN-γreceptor~+ type 1 Tregulatory subset through IFN-γ- secreting Th1 cells[J].J Immunol,2006,177(6):3606-3614.
[46]Bluestone J A,Abbas A K.Natural versus adaptive regulatory T cells[J].Nat Rev Immunol,2003,3(3):253-257.
[47]Lan RY,Ansari AA,Lian ZX,et al.Regulatory T cells:development,function and role in autoimmunity[J].Autoimmun Rev,2005,4(6):351-363.
[48]Gardner LM,Thien F C.Douglass JA,et al.Induction of T regulatory cells by Standardized housedustmite immuno therapy:an increase in CD4~+CD25~+ interleukin-10~+T cells expressing peripheral tissue trafiqcking markers[J].Clin Exp Allergy,2004,34(8):1209-1219.
[49]Francis JN,Til SJ,Durham S R.In duction of IL-10~+CD4~+CD25~+T cells by Grass polen immunotherapy[J].J Allergy Clin Immunol,2003,lll(6):1255-1261.
[50]Kagoshima M,Wilcke T,Ito K,et al.Glucocorticoid-mediated transre pression is regulated by histoneacetylation and DNA methylation [J].Eur J Pharmacol,2001,429 (123):327-334.
[51]Sundstedt A,O'Neill E J,Nicolson KS,et al.Role for IL-10 in suppression mediated by peptide-induced regulatory T cells in vivo[J].J Immunol,2003,170(3):1240-1248.
[52]O'Garra A,Vieira P L,Vieira P,et al.IL-10-producing and naturally occurring CD4~+ T Regs:limiting collateral damage[J].J Clin Invest,2004,114(10):1372-1378.
[53]Conti P,Kempuraj D,Kandere K,et al.IL-10,an inflammatory/inhibitory cytokine,but not always[J].Immunol Lett,2003,86(2):123-129.
[54]Hori S,Nomurat T,Sakaguchi S.Control of regulatory T cell development by the transcription factor Foxp3[J].Science,2003,299(5609):1057-1061.
[55]Ziegler SF.Foxp3:of mice and men [J].Annu Rev Immunol,2006,24 (1):209-226.
[56]Bettelli E,Dastrange M,Oukka M.Foxp3 interacts with nuclear factor of activated T cells and NF-kB to repress cytokine gene expression and effector functions of T helper cells[J].Proc Nat Acad Sci USA,2005,102 (14):5138-5143.
[57]Gambineri E,Torgerson TR,Ochs HD.Immune dysregulation,polyendo-crinopathy,enteropathy,and X-linked inheritance (IPEX),a syndrome of systemic autoimmunity caused by mutations of Foxp3,a critical regulator of T-cell homeostasis [J].Curr Opin Rheumatol,2003,15(4):430-435.
[58]Wu Y,Borde M,Heissmeyer V,et al.FOXP3 controls regulatory T cell function through cooperation with NFAT[J].Cell,2006,126(2):375-387.
[59]Fu S,Zhang N,Yopp AC,et al.TGF-P induces Foxp3~+T-regulatory cells from naive CD4~+CD25~+precursors[J].Am J Transplant,2004,4(10):1614-1627.
[60]Zorn E,Nelson EA,Mohseni M,et al.IL-2 regulates FOXP3 expression in human CD4~+CD25~+ regulatory T cells through a STAT dependent mechanism and induces the expansion of these cells in vivo[J].Blood,2006,108(5):1571-1579.
[1]Spinozzi F,Fizzotti M,Agea E,et al.Defective expression of Fas messenger RNA and Fas receptor on pulmonary T cells from patients with asthma [J].Annal Intern Med,1998,128 (5):363-369.
[2]Harald Wajant,Klaus Pfizenmaier,et al.Non-apoptotic Fas signaling[J].Cytokine Growth Factor Rev,2003,1453-1466.
[3]Wada A,Tada Y,Kawamura K,et al.The effects of FasL on inflammation and tumor survival are dependent on its expression levels[J].Cancer Gene Ther,2007,14(3):262-267.
[4]Gaur U,Aggarwal BB.Regulation of proliferation,survival and apoptosis by members of the TNF superfamily[J].Biochem Pharmacol,2003,66 (8):1403-1408.
[5]Krammer PH.CD95's deadly mission in the immune system [J].Nature,2000,407(6805):789-795.
[6]Liao WT,Chang KL,Yu CL,et al.Arsenic induces human keratinocyte apoptosis by the Fas/Fas ligand pathway,which correlates with alterations in nuclear factor-k.B and activator protein-1 activity[J].Invest Dermatol,2004,122(1):125-129
[7]Nagata S,Golstein P.The Fas death factor[J].Science,1995,267 (5203):1449-1456
[8]Liao X,Wang XH,Gu Y,et al.Involvement of death receptor signaling in mechanical stretch-induced cardiomyocyte apoptosis[J].Life Sci,2005,77(2):160-174.
[9]Donepudi M,Sweeney AM,Briand C,et al.Insights into the regulatory mechanism for Caspase-8 activation[J].Mol Cell,2003,11(2):543-549.
[10]Nitobe J,Yamaguchi S,Okuyama M,et al.Reactive oxygen species regulate FLICE inhibitory protein (FLIP) and susceptibility to Fas-mediated apoptosis in cardiac myocytes[J].Cardiovasc Res,2003,57(1):119-128.
[11]Kataoka T,Budd RC,Holler N,et al.The caspase-8 inhibitor FLIP promotes activation of NF-κB and Erk signaling pathways[J].Curr Boil,2000,10(11):640-648.
[12]Steenbergen C,Afshari CA,Petranka JG.Alterations in apoptotic signaling in human idiopathic cardiomyopathic hearts in failure[J].Am J Physiol Heart Circ Physiol,2003,284(1):H268-276.
[13]Barac YD,Zeevi-Levin N,Yaniv G.The 1,4,5-inositol trisphosphate pathway is a key component in Fas-mediated hypertrophy in neonatal rat ventricular myocytes[J].Cardiovasc Res,2005,68 (1):75-86.
[14]Suzuki I,Fink PJ.Maximal proliferation of cytotoxic T lymphocytes requires reverse signaling through Fas ligand[J].J Exp Med,1998,l87(1):123-128.
[15]Guo ZH,Zhang MH,An HZ,et al.Fas ligation induces IL-1β-dependent maturation and IL-1β-independent survival of dendritic cells:diffrent roles of ERK and NF-κB singaling pathways[J].Blood,2003;102(13):4441-4447.
[16]Leone V,di Palma A,Ricchi P,et al.PGE2 inhibits apoptosis in human adenocarcinoma Caco-2 cell line through Ras-PI3K association and cAMP-dependent kinase A activation[J].Am J Physiol Gastrointest Liver Physiol,2007,293(4):G673-681.
[17]Owen-Schaub LB,Angelo LS,Radinsky R,et al.Soluble Fas/APO-1 in tumor cells:a potential regulator of apoptosis[J]? Cancer Lett,1995,94(1):1-8.
[18]Timmer T,de Vries GE,de Jong S.Fas receptor-mediated apoptosis:a clinical application?[J].J Pathol,2002,196 (2):125-134.
