同种异基因骨髓移植后α-GalCer的应用加速免疫重建并未加重αGVHD
|
摘要
目的:造血干细胞移植后免疫重建及急性移植物抗宿主病(acutegraft-versus-host disease,aGVHD)的研究为本领域研究的热点。NKT细胞是T淋巴细胞中的一新型的调节型细胞,α-GalCer(α-galactosylceramide,α-半乳糖神经酰胺),能特异性识别并激活NKT细胞,迅速的大量的分泌IFN-γ及IL-4。本研究在小鼠同种异基因骨髓移植模型中探讨移植后受鼠体内α-GalCer的应用是否有促进免疫重建的作用,同时不加重aGVHD,并对其机制进行初步的探讨。方法:1.建立同种异基因清髓性骨髓移植模型。C57BL/6小鼠为供鼠,BALB/c小鼠为受鼠。首先摸索出最小的清髓性辐射剂量,之后以此辐射剂量作为骨髓移植前的预处理,建立两个aGVHD严重程度不同的骨髓移植模型。2.利用aGVHD相对较轻的骨髓移植模型,实验组骨髓移植后立即腹腔注射α-GalCer,对照组骨髓移植后立即腹腔注射溶剂DMSO。移植后同一时间点检测两组小鼠脾脏的单个核细胞计数、CD~(3+)、CD4~+、CD8~+、B220~+、CD40~+、CD86~+、CD11c~+、CD80~+细胞的相对数目;供者细胞嵌合率;胸腺的单个核细胞计数和细胞组份;造血重建。并进行体外造血干细胞集落的培养及体内、外T、B细胞的增殖实验。3.利用aGVHD严重程度不同的两个骨髓移植模型,实验组骨髓移植后立即腹腔注射α-GalCer,对照组骨髓移植后立即腹腔注射溶剂DMSO。在每个移植模型中观察两组小鼠的生存期、aGVHD的临床表现和病理改变、供者细胞嵌合率。并进行移植后6小时血清及移植后d27脾脏单个核细胞培养上清细胞因子的检测;体内、外胸腺、脾脏、外周血、外周淋巴结单个核细胞及T细胞的迁移检测。结果:1.≥7.5Gy TBI为清髓剂量。以7.5Gy TBI为预处理,在输注相同的骨髓细胞数的前提下,输注脾细胞数3×10~7及1×10~7,建立两个aGVHD严重程度不同的同种异基因骨髓移植模型。2.在输注脾细胞数1×10~7骨髓移植模型中,骨髓移植后d70,实验组小鼠脾脏单个核细胞计数、CD3~+、CD4~+、CD8~+、B220~+、CD40~+及CD86~+细胞的比例均明显高于对照组,CD11c~+、CD80~+细胞的比例两组间无区别:胸腺单个核细胞计数、CD3~+、CD4~+、CD8~+细胞的比例两组间无区别,且均较正常小鼠明显偏低。移植后早期d7,实验组供者细胞嵌合率高于对照组。移植后d3,实验组外周血白细胞高于对照组。体外造血干细胞集落培养,α-GalCer组较DMSO组CFU数目明显多。体内、外T、B细胞增殖实验,α-GalCer组较DMSO组T、B细胞明显增殖。3.在aGVHD严重程度不同的两个骨髓移植模型中,实验组小鼠较对照组小鼠生存时间明显延长,aGVHD临床表现及病理改变减轻。4.在输注脾细胞数1×10~7移植模型中,移植后6小时血清中IL-4水平实验组小鼠与腹腔注射α-GalCer的正常小鼠、腹腔注射α-GalCer的单纯照射小鼠无差异,均明显高于腹腔注射DMSO的单纯照射小鼠;血清中IFN-γ水平实验组小鼠与腹腔注射α-GalCer的单纯照射小鼠无差异,稍高于腹腔注射DMSO的单纯照射小鼠,均明显低于腹腔注射α-GalCer的正常小鼠。移植后d27脾脏单个核细胞培养上清中IL-4、IL-10水平实验组高于对照组,而IFN-γ、IL-2水平实验组低于对照组。5.体内、外迁移实验:在α-GalCer的作用下单个核细胞、CD3~+、CD4~+、CD8~+细胞从胸腺、脾脏、外周血中出来,迁移至外周淋巴结。结论:1.BALB/c小鼠接受~(60)Coγ射线TBI的致死剂量是≥7.5Gy。在接受7.5Gy TBI的预处理后,输注相同的骨髓细胞数的前提下,输注不同的脾细胞数建立两个aGVHD严重程度不同的骨髓移植模型,随着输注脾细胞数增加,aGVHD的严重程度随之增加。2.移植后α-GalCer的应用促进T细胞、B细胞的免疫重建,同时增加第二刺激信号CD86、CD40的表达。3.α-GalCer加速的免疫重建与α-GalCer促进供者细胞的早期植入、促进造血干细胞的增殖与分化、促进T、B细胞的增殖作用有关,而与改善胸腺的功能无关。4.移植后α-GalCer的应用减轻了aGVHD,而且并未以延迟植入为代价,同时维持植入的持久。减轻aGVHD的机制之一:α-GalCer使受者的NKT细胞分泌大量的IL-4,促使供者的T细胞向Th2分化;减轻aGVHD的机制之二:α-GalCer促使T淋巴细胞从胸腺、脾脏、外周血出来,迁移至外周淋巴结,减少进入至靶器官的淋巴细胞数量,从而减轻淋巴细胞对靶器官的损伤。
Objective:research on immune reconstitution and acute graft-versus-host disease(aGVHD) after hemopoietic stem cell transplantation(HSCT) is the hot in area.NKT cells are a distinct subset of T lymphocytes,as one kind of new regulatory cells.α-GalCer(α-galactosylceramide) can recognize and activate NKT cells,so induces NKT cells rapidly secrete large amounts of IFN-γ「and IL-4.We investigate whetherα-GalCer could enhance immune reconstitution without aggravating aGVHD in an experimental model of HSCT,and futher explore the mechanism.Methods:1.C57BL/6 mice were as donors,and BALB/c mice as recipients,two HSCT model with different severity of aGVHD were estabilished. 2.In HSCT model with lighter aGVHD,mice of experimental group were injected intraperitoneally withα-GalCer immediately after HSCT,while mice of control group received the diluent only.Splenocyte counts,CD3~+,CD4~+,CD8~+,B220~+, CD40~+,CD86~+,CD11c~+ and CD80~+ cell relative counts,donor chimerism, thymocyte counts,thymocyte constitute and hemological reconstitution were compared at the same time post transplantation between two groups,and we performed peripheral blood mobilized stem cell colony forming unit(CFU) assays in methylcellulose in vitro and lymphocyte proliferation assay in vitro and in vivo.3.In two HSCT model,Survival,clinical and pathological aGVHD,and donor chimerism were evaluated between two groups of each HSCT model,and serum 6 hours post transplantation and splenocyte cultural supernant day 27 post transplantation were examined by ELISA for cytokines of IL-4,IL-2,1L-10 and IFN-γ,and migration assays spleen,thymus,periphral blood and LN monocyte were performed in vitro and in vivo.Results:1.Two HSCT models with different severity of aGVHD were estabilished.2.In HSCT model of 1×10~7 splenocyte,on day 70 post transplantation,splenocyte counts,CD3~+,CD4~+,CD8~+,B220~+,CD40~+ and CD86~+ cell relative counts were obviously higher in experimental group than in control group.At the same time thymocyte counts and thymocyte constitute were no different between two groups,and both were obviously lower than normal mice.On day 7,donor chimerism was higher in experimental group than in control group.On day 3,hemological reconstitution was faster in experimental group than in control group,and CFU number per 10~3 CD34~+ cell was higher inα-GalCer culture group than in DMSO culture group.Lymphocyte proliferation assay in vitro and in vivo both showed thatα-GalCer promoted T cells and B cells proliferation.3.In two HSCT model,mice in experimental group both survived longer than in control group,and clinical and pathological aGVHD were lighter.4. In HSCT model of 1×10~7 splenocyte,IL-4 level of serum 6 hours post transplantation were no different among experimental group mice,normal mice injected withα-GalCer and mice irradiated and injected withα-GalCer,and all were higher than mice irradiated and injected with DMSO;IFN-γlevel were no different between experimental group mice and normal mice injected withα-GalCer,both were a litter higher than mice irradiated and injected with DMSO and obviously lower than normal mice injected withα-GalCer.On day 27 post transplantation,IL-4 and IL-10 level of splenocyte cultural supernant in experimental group were higher than in control group,while IFN-γand IL-2 level were lower.5.Migration assays in vitro and in vivo showed thatα-GalCer caused moncyte,CD3~+,CD4~+ and CD8~+ cell egress from thymus,spleen and peripheral blood to LN.Conclusions:1.Two HSCT models with different severity of aGVHD are established.2.