[19]Silvestris F,Cafforio P,Tucci M,et al.VEINCTR-N,an immunogenic epitope of Fas(CD95/Apo-l),and soluble Fas enhance T cell apoptosis in vitro.Ⅱ. Functional analysis and possible implications in HIV-1 disease[J].Mol Med,2000,6(6):509-526.
[20]Proussakova OV,Rabaya NA,Moshnikova AB,etal.Oligomerization of soluble Fas antigen induces its cytotoxicity[J].J Biol Chem,2003,278(38):36236-36241.
[21]Meier P,Blanc E.Plasma level of soluble Fas is an independent marker of cardiovascular disease in ESRD patients[J].Kidney Int,2003,64(4):1532-1533.
[22]Fruman DA.Phosphoinositide 3-kinase and its targets in B-cell and T cell signaling[J]Curr Opin Immunol,2004,16(3):314-320.
[23]Alcazar I,Marques M,Kumar A,et al.Phosphositide 3-kinase y participates in T cell receptor-induced T cell activation[J].J Exp Med,2007,204(12):2977-2987.
[24]McGinn S,Saad S,Poronnik P,et al.High glucose-mediated effects on endothelial cell proliferation occur via p38 MAP kinase[J].Am J Physiol Endocrinol Metab,2003,285(4):E708-717.
[25]Dodeller F,Skapenko A,Kalden JR,et al.The P38 mitogen-activated protein kinase regulates effector functions of primary human CD4 T cells[J].Eur J Immunol,2005,35(12):3631-3642.
[26]Das J,Chen C H,Yang L et al.A critical role for NF-κB in GATA3expression and Th2 differentiation in allergic airway inflammation[J].Nat Immunol,2001,2(1):45-50.
[27]Amigorena S.Fcγ receptors and cross-presentation in dendritic cells[J].J Exp Med,2002,195(1):F1-F3.
[28]Julia V,Hessel EM,Malherbe L,et al.A restricted subset of dendritic cells captures airborne antigens and remains able to activate specific T cells long after antigen exposure[J].Immunity,2002,16(2):271-283
[29]Rescigno M,Piguet V,Valzasina B,et al.Fas engagement induces the maturation of Dendritic cells(DCs),the release of interleukin(IL)-1β,and the production of interferon gamma in the absence of IL-12 during DC-T cell cognate interactions new role for Fas lignad in inflammatory responses[J].J Exp Med,2000,192(11):1661-1668.
[30]Kato Y,Negishi T,Furusako S,et al.An orally active Th1/Th2 balance modulator,M50367,suppresses Th2 differentiation of na(?)ve Th cell in vitro[J].Cell Immunol,2003,224(1):29-37.
[31]Bakir HY,Tomiyam-Miyaji C,Watanabe H,et al.Reasons why DBA /2 mice are resistant to malarial infection:expansion of CD3 int B220~+ γδ T cells with double-negative CD4CD8" phenotype in the liver[J].Immunol,2006,117 (1):127-135.
[32]Giffith TS,Ferguson TA.The role of FasL-induced apoptosis in immune privilege [J].Immunol Today,1997,18(5):240-244
[33]Lenardo M,Chan FKM,Hornung F,et al.Mature T lymphocyte apoptosisimmune regulation in a dynamic and unpredictable antigenic environment [J].Annu Rev Immunol,1999,17:221-253.
[34]Josien R,Müschen M,Gilbert E,et al.Fas ligand,tumor necrosis factor-a expression,and apoptosis during allograft rejection and tolerance[J].Transplantation,1998,66(7):887-893.
[35]Woodside KJ,Hu M,Meng T,et al.Differential effects of interleukin-2 blockade on apoptosis in naive and activated human lymphocytes[J].Transplantation,2003,75(10):1631-1635.
[36]Sobek V,Balkow S,Korner H,et al.Antigen-induced cell death of T effector cells in vitro proceeds via the Fas pathway,requires endogenous interferon-γ and is independent of perforin and granzymes[J].Eur J Immunol,2002,32(9):2490-2499.
[37]Dhein J,Walczak H,Baumler C,et al.Autocrine T-cell suicide mediated by APO-1/(Fas/ CD95 )[J].Nature,1995,373(6513):438-341.
[38]Baumann S,Dostert A,Novac N,et al.Glucocorticoids inhibit activation-induced cell death(AICD) via direct DNA-dependent repression of the CD95 ligand gene by a glucocorticoid receptor dimmer[J].Blood,2005,106(2):617-625.
[39]Yolcu ES,Ash S,Kaminitz A,Sagiv Y,Apoptosis as a mechanism of T-regulatory cell homeostasis and suppression.Immunol Cell Biol,2008,86(8):650-658.
[40]Green DR,Droin N,Pinkoski M.Activation-induced cell death in T cells [J].Immunol Rev,2003,193(1):70-81
[41]Kirchhoff S,Muller WW,Li-Weber M,et al.Up-regulation of c-FLIP short and reduction of activation-induced cell death in CD28-co- stimulated human T cells[J].Eur J Immunol,2000,30(10):2765-2774.
[42]Li XC,Wells AD,Strom TB,et al.The role of T cell apoptosis in transplantation tolerance[J].Curr Opin Immunol,2000,12(5):522-527.
[43]Eder AM,Dominguez L,Franke T F,et al.Phosphoinositide 3-kinase regulation of T cell receptor-mediated interleukin-2 gene expression in normal T cells[J].J Biol Chem,1998,273(43):28025-28031.
[44]Marrack P,Bender J,Hildeman D,et al.Homeostasis of αβTCR+T cells[J].Nat Immunol,2000,1(2):107-111.
[45]Algeciras-Schimnich A,Griffith TS,Lynch DH,et al.Cell cycledependent regulation of FLIP levels and susceptibility to Fas-mediated apoptosis[J].J Immunol,1999,162(9):5205-5211.
[46]Yolcu ES,Gu X,Lacelle C,Zhao H,Induction of tolerance to cardiac allografts using donor splenocytes engineered to display on their surface an exogenous fas ligand protein[J].J Immunol,2008,181(2):931-939.
[47]Tao R,Hancock WW.Regulating regulatory T cells to achieve transplant tolerance [J].HBPD INT,2007,6(4):348-357.
[48]Critchfield JM,Racke MK,Zuniga-Pflucker JC,et al.T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis[J].Science,1994,263(5150):1139-1143.
[49]Dhodapkar MV,Steinman RM,Krasovsky J,et al.Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells [J].J Exp Med,2001,193(2):233-238.
[50]Van Rijt LS,Lambrecht BN.Dendritic cells in asthma:a function beyond sensitization[J].Clin Exp AIlergy,2005,35(9):1125-1134.
[51]Sheng KC,Pietersz GA,Wright MD,et al.Dendritic cells:activation and maturation-applications for cancer immunotherapy[J].Curr Med Chem,2005,12(15):1783-1800.
[52]Chen WJ,Frank ME,Jin W,et al.TGF-p released by apoptotic T cells contributes to an immunosuppressive milieu[J].Immunity,2001,14(6):715-725.
[53]Venet F,Pachot A,Debard AL,et al.Human CD4~+CD25~+ regulatory T lymphocytes inhibit lipopolysaccharide-induced monocyte survival through a Fas /Fas ligand-dependent mechanism[J].J Immunol,2006,177(9):6540-6547.
[54]Hara M,Kingsley Cl,Niimi M,et al.IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo[J].J Immunol,2001,166(6):3789-3796.
[55]Baecher-Allan C,Brown JA,Freeman GJ,et al.CD4~+CD25~(high) regulatory cells from human peripheral blood express very high levels of CD25 ex vivo[J].Novartis Found Symp,2003,252:67-88
[56]Hori S,Nomurat T,Sakaguchi S.Control of regulatory T cell development by the transcription factor Foxp3[J].Science,2003,299(5609):1057-1061.
[57]Bettelli E,Dastrange M,Oukka M.Foxp3 interacts with nuclear factor of activated T cells and NF-κ B to repress cytokine gene expression and effector function of T helper cells[J].Proc Nat Acad Sci USA,2005,102 (14):5138-5143
[58]Murakami M,Sakamoto A,Bender J,et al.CD25~~+CD4~~+T cells contribute to the control of memory CD8~~+ T cells[J].Proc Natl Acad Sci USA,2002,99(13):8832-8837.
[59]Fontenot JD,Gavin MA,Rudensky AY.Foxp3 programs the development and function of CD4~~+CD25~~+ regulatory T cells[J].Nat Immunol,2003,4 (4):330-336.
[60]Li M,Zhang X,Zheng X,et al.Tolerogenic dendritic cells transferring hyporesponsiveness and synergizing T regulatory cells intransplant tolerance[J].Int Immunol,2008(2),20:285-293.
[61]Hainz U,Jurgens B,Heitger A.The role of indoleamine 2,3-dioxygenase in transplantation[J].Transplant Int,2007,20(2):118-127
[62]Boasso A,Herbeuval J P,Hardy AW,et al.Regulation of indoleamine 2,3-dioxygenase and tryptophanyl-tRNA-synthetase by CTLA-4-Fc in human CD4~+ T cells[J].Blood,2005,105 (4):1574-1581.
[63]Sakaguchi S.Naturally arising CD4~+ regulatory T cells for immunologic self-tolerance and negative control of immune responses[J].Annu Rev Immunol,2004,22 (1):531-562.
[64]Zheng SG,Wang JH,Gray JD,et al.Natural and induced CD4~+CD25~+ cells educate CD4~+CD25" cells to develop suppressive activity:the role of IL-2,TGF-β,and IL-10[J].J Immunol,2004,172(9):5213-5221.
[65]Strauss L,Bergmann C,Whiteside TL.Human circulating CD4~+ CD25~(high) Foxp3~+ regulatory T cells kill autologous CD8~+ but not CD4~+ responder cells by Fas-mediated apoptosis[J].J Immunol,2009,182(3):1469-1480.
[66] Sakaguchi S.Reuglatory T cells:key controllers of immunologic self- tolerance [J].Cell,2000,101(5):455-458
[67]Godfrey WR,Spoden DJ,Ge YG,et al.Cord blood CD4~+CD25~+-derived T regulatory cell lines express FoxP3 protein and manifest potent suppressor function [J].Blood,2004,105 (2):750-758.
[68] Roberts A I,Devadas S,Zhang X,et al.The role of activation-induced cell death in the differentiation of T-helper-cell subsets[J].Immunol Res,2003,28(3):285-293.
[69]Akkoc T,de Koning P J,Rückert B,et al.Increased activation-induced cell death of high IFN-y-producing TH1 cells as a mechanism of TH2 predominance in atopic diseases[J]J Allergy Clin Immunol,2008:121(3):652-658.
[70]Jones RG,Elford AR,Parsons M,et al.CD28-dependent activation of protein kinase B /Akt blocks Fas-mediated apoptosis by preventing death-inducing signaling complex assembly [J].J Exp Med,2002,196 (3):335-348.
[71] Pandiyan P,Gartner D,Soezeri O,et al.CD 152 (CTLA-4) determines the unequal resistance of Thl and Th2 cells against activation-induced cell death by a mechanism requiring PI3 kinase function[J].J Exp Med,2004,199 (6):831-842.
[72]Tong J,Bandulwala H S,Clay B S,et al.Fas-positive T cells regulate the resolution of airway inflammation in a murine model of asthma [J].J Exp Med,2006,203(5):1173-1184
[73]Zhang X R,Zhang L Y,Devadas S,et al.Reciprocal expression of TRAIL and CD95L in Thl and Th2 cells:role of apoptosis in T helper subset differentiation [J].Cell Death Differ,2003,10 (2):203-210.
[74]Devadas S,Das J,Liu C,et al.Granzyme B is critical for T cell receptorinduced cell death of type2 helper T cells[J].Immunity,2006,25 (2):237-247.
[75]Varadhachary A S,Perdow S N,Hu C,et al.Differential ability of T cell subsets to undergo activation-induced cell death[J].Proc Natl Acad Sci USA, 1997,94(11):5778-5783
[76]Akdis M,Trautmann A,Klunker S,et al.T helper(Th)2 predominance in atopic diseases is due to preferential apoptosis of circulating memory/effector Th1 cells[J].FASEB J.2003.17(9):1026-1035
[77]Daigle I,Rückert B,Scnetzler G,et al.Induction of the IL-10 gene via the Fas receptor in monocytes:an anti-inflammatory mechanism in the absence of apoptosis[J].Eur J Immunol,2000,30 (10):2991-2997.
[78]Wu C Y,Kirman J R,Rotte M J,et al.Distinct lineages of TH1 cells have differential capacities for memory cell generation in vivo[J].Nat Immunol,2002,3(9):852-858
[79]Van Rijt LS,Kuipers H,Vos N,et al.A rapid flow cytometric method for determining the cellular composition of bronchoalveolar lavage fluid cells in mouse models of asthma[J].J Immunol Methods,2004,288(1-2):111-121
[80]Xu D,Liu H,Komai-Koma M,et al.CD4~+CD25~+regulatory T cells suppress differentiation and functions of Thl and Th2 cells,Leishmania major infection,and colitis in mice[J].J Immunol,2003,170(1):394-399.
[81]Walker C,Bode E,Boer L,et al.Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage[J].Am Rev Respir Dis,1992,146(1):109-115.
[82]Jayarama S,Castro M,O'Sullivan M,et al.Rasistance to Fas mediated T cell apoptosis in asthma[J].J Immunol,1999,162(3):1717-1722
[83]Van Elsas A,Sutmuller RP,Hurwitz AA,et al.Elucidating the autoimmune and antitumor effector mechanisms of a treatment based on cytotoxic T lymphocyte antigen-4 blockade in combination with a B16 melanoma vaccine:comparison of prophylaxis and therapy[J].J Exp Med,2001,194(4):481-489.
[84]Sprent J.Immunological memory[J].Curr Opin Immunol,1997,9(3):371-379.
[85]Chuang YH,Suen JL,Chiang BL.Fas-ligand-expressing adenovirus-trans-fected dendritic cells decrease allergen-specific T cells and airway inflammation in a murine model of asthma[J].J Mol Med,2006,84(7):595-603.