α-GalCer accelerates immune reconstitution of T cells and B cells,and simultaneously enhances expression of the second stimulation signal CD86 and CD40.3.Acceleration of immune reconstitution byα-GalCer is correlated with enhancing early engraftment,hemopoietic stem cell proliferation and differation and proliferation of T cells and B cells byα-GalCer,which is independent of improving thymus.4.α-GalCer reduces aGVHD,which does not at the cost of preventing or impairing engraftment.One mechanism is that stimulation of host NKT cells through administration ofα-GalCer regulates acute aGVHD by inducing Th2 polarization of donor T cells.The other mechanism is thatα-GalCer causes T cells egress from thymus,spleen and peripheral blood to LN,which reduces T cells in circulating blood and prevents T cells from infiltrating into targets organ.
Objective:research on immune reconstitution and acute graft-versus-host disease(aGVHD) after hemopoietic stem cell transplantation(HSCT) is the hot in area.NKT cells are a distinct subset of T lymphocytes,as one kind of new regulatory cells.α-GalCer(α-galactosylceramide) can recognize and activate NKT cells,so induces NKT cells rapidly secrete large amounts of IFN-γ「and IL-4.We investigate whetherα-GalCer could enhance immune reconstitution without aggravating aGVHD in an experimental model of HSCT,and futher explore the mechanism.Methods:1.C57BL/6 mice were as donors,and BALB/c mice as recipients,two HSCT model with different severity of aGVHD were estabilished. 2.In HSCT model with lighter aGVHD,mice of experimental group were injected intraperitoneally withα-GalCer immediately after HSCT,while mice of control group received the diluent only.Splenocyte counts,CD3~+,CD4~+,CD8~+,B220~+, CD40~+,CD86~+,CD11c~+ and CD80~+ cell relative counts,donor chimerism, thymocyte counts,thymocyte constitute and hemological reconstitution were compared at the same time post transplantation between two groups,and we performed peripheral blood mobilized stem cell colony forming unit(CFU) assays in methylcellulose in vitro and lymphocyte proliferation assay in vitro and in vivo.3.In two HSCT model,Survival,clinical and pathological aGVHD,and donor chimerism were evaluated between two groups of each HSCT model,and serum 6 hours post transplantation and splenocyte cultural supernant day 27 post transplantation were examined by ELISA for cytokines of IL-4,IL-2,1L-10 and IFN-γ,and migration assays spleen,thymus,periphral blood and LN monocyte were performed in vitro and in vivo.Results:1.Two HSCT models with different severity of aGVHD were estabilished.2.In HSCT model of 1×10~7 splenocyte,on day 70 post transplantation,splenocyte counts,CD3~+,CD4~+,CD8~+,B220~+,CD40~+ and CD86~+ cell relative counts were obviously higher in experimental group than in control group.At the same time thymocyte counts and thymocyte constitute were no different between two groups,and both were obviously lower than normal mice.On day 7,donor chimerism was higher in experimental group than in control group.On day 3,hemological reconstitution was faster in experimental group than in control group,and CFU number per 10~3 CD34~+ cell was higher inα-GalCer culture group than in DMSO culture group.Lymphocyte proliferation assay in vitro and in vivo both showed thatα-GalCer promoted T cells and B cells proliferation.3.In two HSCT model,mice in experimental group both survived longer than in control group,and clinical and pathological aGVHD were lighter.4. In HSCT model of 1×10~7 splenocyte,IL-4 level of serum 6 hours post transplantation were no different among experimental group mice,normal mice injected withα-GalCer and mice irradiated and injected withα-GalCer,and all were higher than mice irradiated and injected with DMSO;IFN-γlevel were no different between experimental group mice and normal mice injected withα-GalCer,both were a litter higher than mice irradiated and injected with DMSO and obviously lower than normal mice injected withα-GalCer.On day 27 post transplantation,IL-4 and IL-10 level of splenocyte cultural supernant in experimental group were higher than in control group,while IFN-γand IL-2 level were lower.5.Migration assays in vitro and in vivo showed thatα-GalCer caused moncyte,CD3~+,CD4~+ and CD8~+ cell egress from thymus,spleen and peripheral blood to LN.Conclusions:1.Two HSCT models with different severity of aGVHD are established.2.α-GalCer accelerates immune reconstitution of T cells and B cells,and simultaneously enhances expression of the second stimulation signal CD86 and CD40.3.Acceleration of immune reconstitution byα-GalCer is correlated with enhancing early engraftment,hemopoietic stem cell proliferation and differation and proliferation of T cells and B cells byα-GalCer,which is independent of improving thymus.4.α-GalCer reduces aGVHD,which does not at the cost of preventing or impairing engraftment.One mechanism is that stimulation of host NKT cells through administration ofα-GalCer regulates acute aGVHD by inducing Th2 polarization of donor T cells.The other mechanism is thatα-GalCer causes T cells egress from thymus,spleen and peripheral blood to LN,which reduces T cells in circulating blood and prevents T cells from infiltrating into targets organ.