[86]Wen FQ,Liu X,Manda W,et al.TH2 Cytokine-enhanced and TGF-β-enhanced vascular endothelial growth factor production by cultured human airway smooth muscle cells is attenuated by IFN-γ and corticosteroids[J].J Allergy Clin Immnuol,2003,ll(6):1307-1308
[87]Chang H S,Jeon K W,Kim Y H,et al.Role of cAMP-dependent pathway in eosinophil apoptosis and survival[J].Cell Immunol,2000,203(1):29-38
[88]Shulamit B,Wallach-Dayan,Regina Golan-Gerstl,et al.Evasion of myofibroblasts from immune surveillance:A mechanism for tissue fibrosis[J].PNAS,2007,104 (51):20460-20465
[89]Tadokoro CE,Shakhar G,Shen S,et al.Regulatory T cells inhibit stable contacts between CD4~+T cells and dendritic cells in vivo[J].J Exp Med,2006,203(3):505-511.
[90]Lewkowich IP,Herman NS,Schleifer KW,et al.CD4~+CD25~+T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function[J].J Exp Med,2005,202 (11):1549-1561.
[91]Strickland DH,Stumbles PA,Zosky GR,et al.Reversal of airway hyperresponsiveness by induction of airway mucosal CD4 CD25~+ regulatory T cells[J].J Exp Med,2006,203(12):2649-2660.
[92]Thompson C,Powrie F.Regulatory T cells[J].Curr Opin Pharmacl,2004,4 (4):408-414.
[93]Karagiannidis C,Akdis M,Holopainen P,et al.Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma[J].J Allergy Clin Immunol,2004,114 (6):1425-1433.
[94]Simon A K,Jones E,Richards H,et al.Regulatory T cells inhibit Fas ligand-induced innate and adaptive tumour immunity [J].Eur J Immunol,2007,37(3):758-767.
[95]Baatar D,Olkhanud P,Sumitomo K,et al.Human peripheral blood T regulatory cells (Tregs),functionally primed CCR4~+ Tregs and unprimed CCR4~-Tregs,regulate effector T cells using FasL [J].J Immunol,2007,178(8):4891-4900.
[96]Chen A,Liu S,Park D,et al.Depleting intratumoral CD4~+CD25~+regulatory T cells via FasL Protein transfer enhances the therapeutic efficacy of adoptive T cell transfer[J].CancerRes,2007,67(3)1291-1298.
[97]Gordon JR,Li F,Nayyar A,et al.CD8~+,but Not CD8~-,Dendritic cells tolerize Th2 responses via contact-dependent and-Independent mechanisms,and reverse airway hyperresponsiveness,Th2,and Eosinophil responses in a mouse model of asthma[J].J Immunol,2005,175(3):1516-1522.
[98]Spinozzi F,Agea E,Bistoni O,et al.T lymphocytes bearing the y8T cell receptor are susceptible to steroid-induced programmed cell death[J].Scand J Immunol,1995,41(5):504-508
[2]Eagan TM,Brogger JC,Eide GE,et al.The incidence of adult asthma:a review[J].Int J Tuberc Lung Dis,2005,9(6):603-612.
[3]Masoli MFD,Holt S,Beasley R.Global Initiative for Asthma(GNIA) Porgram The global burden of asthma:executive summary of the GINA Dissemination Committee report[J].Allergy,2004,59(5):469-478.
[4]Hawrylowicz CM,O'Garra A.Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma[J].Immunology,2005,5(4):271-283.
[5]Ling E M,Smith T,Nguyen X D,et al.Relation of CD4~+CD25~+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease[J].Lancet,2004,363(9409):608-615.
[6]Akbari O,Freeman GJ,Meyer EH,et al.Antigen-specific regulatory T cells develop via the ICOS-ICOS-ligand pathway and inhibit allergeninduced airway hyperreactivity[J].Nature Med,2002,8(9):1024-1032.
[7]Hawrylowicz CM.Correction of the defect in glucocorticoid induced IL-10synthesis in T cells from glucocorticoid resistant asthmatic patients[J].J Allergy Clin Immunol,2004,113(Suppl),A735.
[8]Akdis M,Verhagen J.Immune responses in healthy and allergic individuals are characterized by a fine balance between allergen-specific T regulatory 1 and T helper 2 cells[J].J Exp Med,2004,199(11):1567-1575.
[9]Borish L,Aarons A,Rumbyrt J,et al.Interleukin-10 regulation in normal subjects and patients with asthma[J].J Allergy Clin Immunol,1996,97(6):1288-1296.
[10]van Oosterhout AJM,Bloksma N.Regulatory T-lymphocytes in asthma[J].Eur Respir J.2005;26(5):918-932.
[11]Akdis M.Healthy immune response to allergens:T regulatory cells and more[J].Curr Opin Immunol,2006,18(6):738-744.
[12]Jutel M,Akdis M,Blaser K,et al.Mechanisms of allergen specific immunotherapy-T-cell tolerance and more[J].Allergy,2006,61(7):796-807.
[13]Xystrakis E,Kusumakar S,Boswell S,et al.Reversing the defective induction of IL-10-secreting regulatory T cells in glucocorticoid- resistant asthma patients[J].J Clin Invest,2006,116(1):146-155.
[14]Moore KW,de Waal Malefyt R,Coffman RL,et al.Interleukin-10 and the interleukin-10 receptor[J].Annu Rev Immunol,2001,19:683-765.
[15]Peek EJ,Richards DF,Faith A,et al.Interleukin-10-secreting"regulatory" T cells induced by glucocorticoids and beta2-agonists[J].Am J Respir Cell Mol Biol,
2005,33(1):105-111.
[16]Akdis M,Akdis CA.Mechanisms of allergen-specific immunotherapy[J].J Allergy Clin Immunol,2007,119(4):780-789.
[17]Appleman L J,Boussiotis V A.T cell anergy and costimulation[J].Immunol Rev,2003,192(2):161-180.
[18]Asadullah K,Sterry W,Volk HD.Interleukin-10 therapy- review of a new approach [J].Pharmacol Rev,2003,55(2):241-269.
[19]Cobbold S P,Castejon R,Adams E,et al.Induction of Foxp3~+ regulatory T cells in the periphery of T cell receptor transgenic mice tolerized to transplants[J].J Immunol,2004,172(10):6003-6010
[20]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].J Exp Med,2002,195(5):603-616.
[21]Hawrylowicz C,Richards D,Loke T K,et al.A defect in corticosteroid-induced IL-10 production in T lymphocytes from corticosteroid-resistant asthmatic patients [J].J Allergy Clin Immunol,2002,109(2):369-370.
[22]Vieira PL,Christensen JR,Minaee S,et al.IL-10-secreting regulatory T cells do not express Foxp3 but have comparable regulatory function to naturally occurring CD4~+CD25~+ regulatory T cells[J].J Immunol,2004,172(10):5986-5993.
[23]Karagiannidis C,Akdis M,Holopainen P,et al.Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma[J].J Allergy Clin Immunol,2004,114 (6):1425-1433.
[24]Dunn C J,Wagstaff A J,Perry CM,et al.Cyclosporin:an updated review of the pharmacokinetic properties,clinical efficacy and tolerability of a microemulsionbased formulation (neoral)1 in organ transplantation[J].Drugs,2001,61(13):1957-2016.
[25]Lock SH,Kay AB,Barnes NC.Double-blind,placebo-controlled study of cyclosporin A as a corticosteroid-sparing agent in corticosteroid-dependent asthma[J].Am J Respir Crit Care Med,1996,153(2):509-514.
[26]Mantel PY,Ouaked N,Ruckert B,et al.Molecular mechanisms underlying FOXP3 induction in human T cells[J].J Immunol,2006,176(6):3593-3602.