引文
[1]Zimmer MI,Colmone A,Felio K,et al.A cell-type specific CDld expression program modulates invariant NKT cell development and function.J Immunol.2006,176(3):1421-30.
[2]McNab FW,Berzins SP,Pellicci DG,et al.The influence of CDld in postselection NKT cell maturation and homeostasis.J Immunol.2005,175(6):3762-8.
[3]Budd RC,Miescher GC,Howe RC,et al.Developmentally regulated expression of T cell receptor beta chain variable domains in immature thymocytes.J Exp Med.1987,166(2),577-82.
[4]Fowlkes BJ,Kruisbeek AM,Ton-That H,et al.A novel population of T-cell receptor αβ-bearing thymocytes which predominantly expresses a single Vβ-gene family.Nature.1987,329(6136),251-4.
[5]Ceredig R,Lynch F,Newman P.Phenotypic properties,interleukin 2 production,and developmental origin of a"mature" subpopulation of Lyt-2-L3T4- mouse thymocytes.Proc Natl Acad Sci USA.1987,84(23),8578-82.
[6]Sykes M.Unusual T cell populations in adult murine bone marrow.Prevalence of CD3+CD4-CD8-and αβ TCR+NK1.1+cells.J Immunol.1990,145(10):3209-15.
[7]Levitsky HI,Golumbek PT,Pardoll DM.The fate of CD4-8-T cell receptor-αβ+thymocytes.J Immunol.1991,146(4):1113-7.
[8]Arase H,Arase N,Nakagawa K,et al.NK1.1+ CD4+ CD8- thymocytes with specific lymphokine secretion.Eur J Immunol.1993,23(1):307-10.
[9]Yoshimoto T,Paul W E.CD4+,NK1.1+T cells promptly produce interleukin 4in response to in vivo challenge with anti-CD3.J Exp Med.1994,179(4):1285-95.
[10]Godfrey DI,MacDonald HR,Kronenberg M,et al.NKT cells:What's in a name? Nat.Rev.Immunol,2004,4(3):231-7.
[11]Gapin L,Matsuda JL,Surh CD,et al.NKT cells derive from double-positive thymocytes that are positively selected by CDld.Nat Immunol.2001,2(10):971-8.
[12]Benlagha K,Kyin T,Beavis A,et al.A thymic precursor to the NKT cell lineage.Science.2002,296(5567):553-5
[13]Pellicci DG,Hammond KJ,Uldrich AP,et al.A natural killer T(NKT)cell developmental pathway involving a thymus-dependent NKl.l-CD4+CDld dependentprecursor stage.J Exp Med.2002,195(7):835-44.
[14]Bendelac A,Rivera MN,Park SH,et al.Mouse CD1-specific NKT cells:development,specificity,and function.Annu Rev Immunol.1997,15:535-62.
[15]Coles MC,Raulet DH.NK1.1+T cells in the liver arise in the thymus and are selected by interactions with class I molecules on CD4+CD8+cells.J.Immunol.2000,164(5):2412-8.
[16]Forestier C,Park SH,Wei D,et al.T cell development in mice expressing CD1d directed by a classical MHC class II promoter.J Immunol.2003,171(8):4096-104.
[17]Stanic AK,Bezbradica JS,Park JJ,Matsuki N,Mora AL,et al.NF-kB controls cell fate specification,survival,and molecular differentiation of immunoregulatory natural T lymphocytes.J Immunol.2004,172(4):2265-73.
[18]Gadue P,Stein PL.NK T cell precursors exhibit differential cytokine regulation and require Itk for efficient maturation.J Immunol.2002,169(5):2397-406.
[19]Kronenberg M,Engel I.On the road:progress in finding the unique pathway of invariant NKT cell differentiation.Curr Opin Immunol.2007,19(2):186-93.
[20]Kronenberg M ,Gapin L.The unconventional lifestyle of NKT cells.Nat Rev Immunol.2002,2(8):557-68.
[21]Hammond KJ,Pelikan SB,Crowe NY,et al.NKT cells are phenotypically and functionally diverse.Eur J Immunol.1999,29(11):3768-81.
[22]Baev DV,Peng XH,Song L,et al.Distinct homeostatic requirements of CD4+and CD4-subsets of Va24-invariant natural killer T cells in humans.Blood.2004,104(13):4150-6.
[23]Kronenberg M.Toward an understanding of NKT cell biology:Progress and Paradoxes.Annu Rev Immunol.2005,23:877-90.
[24]Nieuwenhuis EE,Matsumoto T,ExleyM,et al.CDld-dependent macrophage mediated clearance of Pseudomonas aeruginosa from lung.Nat.Med.2002,8(6):588-93.
[25]Akbari O,Stock P,Meyer E,et al.Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity.Nat Med.2003,9(5):582-8.
[26]Lisbonne M,Diem S,Castro D,et al.Cutting edge:Invariant Val4 NKT cells are required for allergen-induced airway inflammation and hyperreactivity in an experimental asthma model.J Immunol.2003,171(4):1637-41.
[27]Mempel M,Ronet C,Suarez F,et al.Natural killer T cells restricted by the monomorphic MHC class lb CDld1 molecules behave like inflammatory cells.J Immunol.2002,168(1):365-71.
[28]Kim CH,Butcher EC,Johnston B.Distinct subsets of human Va24-invariant NKT cells:cytokine responses andchemokine receptor expression.Trends Immunol.2002,23(11):516-9.
[29]Mattner J,DeBord KL,Ismail N,et al.Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections.Nature.2005,434(7032):525-9.
[30]Chang YJ,Huang JR,Tsai YC,et al.Potent immune-modulating and anticancer effects of NKT cell stimulatory glycolipids.Proc Natl Acad Sci USA.2007,104(25):10299-304.