[27]Corrigan CJ,Brown PH,Barnes NC,et al.Glucocorticoid resistance in chronic asthma.Peripheral blood T lymphocyte activation and comparison of the T lymphocyte inhibitory effects of glucocorticoids and cyclosporin A [J].Am Rev Respir Dis,1991,144(5):1026-1032.
[28]Windt LJ,Lim HW,Haq S,etal.Caleineurin promotes protein kinase C and c-Jun NH2-terminal kinase activation in the heart[J].J Biol Chem,2000,275(8):13571-13579.
[29]Wassim Y,Almawi,Ohaaes K,et al.Clinical and mechanistic differences between FK506(tacrolimus) and cyclosporin A[J].Nephrol Dial Transplant,2000,15(12):1916-1918.
[30]Feske S,Giltuane J,Dolmetsh R,et al.Gene regulation mediated by calcium signals in T lymphocytes[J].Nat Immunol,2001,(4)2:316-324.
[31]Sigal NH,Dumont FJ.Cyclosporin A,FK-506,and rapamycin:pharmacologic probes of lymphocyte signal transduction[J].Annu Rev Immunol,1992,10(4):519-560.
[32]Tajjma K,Amakawa R,Ito T et al.Immunomodulatory effect of cyclosporin A on humanperipheral blood dentritic cell subsets[J].Immunology,2003,108(3):321-328.
[33]Dao Nguyen X,ORbinson DS.Fluticasone propionate increases CD4~+CD25~+ T Regulatory cell suppression of allergen stimulated CD4~+CD25~- T cells by an IL-10-dependent mechanism[J].J Allergy Clin Immunol,2004,114(2):296-301.
[34]Zhou J,Liu DF,Liu C,et al.Glucocorticoids inhibit degranulation of mast cells in allergic asthma via nongenomic mechanism[J].AUergy,2008,63(9):1177-1185.
[35]Taylor A,Verhagen J,Blaser K,et al.Mechanisms of immune suppression by interleukin-10 and transforming growth factor-p:the role of T regulatory cells [J].Immunology,2006,117(4):433-442.
[36]Zheng SG,Wang JH,Gray JD,et al.Natural and induced CD4~+CD25~+ cells educate CD4~+ CD25~- cells to develop suppressive activity:the role of IL-2,TGF-β,and IL-10[J].J Immunol,2004,172(9):5213-5221.
[37]Murray PJ.STAT3-mediated anti-inflammatory signalling[J].Biochem Soc Trans,2006,34(Pt 6):1028-1031.
[38]Finbloom DS,Winestock KD.IL-10 induces the tyrosine phosphorylation of tyk2 and Jak 1 and the differential assembly of STAT1 alpha and STAT3complexes in human T cells and monocytes[J].J Immunol,1995,155(3):1079-1090.
[39]Tsuji-Takayama K,Suzuki M,Yamamoto M,et al.IL-2 activation of STAT5enhances production of IL-10 from human cytotoxic regulatory T cells[J].Exp Hematol,2008,36(2):181-192.
[40]Sheng KC,Pietersz GA,Wright MD,et al.Dendritic cells:activation and maturation-applications for cancer immunotherapy[J].Curr Med Chem,2005,12(15):1783-1800.
[41]Venet F,Pachot A,Debard AL,et al.Human CD4~+CD25~+ regulatory T lymphocytes inhibit lipopolysaccharide-induced monocyte survival through a Fas/Fas ligand-dependent mechanism[J].J Immunol,2006,177(9):6540-6547
[42]Dieckmann D,Bruett CH,Ploettner H,et al.Human CD4~+CD25~+ regulatory,contact-dependent T cells induce interleukin 10-producing,contact-independent type 1-like regulatory T cells[J].J Exp Med,2002,196(2):247-253.
[43]Xia ZW,Zhong WW,Xu LQ,et al.Heme oxygenase-1-mediated CD4~+CD25~(high)regulatory T cells suppress allergic airway inflammation[J].J Immunol,2006,177(9):5936-5945.
[44]Levings MK,Sangregorio R,Galbiati F,et al.IFN- alpha and IL-10 induce the differentiation of human type 1 T regulatory cells[J].J Immunol,2001,166(9):5530-5539.
[45]Ding Q,Lu L,Wang B,et al.B7H1-Ig fusion protein activates the CD4~+ IFN-γreceptor~+ type 1 Tregulatory subset through IFN-γ- secreting Th1 cells[J].J Immunol,2006,177(6):3606-3614.
[46]Bluestone J A,Abbas A K.Natural versus adaptive regulatory T cells[J].Nat Rev Immunol,2003,3(3):253-257.
[47]Lan RY,Ansari AA,Lian ZX,et al.Regulatory T cells:development,function and role in autoimmunity[J].Autoimmun Rev,2005,4(6):351-363.
[48]Gardner LM,Thien F C.Douglass JA,et al.Induction of T regulatory cells by Standardized housedustmite immuno therapy:an increase in CD4~+CD25~+ interleukin-10~+T cells expressing peripheral tissue trafiqcking markers[J].Clin Exp Allergy,2004,34(8):1209-1219.
[49]Francis JN,Til SJ,Durham S R.In duction of IL-10~+CD4~+CD25~+T cells by Grass polen immunotherapy[J].J Allergy Clin Immunol,2003,lll(6):1255-1261.
[50]Kagoshima M,Wilcke T,Ito K,et al.Glucocorticoid-mediated transre pression is regulated by histoneacetylation and DNA methylation [J].Eur J Pharmacol,2001,429 (123):327-334.
[51]Sundstedt A,O'Neill E J,Nicolson KS,et al.Role for IL-10 in suppression mediated by peptide-induced regulatory T cells in vivo[J].J Immunol,2003,170(3):1240-1248.
[52]O'Garra A,Vieira P L,Vieira P,et al.IL-10-producing and naturally occurring CD4~+ T Regs:limiting collateral damage[J].J Clin Invest,2004,114(10):1372-1378.
[53]Conti P,Kempuraj D,Kandere K,et al.IL-10,an inflammatory/inhibitory cytokine,but not always[J].Immunol Lett,2003,86(2):123-129.
[54]Hori S,Nomurat T,Sakaguchi S.Control of regulatory T cell development by the transcription factor Foxp3[J].Science,2003,299(5609):1057-1061.
[55]Ziegler SF.Foxp3:of mice and men [J].Annu Rev Immunol,2006,24 (1):209-226.
[56]Bettelli E,Dastrange M,Oukka M.Foxp3 interacts with nuclear factor of activated T cells and NF-kB to repress cytokine gene expression and effector functions of T helper cells[J].Proc Nat Acad Sci USA,2005,102 (14):5138-5143.
[57]Gambineri E,Torgerson TR,Ochs HD.Immune dysregulation,polyendo-crinopathy,enteropathy,and X-linked inheritance (IPEX),a syndrome of systemic autoimmunity caused by mutations of Foxp3,a critical regulator of T-cell homeostasis [J].Curr Opin Rheumatol,2003,15(4):430-435.
[58]Wu Y,Borde M,Heissmeyer V,et al.FOXP3 controls regulatory T cell function through cooperation with NFAT[J].Cell,2006,126(2):375-387.