[31]Ragin MJ,Sahu N ,August A.Differential regulation of cytokine production by CD Id-restricted NKT cells in response to superantigen staphylococcal enterotoxin B exposure.Infect Immun.2006,74(l):282-8.
[32]Fischer K,Scotet E,Niemever,et al.Mycobacterial phosphatidylinositol mannoside is a natural antigen for CD 1d restricted T cells.Proc Natl Acad Sci USA.2004,101(29).10685-90.
[33]Nomizo A,Postol E,Alencar R,et al.Natural killer T cells are required for the development of a superantigen-driven T helper type2 immune response in mice.Immunology.2005,116(2):233-44.
[34]Zhou D,Mattner J,Cantu C,et al.Lysosomal Glycosphingolipid Recognition by NKT cells.Science,2004,306(5702):1786-9.
[35]Porubsky S,Speak AO,Luckow B,et al.Normal development and function of invariant natural killer T cells in mice with isoglobotrihexosylceramide(iGb3)deficiency.Proc Natl Acad Sci USA.2007,104(14):5977-82.
[36]Seino K,Harada M,Taniguchi M.NKT cells are relatively resistant to apoptosis.Trends Immunol.2004,25(5):219-21.
[37]Rogersa PR,Matsumotoa A,Naidenko 0,et al.Expansion of human Va24+NKT cells by repeated stimulation with KRN7000.J Immunol Methods.2004,285(2):197-214.
[38]Ikarashi Y,Iizuka A,Koshidaka Y,et al.Phenotypical and functional alterations during the expansion phase of invariant Val4 natural killer T(Val4i NKT)cells in mice primed with a-galactosylceramide.Immunology.2005,116(1):30-7.
[39]Hayakawa Y,Berzins SP,Crowe NY,et al.Antigen-induced tolerance by intrathymic modulation of self-recognizing inhibitory receptors.Nat Immunol.2004,5(6):590-6.
[40]Uldrich AP,Crowe NY,Kyparissoudis K,et al.NKT cell stimulation with glycolipid antigen in vivo:costimulation-dependent expansion,Bim-dependent contraction, and hyporesponsiveness to further antigenic challenge.J Immunol.2005,175(5):3092-101.
[41]Galli G,Pittoni P,Tonti E,et al.Invariant NKT cells sustain specific B cell responses and memory.Proc Natl Acad Sci USA.2007,104(10):3984-9.
[42]Wu L,Van Kaer L.Natural killer T cells and autoimmune disease.Curr Mol Med.2009,9(l):4-14.
[43]Wang ZY,Kusam S,Munugalavadla V,et al.Regulation of Th2 cytokine expression in NKT cells:unconventional use of Stat6,GATA-3,and NFAT2.J Immunol.2006,176(2):880-8.
[44]Lee PT,Benlagha K,Teyton L,et al.Distinct functional lineages of human Va24 natural killer T cells.J Exp Med.2002,195(5):637-41.
[45]Thomas SY,Hou R,Boyson JE,et al.CD 1d-restricted NKT cells express a chemokine receptor profile indicative of Th1-type inflammatory homing cells.J Immunol.2003,171(5):2571-80.
[46]Yu KO,Porcelli SA.The diverse functions of CD 1d-restricted NKT cells and their potential for immunotherapy.Immunol Lett.2005,100(1):42-55.
[47]Vincent MS,Leslie DS,Gumperz JE,et al.CD1-dependent dendritic cell instruction.Nat Immunol.2002,3(112):1163-8.
[48]Hermans IF,Silk JD,Gileadi U,et al.NKT cells enhance CD4+and CD8+T cell responses to soluble antigen in vivo through direct interaction with dendritic cells.J Immunol.2003,171(10):5140-7.
[49]Fujii S,Shimizu K,Smith C,Bonifaz L,Steinman RM.Activation of natural killer T cells by a-galactosylceramide rapidly induces the full maturation of dendritic cells in vivo and thereby acts as an adjuvant for combined CD4 and CD8 T cell immunity to a coadministered protein.J Exp Med.2003,198(2):267-79.
[50]Chung Y,Chang WS,Kim S,Kang CY.NKT cell ligand a-galactosylceramide blocks the induction of oral tolerance by triggering dendritic cell maturation.Eur J Immunol.2004,34(9):2471-9.
[51]Kojo S,Seino K,Harada M,et.al.Induction of regulatory properties in dendritic cells by Valphal4 NKT cells.J Immunol.2005,175(6):3648-55.
[52]Metelitsa LS,Naidenko OV,Kant A,et al.Human NKT cells mediate antitumor cytotoxicity directly by recognizing target cell CD1d with bound ligand or indirectly by producing IL-2 to activate NK cells.J Immunol.2001,167(6):3114-22.
[53]Matsuda JL,Gapin L,Baron JL,et al.Mouse Val4i natural killer T cells are resistant to cytokine polarization in vivo.Proc Natl Acad Sci USA.2003,100(14):8395-400
[54]Carnaud C,Lee D,Donnars O,et al.Cutting edge:Crosstalk between cells of the innate immune system:NKT cells rapidly activate NK cells.J Immunol.1999,163(9):4647-50
[55]Eberl G,MacDonald HR.Selective induction of NK cell proliferation and cytotoxicity by activated NKT cells.Eur.J.Immunol.2000,30(4):985-92.
[56]Kitamura H,Ohta A,Sekimoto M,Sato M,Iwakabe K,et al.a-galacto-sylceramide induces early B-cell activation through IL-4 production by NKT cells.Cell Immunol.2000,199(1):37-42.
[57]Galli G,Nuti S,Tavarini S,et al.CD Id-restricted help to B cells by human invariant natural killer T lymphocytes.J Exp Med.2003,197(8):1051-7.
[58]Stober D,Jomantaite I,Schirmbeck R,et al.NKT cells provide help for dendritic cell-dependent priming of MHC class I-restricted CD8+T cells in vivo.J Immunol.2003,170(5):2540-8.
[59]Nishimura T,Kitamura H,Iwakabe K,et al.The interface between innate and acquired immunity:glycolipid antigen presentation by CD1d-expressing dendritic cells to NKT cells induces the differentiation of antigen-specific cytotoxic T lymphocytes.Int Immunol.2000,12(7):987-94.
[60]Gonzalez-Aseguinolaza G,Van Kaer L,Bergmann CC,et al.Natural killer T cell ligand a-galactosylceramide enhances protective immunity induced by malaria vaccines.J Exp Med.2002,195(5):617-24.