[59]Fu S,Zhang N,Yopp AC,et al.TGF-P induces Foxp3~+T-regulatory cells from naive CD4~+CD25~+precursors[J].Am J Transplant,2004,4(10):1614-1627.
[60]Zorn E,Nelson EA,Mohseni M,et al.IL-2 regulates FOXP3 expression in human CD4~+CD25~+ regulatory T cells through a STAT dependent mechanism and induces the expansion of these cells in vivo[J].Blood,2006,108(5):1571-1579.
[1]Spinozzi F,Fizzotti M,Agea E,et al.Defective expression of Fas messenger RNA and Fas receptor on pulmonary T cells from patients with asthma [J].Annal Intern Med,1998,128 (5):363-369.
[2]Harald Wajant,Klaus Pfizenmaier,et al.Non-apoptotic Fas signaling[J].Cytokine Growth Factor Rev,2003,1453-1466.
[3]Wada A,Tada Y,Kawamura K,et al.The effects of FasL on inflammation and tumor survival are dependent on its expression levels[J].Cancer Gene Ther,2007,14(3):262-267.
[4]Gaur U,Aggarwal BB.Regulation of proliferation,survival and apoptosis by members of the TNF superfamily[J].Biochem Pharmacol,2003,66 (8):1403-1408.
[5]Krammer PH.CD95's deadly mission in the immune system [J].Nature,2000,407(6805):789-795.
[6]Liao WT,Chang KL,Yu CL,et al.Arsenic induces human keratinocyte apoptosis by the Fas/Fas ligand pathway,which correlates with alterations in nuclear factor-k.B and activator protein-1 activity[J].Invest Dermatol,2004,122(1):125-129
[7]Nagata S,Golstein P.The Fas death factor[J].Science,1995,267 (5203):1449-1456
[8]Liao X,Wang XH,Gu Y,et al.Involvement of death receptor signaling in mechanical stretch-induced cardiomyocyte apoptosis[J].Life Sci,2005,77(2):160-174.
[9]Donepudi M,Sweeney AM,Briand C,et al.Insights into the regulatory mechanism for Caspase-8 activation[J].Mol Cell,2003,11(2):543-549.
[10]Nitobe J,Yamaguchi S,Okuyama M,et al.Reactive oxygen species regulate FLICE inhibitory protein (FLIP) and susceptibility to Fas-mediated apoptosis in cardiac myocytes[J].Cardiovasc Res,2003,57(1):119-128.
[11]Kataoka T,Budd RC,Holler N,et al.The caspase-8 inhibitor FLIP promotes activation of NF-κB and Erk signaling pathways[J].Curr Boil,2000,10(11):640-648.
[12]Steenbergen C,Afshari CA,Petranka JG.Alterations in apoptotic signaling in human idiopathic cardiomyopathic hearts in failure[J].Am J Physiol Heart Circ Physiol,2003,284(1):H268-276.
[13]Barac YD,Zeevi-Levin N,Yaniv G.The 1,4,5-inositol trisphosphate pathway is a key component in Fas-mediated hypertrophy in neonatal rat ventricular myocytes[J].Cardiovasc Res,2005,68 (1):75-86.
[14]Suzuki I,Fink PJ.Maximal proliferation of cytotoxic T lymphocytes requires reverse signaling through Fas ligand[J].J Exp Med,1998,l87(1):123-128.
[15]Guo ZH,Zhang MH,An HZ,et al.Fas ligation induces IL-1β-dependent maturation and IL-1β-independent survival of dendritic cells:diffrent roles of ERK and NF-κB singaling pathways[J].Blood,2003;102(13):4441-4447.
[16]Leone V,di Palma A,Ricchi P,et al.PGE2 inhibits apoptosis in human adenocarcinoma Caco-2 cell line through Ras-PI3K association and cAMP-dependent kinase A activation[J].Am J Physiol Gastrointest Liver Physiol,2007,293(4):G673-681.
[17]Owen-Schaub LB,Angelo LS,Radinsky R,et al.Soluble Fas/APO-1 in tumor cells:a potential regulator of apoptosis[J]? Cancer Lett,1995,94(1):1-8.
[18]Timmer T,de Vries GE,de Jong S.Fas receptor-mediated apoptosis:a clinical application?[J].J Pathol,2002,196 (2):125-134.
[19]Silvestris F,Cafforio P,Tucci M,et al.VEINCTR-N,an immunogenic epitope of Fas(CD95/Apo-l),and soluble Fas enhance T cell apoptosis in vitro.Ⅱ. Functional analysis and possible implications in HIV-1 disease[J].Mol Med,2000,6(6):509-526.
[20]Proussakova OV,Rabaya NA,Moshnikova AB,etal.Oligomerization of soluble Fas antigen induces its cytotoxicity[J].J Biol Chem,2003,278(38):36236-36241.
[21]Meier P,Blanc E.Plasma level of soluble Fas is an independent marker of cardiovascular disease in ESRD patients[J].Kidney Int,2003,64(4):1532-1533.
[22]Fruman DA.Phosphoinositide 3-kinase and its targets in B-cell and T cell signaling[J]Curr Opin Immunol,2004,16(3):314-320.
[23]Alcazar I,Marques M,Kumar A,et al.Phosphositide 3-kinase y participates in T cell receptor-induced T cell activation[J].J Exp Med,2007,204(12):2977-2987.
[24]McGinn S,Saad S,Poronnik P,et al.High glucose-mediated effects on endothelial cell proliferation occur via p38 MAP kinase[J].Am J Physiol Endocrinol Metab,2003,285(4):E708-717.
[25]Dodeller F,Skapenko A,Kalden JR,et al.The P38 mitogen-activated protein kinase regulates effector functions of primary human CD4 T cells[J].Eur J Immunol,2005,35(12):3631-3642.
[26]Das J,Chen C H,Yang L et al.A critical role for NF-κB in GATA3expression and Th2 differentiation in allergic airway inflammation[J].Nat Immunol,2001,2(1):45-50.
[27]Amigorena S.Fcγ receptors and cross-presentation in dendritic cells[J].J Exp Med,2002,195(1):F1-F3.
[28]Julia V,Hessel EM,Malherbe L,et al.A restricted subset of dendritic cells captures airborne antigens and remains able to activate specific T cells long after antigen exposure[J].Immunity,2002,16(2):271-283
[29]Rescigno M,Piguet V,Valzasina B,et al.Fas engagement induces the maturation of Dendritic cells(DCs),the release of interleukin(IL)-1β,and the production of interferon gamma in the absence of IL-12 during DC-T cell cognate interactions new role for Fas lignad in inflammatory responses[J].J Exp Med,2000,192(11):1661-1668.
[30]Kato Y,Negishi T,Furusako S,et al.An orally active Th1/Th2 balance modulator,M50367,suppresses Th2 differentiation of na(?)ve Th cell in vitro[J].Cell Immunol,2003,224(1):29-37.
[31]Bakir HY,Tomiyam-Miyaji C,Watanabe H,et al.Reasons why DBA /2 mice are resistant to malarial infection:expansion of CD3 int B220~+ γδ T cells with double-negative CD4CD8" phenotype in the liver[J].Immunol,2006,117 (1):127-135.
[32]Giffith TS,Ferguson TA.The role of FasL-induced apoptosis in immune privilege [J].Immunol Today,1997,18(5):240-244
[33]Lenardo M,Chan FKM,Hornung F,et al.Mature T lymphocyte apoptosisimmune regulation in a dynamic and unpredictable antigenic environment [J].Annu Rev Immunol,1999,17:221-253.