[61]Mariapia A.NKT cell and viral immunity.Immunol and cell Biol.2004,82(3):332-41.
[62]Grubor-Bauk B,Simmons,A,Mayrhofer G,et al.Impaired clearance of herpes simplex virus type 1 from mice lacking CD1d or NKT cells expressing the semivariant Vαl4-Jα281 TCR.J Immunol.2003,170(3):1430-4.
[63]Chackerian A,Alt J,Perera V,et al.Activation of NKT cells protects mice from tuberculosis.Infect Immun.2002,70(11):6302-9.
[64]Yonedaa K,Moriia T,Niedab M,et al.The peripheral blood Vα24~+NKT cell numbers decrease in patients with haematopoietic malignancy.Leuk Res.2005,29(2):147-52.
[65]Seino K,Fujii S,Harada M,et al.Valphal4 NKT cell-mediated anti-tumor responses and their clinical application.Springer Semin Immunopathol.2005,27(1):65-74.
[66]Nakagawa,R,Motoki,K,Ueno,H,et al.Treatment of hepatic metastasis of the colon26 adenocarcinoma with an a-galactosylceramide,KRN7000.Cancer Res.1998,58(6):1202-7.
[67]Kobayashi E,Motoki K,Uchida T,et al.KRN7000,a novel immunomodulator,and its antitumor activities.Oncol Res.1995,7(10-11):529-34.
[68]Seino K,Motohashi S,Fujisawa T,et al.Natural killer T cell-mediated antitumor immune responses and their clinical applications.Cancer Sci.2006,97(9):807-12.
[69]Kawano T,Nakayama T,Kamada N,et al.Antitumor cytotoxicity mediated by ligand-activated human Va24 NKT cells.Cancer Res.1999,59(20):5102-5.
[70]Fujii S,Shimizu K,Hemmi H,et al.Glycolipid a-C-galactosylceramide is a distinct inducer of dendritic cell function during innate and adaptive immune responses of mice.Proc Natl Acad Sci USA.2006,103(30):11252-7.
[71]Margalit M,Shibolet 0,Klein A,et al.Suppression of hepatocellular carcinoma by transplantation of ex-vivo immune-modulated NKT lymphocytes.Int J Cancer.2005,115(3):443-9.
[72]Araki M,Kondeto T,Gumperz JE,et al.Th2 bias of CD4+NKT cells derived from multiple sclerosis in remission.Int Immunol.2003,15(2):279-88.
[73]Lee PT,Putnam A,Benlagha K,et al.Testing the NKT cell hypothesis of human IDDM pathogenesis.J Clin Invest.2002,110(6):793-800.
[74]Kojo S,Adachi Y,Keino H,et al.Dysfunction of T cell receptor AV24AJ18+,BV11+double-negative regulatory natural killer T cells in autoimmune diseases.Arthritis Rheum.2001,44(5):1127-38.
[75]Hammond KJ,Godfrey DI.NKT cells:potential targets for autoimmune disease therapy? Tissue Antigens.2002,59(5):353-63.
[76]Kukreja A,Maclaren NK.NKT cells and type-1 diabetes and the "hygiene hypothesis" to explain the rising incidence rates.Diabetes Technol Ther.2002;493):323-33.
[77]Kukreja A,Cost G,Marker J,et al.Multiple immuno-regulatory defects in type-1 diabetes.J Clin Invest.2002,109(1):131-40.
[78]Trop S,Samsonov D,Gotsman I,et al.Liver-associated lymphocytes expressing NKl.l are essential for oral immune tolerance induction in a murine model.Hepatology.1999,29(3):746-55.
[79]Jahng AW,Maricic I,Pedersen B,et al.Activation of natural killer T cells potentiates or prevents experimental autoimmune encephalomyelitis.J Exp Med.2001,194(2):1789-99.
[80]Hong S,Wilson MT,Serizawa I,et al.The natural killer T-cell ligand alphagalactosylceramide prevents autoimmune diabetes in nonobese diabetic mice.Nat Med.2001,7(9):1052-6.
[81]Sharif S,Arreaza GA,Zucker P,et al.Activation of natural killer T cells by alpha-galactosylceramide treatment prevents the onset and recurrence of autoimmune Type 1 diabetes.Nat Med.2001,7(9):1057-62.
[82]Gombert JM,Herbelin A,Tancrede-Bohin E,et al.Early quantitative and functional deficiency of NKl+-like thymocytes in the NOD mouse.Eur J Immunol.1996;26(12):2989-98.
[83]Baxter AG,Kinder SJ,Hammond KJ,et al.Association between alphabeta TCR+CD4-CD8-T-cell deficiency and IDDM in NOD/Lt mice.Diabetes.1997, 46(4):572-82.
[84]Carnaud C,Gombert J,Donnars O,et al.Protection against diabetes and improved NK/NKT cell performance in NOD.NK1.1 mice congenic at the NK complex.J Immunol.2001,166(4):2404-11.
[85]Chen YG,Morgane C,Thomas M,et al.Activated NKT cells inhibit autoimmune diabetes through tolerogenic recruitment of dendritic cells to pancreatic lymph nodes.J Immunol.2005 ,174(3):1196-204.
[86]Jaksch M,Mattsson J.The Pathophysiology of acute graft-versus-host disease.J Immunol.2005,61(5):398-409.
[87]Couriel D,Caldera H,Champlin R,et al.Acute graft-versus-host disease:pathophysiology,clinical manifestations,and management.Cancer.2004,101(9):1936-46.
[88]Sun Y,Tawara I,Toubai T,et al.Pathophysiology of acute graft-vs-host disease:recent advances.Transl Res.2007,150(4):197-214.
[89]Zeng D,Lewi D,Dejbakhsh-Jones S,et al.Bone marrow NK1.1-andNK 1.1+T cells reciprocally regulate acute graft versus host disease.J Exp Med.1999,189(7):1073-81.
[90]Kuwatani M,Ikarashi Y,Iizuka A,et al.Modulation of acute graft-versus-host disease and chimerism after adoptive transfer of in vitro-expanded invariant Valphal4 natural killer T cells.Immunol Lett.2006,106(1):82-90.
[91]Haraguchi K,Takahashi T,Hiruma K,et al.Recovery of Va24+NKT cells after hematopoietic stem cell transplantation.Bone Marrow Transplant.2004,34(7):595-602.
[92]Morecki S,Panigrahi S,Pizov G,et al.Effect of KRN7000 on induced graft-vs-host disease.Exp Hematol.2004,32(7):630-7.
[93]Hashimoto D,Asakura S,Miyake S,et al.Stimulation of host NKT cells by synthetic glycolipid regulates acute graft-versus-host disease by inducing Th2 polarization of donor T cells.J Immunol.2005,174(l):551-6.
[94]Minami K,Yanagawa Y,Iwabuchi K,et al.Negative feedback regulation of T helper type 1(Thl)/Th2 cytokine balance via dendritic cell and natural killer T cell interactions.Blood.2005,106(5):1685-93.
[95]Haraguchi K,Takahashi T,Matsumoto A,et al.Host-residual invariant NKT cells attenuate graft-versus-host immunity.J Immunol.2005,175(2):1320-8.
[96]Ho LP,Urban BC,Jones L,et al.CD4(-)CD8alphaalpha subset of CD1d-restricted NKT cells controls T cell expansion.J Immunol.2004,172(12):7350-8.
[97]Novak J,Beaudoin L,Griseri T,et al.Inhibition of T Cell differentiation into effectors by NKT cells requires cell contacts.J Immunol.2005,174(4):1954-61.
[2]McNab FW,Berzins SP,Pellicci DG,et al.The influence of CDld in postselection NKT cell maturation and homeostasis.J Immunol.2005,175(6):3762-8.
[3]Budd RC,Miescher GC,Howe RC,et al.Developmentally regulated expression of T cell receptor beta chain variable domains in immature thymocytes.J Exp Med.1987,166(2),577-82.
[4]Fowlkes BJ,Kruisbeek AM,Ton-That H,et al.A novel population of T-cell receptor αβ-bearing thymocytes which predominantly expresses a single Vβ-gene family.Nature.1987,329(6136),251-4.
[5]Ceredig R,Lynch F,Newman P.Phenotypic properties,interleukin 2 production,and developmental origin of a"mature" subpopulation of Lyt-2-L3T4- mouse thymocytes.Proc Natl Acad Sci USA.1987,84(23),8578-82.
[6]Sykes M.Unusual T cell populations in adult murine bone marrow.Prevalence of CD3+CD4-CD8-and αβ TCR+NK1.1+cells.J Immunol.1990,145(10):3209-15.
[7]Levitsky HI,Golumbek PT,Pardoll DM.The fate of CD4-8-T cell receptor-αβ+thymocytes.J Immunol.1991,146(4):1113-7.
[8]Arase H,Arase N,Nakagawa K,et al.NK1.1+ CD4+ CD8- thymocytes with specific lymphokine secretion.Eur J Immunol.1993,23(1):307-10.
[9]Yoshimoto T,Paul W E.CD4+,NK1.1+T cells promptly produce interleukin 4in response to in vivo challenge with anti-CD3.J Exp Med.1994,179(4):1285-95.
[10]Godfrey DI,MacDonald HR,Kronenberg M,et al.NKT cells:What's in a name? Nat.Rev.Immunol,2004,4(3):231-7.
[11]Gapin L,Matsuda JL,Surh CD,et al.NKT cells derive from double-positive thymocytes that are positively selected by CDld.Nat Immunol.2001,2(10):971-8.
[12]Benlagha K,Kyin T,Beavis A,et al.A thymic precursor to the NKT cell lineage.Science.2002,296(5567):553-5
[13]Pellicci DG,Hammond KJ,Uldrich AP,et al.A natural killer T(NKT)cell developmental pathway involving a thymus-dependent NKl.l-CD4+CDld dependentprecursor stage.J Exp Med.2002,195(7):835-44.
[14]Bendelac A,Rivera MN,Park SH,et al.Mouse CD1-specific NKT cells:development,specificity,and function.Annu Rev Immunol.1997,15:535-62.
[15]Coles MC,Raulet DH.NK1.1+T cells in the liver arise in the thymus and are selected by interactions with class I molecules on CD4+CD8+cells.J.Immunol.2000,164(5):2412-8.
[16]Forestier C,Park SH,Wei D,et al.T cell development in mice expressing CD1d directed by a classical MHC class II promoter.J Immunol.2003,171(8):4096-104.
[17]Stanic AK,Bezbradica JS,Park JJ,Matsuki N,Mora AL,et al.NF-kB controls cell fate specification,survival,and molecular differentiation of immunoregulatory natural T lymphocytes.J Immunol.2004,172(4):2265-73.
[18]Gadue P,Stein PL.NK T cell precursors exhibit differential cytokine regulation and require Itk for efficient maturation.J Immunol.2002,169(5):2397-406.
[19]Kronenberg M,Engel I.On the road:progress in finding the unique pathway of invariant NKT cell differentiation.Curr Opin Immunol.2007,19(2):186-93.
[20]Kronenberg M ,Gapin L.The unconventional lifestyle of NKT cells.Nat Rev Immunol.2002,2(8):557-68.
[21]Hammond KJ,Pelikan SB,Crowe NY,et al.NKT cells are phenotypically and functionally diverse.Eur J Immunol.1999,29(11):3768-81.
[22]Baev DV,Peng XH,Song L,et al.Distinct homeostatic requirements of CD4+and CD4-subsets of Va24-invariant natural killer T cells in humans.Blood.2004,104(13):4150-6.
[23]Kronenberg M.Toward an understanding of NKT cell biology:Progress and Paradoxes.Annu Rev Immunol.2005,23:877-90.
[24]Nieuwenhuis EE,Matsumoto T,ExleyM,et al.CDld-dependent macrophage mediated clearance of Pseudomonas aeruginosa from lung.Nat.Med.2002,8(6):588-93.
[25]Akbari O,Stock P,Meyer E,et al.Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity.Nat Med.2003,9(5):582-8.
[26]Lisbonne M,Diem S,Castro D,et al.Cutting edge:Invariant Val4 NKT cells are required for allergen-induced airway inflammation and hyperreactivity in an experimental asthma model.J Immunol.2003,171(4):1637-41.
[27]Mempel M,Ronet C,Suarez F,et al.Natural killer T cells restricted by the monomorphic MHC class lb CDld1 molecules behave like inflammatory cells.J Immunol.2002,168(1):365-71.
[28]Kim CH,Butcher EC,Johnston B.Distinct subsets of human Va24-invariant NKT cells:cytokine responses andchemokine receptor expression.Trends Immunol.2002,23(11):516-9.
[29]Mattner J,DeBord KL,Ismail N,et al.Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections.Nature.2005,434(7032):525-9.
[30]Chang YJ,Huang JR,Tsai YC,et al.Potent immune-modulating and anticancer effects of NKT cell stimulatory glycolipids.Proc Natl Acad Sci USA.2007,104(25):10299-304.