[34]Josien R,Müschen M,Gilbert E,et al.Fas ligand,tumor necrosis factor-a expression,and apoptosis during allograft rejection and tolerance[J].Transplantation,1998,66(7):887-893.
[35]Woodside KJ,Hu M,Meng T,et al.Differential effects of interleukin-2 blockade on apoptosis in naive and activated human lymphocytes[J].Transplantation,2003,75(10):1631-1635.
[36]Sobek V,Balkow S,Korner H,et al.Antigen-induced cell death of T effector cells in vitro proceeds via the Fas pathway,requires endogenous interferon-γ and is independent of perforin and granzymes[J].Eur J Immunol,2002,32(9):2490-2499.
[37]Dhein J,Walczak H,Baumler C,et al.Autocrine T-cell suicide mediated by APO-1/(Fas/ CD95 )[J].Nature,1995,373(6513):438-341.
[38]Baumann S,Dostert A,Novac N,et al.Glucocorticoids inhibit activation-induced cell death(AICD) via direct DNA-dependent repression of the CD95 ligand gene by a glucocorticoid receptor dimmer[J].Blood,2005,106(2):617-625.
[39]Yolcu ES,Ash S,Kaminitz A,Sagiv Y,Apoptosis as a mechanism of T-regulatory cell homeostasis and suppression.Immunol Cell Biol,2008,86(8):650-658.
[40]Green DR,Droin N,Pinkoski M.Activation-induced cell death in T cells [J].Immunol Rev,2003,193(1):70-81
[41]Kirchhoff S,Muller WW,Li-Weber M,et al.Up-regulation of c-FLIP short and reduction of activation-induced cell death in CD28-co- stimulated human T cells[J].Eur J Immunol,2000,30(10):2765-2774.
[42]Li XC,Wells AD,Strom TB,et al.The role of T cell apoptosis in transplantation tolerance[J].Curr Opin Immunol,2000,12(5):522-527.
[43]Eder AM,Dominguez L,Franke T F,et al.Phosphoinositide 3-kinase regulation of T cell receptor-mediated interleukin-2 gene expression in normal T cells[J].J Biol Chem,1998,273(43):28025-28031.
[44]Marrack P,Bender J,Hildeman D,et al.Homeostasis of αβTCR+T cells[J].Nat Immunol,2000,1(2):107-111.
[45]Algeciras-Schimnich A,Griffith TS,Lynch DH,et al.Cell cycledependent regulation of FLIP levels and susceptibility to Fas-mediated apoptosis[J].J Immunol,1999,162(9):5205-5211.
[46]Yolcu ES,Gu X,Lacelle C,Zhao H,Induction of tolerance to cardiac allografts using donor splenocytes engineered to display on their surface an exogenous fas ligand protein[J].J Immunol,2008,181(2):931-939.
[47]Tao R,Hancock WW.Regulating regulatory T cells to achieve transplant tolerance [J].HBPD INT,2007,6(4):348-357.
[48]Critchfield JM,Racke MK,Zuniga-Pflucker JC,et al.T cell deletion in high antigen dose therapy of autoimmune encephalomyelitis[J].Science,1994,263(5150):1139-1143.
[49]Dhodapkar MV,Steinman RM,Krasovsky J,et al.Antigen-specific inhibition of effector T cell function in humans after injection of immature dendritic cells [J].J Exp Med,2001,193(2):233-238.
[50]Van Rijt LS,Lambrecht BN.Dendritic cells in asthma:a function beyond sensitization[J].Clin Exp AIlergy,2005,35(9):1125-1134.
[51]Sheng KC,Pietersz GA,Wright MD,et al.Dendritic cells:activation and maturation-applications for cancer immunotherapy[J].Curr Med Chem,2005,12(15):1783-1800.
[52]Chen WJ,Frank ME,Jin W,et al.TGF-p released by apoptotic T cells contributes to an immunosuppressive milieu[J].Immunity,2001,14(6):715-725.
[53]Venet F,Pachot A,Debard AL,et al.Human CD4~+CD25~+ regulatory T lymphocytes inhibit lipopolysaccharide-induced monocyte survival through a Fas /Fas ligand-dependent mechanism[J].J Immunol,2006,177(9):6540-6547.
[54]Hara M,Kingsley Cl,Niimi M,et al.IL-10 is required for regulatory T cells to mediate tolerance to alloantigens in vivo[J].J Immunol,2001,166(6):3789-3796.
[55]Baecher-Allan C,Brown JA,Freeman GJ,et al.CD4~+CD25~(high) regulatory cells from human peripheral blood express very high levels of CD25 ex vivo[J].Novartis Found Symp,2003,252:67-88
[56]Hori S,Nomurat T,Sakaguchi S.Control of regulatory T cell development by the transcription factor Foxp3[J].Science,2003,299(5609):1057-1061.
[57]Bettelli E,Dastrange M,Oukka M.Foxp3 interacts with nuclear factor of activated T cells and NF-κ B to repress cytokine gene expression and effector function of T helper cells[J].Proc Nat Acad Sci USA,2005,102 (14):5138-5143
[58]Murakami M,Sakamoto A,Bender J,et al.CD25~~+CD4~~+T cells contribute to the control of memory CD8~~+ T cells[J].Proc Natl Acad Sci USA,2002,99(13):8832-8837.
[59]Fontenot JD,Gavin MA,Rudensky AY.Foxp3 programs the development and function of CD4~~+CD25~~+ regulatory T cells[J].Nat Immunol,2003,4 (4):330-336.
[60]Li M,Zhang X,Zheng X,et al.Tolerogenic dendritic cells transferring hyporesponsiveness and synergizing T regulatory cells intransplant tolerance[J].Int Immunol,2008(2),20:285-293.
[61]Hainz U,Jurgens B,Heitger A.The role of indoleamine 2,3-dioxygenase in transplantation[J].Transplant Int,2007,20(2):118-127
[62]Boasso A,Herbeuval J P,Hardy AW,et al.Regulation of indoleamine 2,3-dioxygenase and tryptophanyl-tRNA-synthetase by CTLA-4-Fc in human CD4~+ T cells[J].Blood,2005,105 (4):1574-1581.
[63]Sakaguchi S.Naturally arising CD4~+ regulatory T cells for immunologic self-tolerance and negative control of immune responses[J].Annu Rev Immunol,2004,22 (1):531-562.
[64]Zheng SG,Wang JH,Gray JD,et al.Natural and induced CD4~+CD25~+ cells educate CD4~+CD25" cells to develop suppressive activity:the role of IL-2,TGF-β,and IL-10[J].J Immunol,2004,172(9):5213-5221.
[65]Strauss L,Bergmann C,Whiteside TL.Human circulating CD4~+ CD25~(high) Foxp3~+ regulatory T cells kill autologous CD8~+ but not CD4~+ responder cells by Fas-mediated apoptosis[J].J Immunol,2009,182(3):1469-1480.
[66] Sakaguchi S.Reuglatory T cells:key controllers of immunologic self- tolerance [J].Cell,2000,101(5):455-458
[67]Godfrey WR,Spoden DJ,Ge YG,et al.Cord blood CD4~+CD25~+-derived T regulatory cell lines express FoxP3 protein and manifest potent suppressor function [J].Blood,2004,105 (2):750-758.