[31]Ragin MJ,Sahu N ,August A.Differential regulation of cytokine production by CD Id-restricted NKT cells in response to superantigen staphylococcal enterotoxin B exposure.Infect Immun.2006,74(l):282-8.
[32]Fischer K,Scotet E,Niemever,et al.Mycobacterial phosphatidylinositol mannoside is a natural antigen for CD 1d restricted T cells.Proc Natl Acad Sci USA.2004,101(29).10685-90.
[33]Nomizo A,Postol E,Alencar R,et al.Natural killer T cells are required for the development of a superantigen-driven T helper type2 immune response in mice.Immunology.2005,116(2):233-44.
[34]Zhou D,Mattner J,Cantu C,et al.Lysosomal Glycosphingolipid Recognition by NKT cells.Science,2004,306(5702):1786-9.
[35]Porubsky S,Speak AO,Luckow B,et al.Normal development and function of invariant natural killer T cells in mice with isoglobotrihexosylceramide(iGb3)deficiency.Proc Natl Acad Sci USA.2007,104(14):5977-82.
[36]Seino K,Harada M,Taniguchi M.NKT cells are relatively resistant to apoptosis.Trends Immunol.2004,25(5):219-21.
[37]Rogersa PR,Matsumotoa A,Naidenko 0,et al.Expansion of human Va24+NKT cells by repeated stimulation with KRN7000.J Immunol Methods.2004,285(2):197-214.
[38]Ikarashi Y,Iizuka A,Koshidaka Y,et al.Phenotypical and functional alterations during the expansion phase of invariant Val4 natural killer T(Val4i NKT)cells in mice primed with a-galactosylceramide.Immunology.2005,116(1):30-7.
[39]Hayakawa Y,Berzins SP,Crowe NY,et al.Antigen-induced tolerance by intrathymic modulation of self-recognizing inhibitory receptors.Nat Immunol.2004,5(6):590-6.
[40]Uldrich AP,Crowe NY,Kyparissoudis K,et al.NKT cell stimulation with glycolipid antigen in vivo:costimulation-dependent expansion,Bim-dependent contraction, and hyporesponsiveness to further antigenic challenge.J Immunol.2005,175(5):3092-101.
[41]Galli G,Pittoni P,Tonti E,et al.Invariant NKT cells sustain specific B cell responses and memory.Proc Natl Acad Sci USA.2007,104(10):3984-9.
[42]Wu L,Van Kaer L.Natural killer T cells and autoimmune disease.Curr Mol Med.2009,9(l):4-14.
[43]Wang ZY,Kusam S,Munugalavadla V,et al.Regulation of Th2 cytokine expression in NKT cells:unconventional use of Stat6,GATA-3,and NFAT2.J Immunol.2006,176(2):880-8.
[44]Lee PT,Benlagha K,Teyton L,et al.Distinct functional lineages of human Va24 natural killer T cells.J Exp Med.2002,195(5):637-41.
[45]Thomas SY,Hou R,Boyson JE,et al.CD 1d-restricted NKT cells express a chemokine receptor profile indicative of Th1-type inflammatory homing cells.J Immunol.2003,171(5):2571-80.
[46]Yu KO,Porcelli SA.The diverse functions of CD 1d-restricted NKT cells and their potential for immunotherapy.Immunol Lett.2005,100(1):42-55.
[47]Vincent MS,Leslie DS,Gumperz JE,et al.CD1-dependent dendritic cell instruction.Nat Immunol.2002,3(112):1163-8.
[48]Hermans IF,Silk JD,Gileadi U,et al.NKT cells enhance CD4+and CD8+T cell responses to soluble antigen in vivo through direct interaction with dendritic cells.J Immunol.2003,171(10):5140-7.
[49]Fujii S,Shimizu K,Smith C,Bonifaz L,Steinman RM.Activation of natural killer T cells by a-galactosylceramide rapidly induces the full maturation of dendritic cells in vivo and thereby acts as an adjuvant for combined CD4 and CD8 T cell immunity to a coadministered protein.J Exp Med.2003,198(2):267-79.
[50]Chung Y,Chang WS,Kim S,Kang CY.NKT cell ligand a-galactosylceramide blocks the induction of oral tolerance by triggering dendritic cell maturation.Eur J Immunol.2004,34(9):2471-9.
[51]Kojo S,Seino K,Harada M,et.al.Induction of regulatory properties in dendritic cells by Valphal4 NKT cells.J Immunol.2005,175(6):3648-55.
[52]Metelitsa LS,Naidenko OV,Kant A,et al.Human NKT cells mediate antitumor cytotoxicity directly by recognizing target cell CD1d with bound ligand or indirectly by producing IL-2 to activate NK cells.J Immunol.2001,167(6):3114-22.
[53]Matsuda JL,Gapin L,Baron JL,et al.Mouse Val4i natural killer T cells are resistant to cytokine polarization in vivo.Proc Natl Acad Sci USA.2003,100(14):8395-400
[54]Carnaud C,Lee D,Donnars O,et al.Cutting edge:Crosstalk between cells of the innate immune system:NKT cells rapidly activate NK cells.J Immunol.1999,163(9):4647-50
[55]Eberl G,MacDonald HR.Selective induction of NK cell proliferation and cytotoxicity by activated NKT cells.Eur.J.Immunol.2000,30(4):985-92.
[56]Kitamura H,Ohta A,Sekimoto M,Sato M,Iwakabe K,et al.a-galacto-sylceramide induces early B-cell activation through IL-4 production by NKT cells.Cell Immunol.2000,199(1):37-42.
[57]Galli G,Nuti S,Tavarini S,et al.CD Id-restricted help to B cells by human invariant natural killer T lymphocytes.J Exp Med.2003,197(8):1051-7.
[58]Stober D,Jomantaite I,Schirmbeck R,et al.NKT cells provide help for dendritic cell-dependent priming of MHC class I-restricted CD8+T cells in vivo.J Immunol.2003,170(5):2540-8.
[59]Nishimura T,Kitamura H,Iwakabe K,et al.The interface between innate and acquired immunity:glycolipid antigen presentation by CD1d-expressing dendritic cells to NKT cells induces the differentiation of antigen-specific cytotoxic T lymphocytes.Int Immunol.2000,12(7):987-94.
[60]Gonzalez-Aseguinolaza G,Van Kaer L,Bergmann CC,et al.Natural killer T cell ligand a-galactosylceramide enhances protective immunity induced by malaria vaccines.J Exp Med.2002,195(5):617-24.