[68] Roberts A I,Devadas S,Zhang X,et al.The role of activation-induced cell death in the differentiation of T-helper-cell subsets[J].Immunol Res,2003,28(3):285-293.
[69]Akkoc T,de Koning P J,Rückert B,et al.Increased activation-induced cell death of high IFN-y-producing TH1 cells as a mechanism of TH2 predominance in atopic diseases[J]J Allergy Clin Immunol,2008:121(3):652-658.
[70]Jones RG,Elford AR,Parsons M,et al.CD28-dependent activation of protein kinase B /Akt blocks Fas-mediated apoptosis by preventing death-inducing signaling complex assembly [J].J Exp Med,2002,196 (3):335-348.
[71] Pandiyan P,Gartner D,Soezeri O,et al.CD 152 (CTLA-4) determines the unequal resistance of Thl and Th2 cells against activation-induced cell death by a mechanism requiring PI3 kinase function[J].J Exp Med,2004,199 (6):831-842.
[72]Tong J,Bandulwala H S,Clay B S,et al.Fas-positive T cells regulate the resolution of airway inflammation in a murine model of asthma [J].J Exp Med,2006,203(5):1173-1184
[73]Zhang X R,Zhang L Y,Devadas S,et al.Reciprocal expression of TRAIL and CD95L in Thl and Th2 cells:role of apoptosis in T helper subset differentiation [J].Cell Death Differ,2003,10 (2):203-210.
[74]Devadas S,Das J,Liu C,et al.Granzyme B is critical for T cell receptorinduced cell death of type2 helper T cells[J].Immunity,2006,25 (2):237-247.
[75]Varadhachary A S,Perdow S N,Hu C,et al.Differential ability of T cell subsets to undergo activation-induced cell death[J].Proc Natl Acad Sci USA, 1997,94(11):5778-5783
[76]Akdis M,Trautmann A,Klunker S,et al.T helper(Th)2 predominance in atopic diseases is due to preferential apoptosis of circulating memory/effector Th1 cells[J].FASEB J.2003.17(9):1026-1035
[77]Daigle I,Rückert B,Scnetzler G,et al.Induction of the IL-10 gene via the Fas receptor in monocytes:an anti-inflammatory mechanism in the absence of apoptosis[J].Eur J Immunol,2000,30 (10):2991-2997.
[78]Wu C Y,Kirman J R,Rotte M J,et al.Distinct lineages of TH1 cells have differential capacities for memory cell generation in vivo[J].Nat Immunol,2002,3(9):852-858
[79]Van Rijt LS,Kuipers H,Vos N,et al.A rapid flow cytometric method for determining the cellular composition of bronchoalveolar lavage fluid cells in mouse models of asthma[J].J Immunol Methods,2004,288(1-2):111-121
[80]Xu D,Liu H,Komai-Koma M,et al.CD4~+CD25~+regulatory T cells suppress differentiation and functions of Thl and Th2 cells,Leishmania major infection,and colitis in mice[J].J Immunol,2003,170(1):394-399.
[81]Walker C,Bode E,Boer L,et al.Allergic and nonallergic asthmatics have distinct patterns of T-cell activation and cytokine production in peripheral blood and bronchoalveolar lavage[J].Am Rev Respir Dis,1992,146(1):109-115.
[82]Jayarama S,Castro M,O'Sullivan M,et al.Rasistance to Fas mediated T cell apoptosis in asthma[J].J Immunol,1999,162(3):1717-1722
[83]Van Elsas A,Sutmuller RP,Hurwitz AA,et al.Elucidating the autoimmune and antitumor effector mechanisms of a treatment based on cytotoxic T lymphocyte antigen-4 blockade in combination with a B16 melanoma vaccine:comparison of prophylaxis and therapy[J].J Exp Med,2001,194(4):481-489.
[84]Sprent J.Immunological memory[J].Curr Opin Immunol,1997,9(3):371-379.
[85]Chuang YH,Suen JL,Chiang BL.Fas-ligand-expressing adenovirus-trans-fected dendritic cells decrease allergen-specific T cells and airway inflammation in a murine model of asthma[J].J Mol Med,2006,84(7):595-603.
[86]Wen FQ,Liu X,Manda W,et al.TH2 Cytokine-enhanced and TGF-β-enhanced vascular endothelial growth factor production by cultured human airway smooth muscle cells is attenuated by IFN-γ and corticosteroids[J].J Allergy Clin Immnuol,2003,ll(6):1307-1308
[87]Chang H S,Jeon K W,Kim Y H,et al.Role of cAMP-dependent pathway in eosinophil apoptosis and survival[J].Cell Immunol,2000,203(1):29-38
[88]Shulamit B,Wallach-Dayan,Regina Golan-Gerstl,et al.Evasion of myofibroblasts from immune surveillance:A mechanism for tissue fibrosis[J].PNAS,2007,104 (51):20460-20465
[89]Tadokoro CE,Shakhar G,Shen S,et al.Regulatory T cells inhibit stable contacts between CD4~+T cells and dendritic cells in vivo[J].J Exp Med,2006,203(3):505-511.
[90]Lewkowich IP,Herman NS,Schleifer KW,et al.CD4~+CD25~+T cells protect against experimentally induced asthma and alter pulmonary dendritic cell phenotype and function[J].J Exp Med,2005,202 (11):1549-1561.
[91]Strickland DH,Stumbles PA,Zosky GR,et al.Reversal of airway hyperresponsiveness by induction of airway mucosal CD4 CD25~+ regulatory T cells[J].J Exp Med,2006,203(12):2649-2660.
[92]Thompson C,Powrie F.Regulatory T cells[J].Curr Opin Pharmacl,2004,4 (4):408-414.
[93]Karagiannidis C,Akdis M,Holopainen P,et al.Glucocorticoids upregulate FOXP3 expression and regulatory T cells in asthma[J].J Allergy Clin Immunol,2004,114 (6):1425-1433.
[94]Simon A K,Jones E,Richards H,et al.Regulatory T cells inhibit Fas ligand-induced innate and adaptive tumour immunity [J].Eur J Immunol,2007,37(3):758-767.
[95]Baatar D,Olkhanud P,Sumitomo K,et al.Human peripheral blood T regulatory cells (Tregs),functionally primed CCR4~+ Tregs and unprimed CCR4~-Tregs,regulate effector T cells using FasL [J].J Immunol,2007,178(8):4891-4900.
[96]Chen A,Liu S,Park D,et al.Depleting intratumoral CD4~+CD25~+regulatory T cells via FasL Protein transfer enhances the therapeutic efficacy of adoptive T cell transfer[J].CancerRes,2007,67(3)1291-1298.
[97]Gordon JR,Li F,Nayyar A,et al.CD8~+,but Not CD8~-,Dendritic cells tolerize Th2 responses via contact-dependent and-Independent mechanisms,and reverse airway hyperresponsiveness,Th2,and Eosinophil responses in a mouse model of asthma[J].J Immunol,2005,175(3):1516-1522.
[98]Spinozzi F,Agea E,Bistoni O,et al.T lymphocytes bearing the y8T cell receptor are susceptible to steroid-induced programmed cell death[J].Scand J Immunol,1995,41(5):504-508