[61]Mariapia A.NKT cell and viral immunity.Immunol and cell Biol.2004,82(3):332-41.
[62]Grubor-Bauk B,Simmons,A,Mayrhofer G,et al.Impaired clearance of herpes simplex virus type 1 from mice lacking CD1d or NKT cells expressing the semivariant Vαl4-Jα281 TCR.J Immunol.2003,170(3):1430-4.
[63]Chackerian A,Alt J,Perera V,et al.Activation of NKT cells protects mice from tuberculosis.Infect Immun.2002,70(11):6302-9.
[64]Yonedaa K,Moriia T,Niedab M,et al.The peripheral blood Vα24~+NKT cell numbers decrease in patients with haematopoietic malignancy.Leuk Res.2005,29(2):147-52.
[65]Seino K,Fujii S,Harada M,et al.Valphal4 NKT cell-mediated anti-tumor responses and their clinical application.Springer Semin Immunopathol.2005,27(1):65-74.
[66]Nakagawa,R,Motoki,K,Ueno,H,et al.Treatment of hepatic metastasis of the colon26 adenocarcinoma with an a-galactosylceramide,KRN7000.Cancer Res.1998,58(6):1202-7.
[67]Kobayashi E,Motoki K,Uchida T,et al.KRN7000,a novel immunomodulator,and its antitumor activities.Oncol Res.1995,7(10-11):529-34.
[68]Seino K,Motohashi S,Fujisawa T,et al.Natural killer T cell-mediated antitumor immune responses and their clinical applications.Cancer Sci.2006,97(9):807-12.
[69]Kawano T,Nakayama T,Kamada N,et al.Antitumor cytotoxicity mediated by ligand-activated human Va24 NKT cells.Cancer Res.1999,59(20):5102-5.
[70]Fujii S,Shimizu K,Hemmi H,et al.Glycolipid a-C-galactosylceramide is a distinct inducer of dendritic cell function during innate and adaptive immune responses of mice.Proc Natl Acad Sci USA.2006,103(30):11252-7.
[71]Margalit M,Shibolet 0,Klein A,et al.Suppression of hepatocellular carcinoma by transplantation of ex-vivo immune-modulated NKT lymphocytes.Int J Cancer.2005,115(3):443-9.
[72]Araki M,Kondeto T,Gumperz JE,et al.Th2 bias of CD4+NKT cells derived from multiple sclerosis in remission.Int Immunol.2003,15(2):279-88.
[73]Lee PT,Putnam A,Benlagha K,et al.Testing the NKT cell hypothesis of human IDDM pathogenesis.J Clin Invest.2002,110(6):793-800.
[74]Kojo S,Adachi Y,Keino H,et al.Dysfunction of T cell receptor AV24AJ18+,BV11+double-negative regulatory natural killer T cells in autoimmune diseases.Arthritis Rheum.2001,44(5):1127-38.
[75]Hammond KJ,Godfrey DI.NKT cells:potential targets for autoimmune disease therapy? Tissue Antigens.2002,59(5):353-63.
[76]Kukreja A,Maclaren NK.NKT cells and type-1 diabetes and the "hygiene hypothesis" to explain the rising incidence rates.Diabetes Technol Ther.2002;493):323-33.
[77]Kukreja A,Cost G,Marker J,et al.Multiple immuno-regulatory defects in type-1 diabetes.J Clin Invest.2002,109(1):131-40.
[78]Trop S,Samsonov D,Gotsman I,et al.Liver-associated lymphocytes expressing NKl.l are essential for oral immune tolerance induction in a murine model.Hepatology.1999,29(3):746-55.
[79]Jahng AW,Maricic I,Pedersen B,et al.Activation of natural killer T cells potentiates or prevents experimental autoimmune encephalomyelitis.J Exp Med.2001,194(2):1789-99.
[80]Hong S,Wilson MT,Serizawa I,et al.The natural killer T-cell ligand alphagalactosylceramide prevents autoimmune diabetes in nonobese diabetic mice.Nat Med.2001,7(9):1052-6.
[81]Sharif S,Arreaza GA,Zucker P,et al.Activation of natural killer T cells by alpha-galactosylceramide treatment prevents the onset and recurrence of autoimmune Type 1 diabetes.Nat Med.2001,7(9):1057-62.
[82]Gombert JM,Herbelin A,Tancrede-Bohin E,et al.Early quantitative and functional deficiency of NKl+-like thymocytes in the NOD mouse.Eur J Immunol.1996;26(12):2989-98.
[83]Baxter AG,Kinder SJ,Hammond KJ,et al.Association between alphabeta TCR+CD4-CD8-T-cell deficiency and IDDM in NOD/Lt mice.Diabetes.1997, 46(4):572-82.
[84]Carnaud C,Gombert J,Donnars O,et al.Protection against diabetes and improved NK/NKT cell performance in NOD.NK1.1 mice congenic at the NK complex.J Immunol.2001,166(4):2404-11.
[85]Chen YG,Morgane C,Thomas M,et al.Activated NKT cells inhibit autoimmune diabetes through tolerogenic recruitment of dendritic cells to pancreatic lymph nodes.J Immunol.2005 ,174(3):1196-204.
[86]Jaksch M,Mattsson J.The Pathophysiology of acute graft-versus-host disease.J Immunol.2005,61(5):398-409.
[87]Couriel D,Caldera H,Champlin R,et al.Acute graft-versus-host disease:pathophysiology,clinical manifestations,and management.Cancer.2004,101(9):1936-46.
[88]Sun Y,Tawara I,Toubai T,et al.Pathophysiology of acute graft-vs-host disease:recent advances.Transl Res.2007,150(4):197-214.
[89]Zeng D,Lewi D,Dejbakhsh-Jones S,et al.Bone marrow NK1.1-andNK 1.1+T cells reciprocally regulate acute graft versus host disease.J Exp Med.1999,189(7):1073-81.
[90]Kuwatani M,Ikarashi Y,Iizuka A,et al.Modulation of acute graft-versus-host disease and chimerism after adoptive transfer of in vitro-expanded invariant Valphal4 natural killer T cells.Immunol Lett.2006,106(1):82-90.
[91]Haraguchi K,Takahashi T,Hiruma K,et al.Recovery of Va24+NKT cells after hematopoietic stem cell transplantation.Bone Marrow Transplant.2004,34(7):595-602.
[92]Morecki S,Panigrahi S,Pizov G,et al.Effect of KRN7000 on induced graft-vs-host disease.Exp Hematol.2004,32(7):630-7.
[93]Hashimoto D,Asakura S,Miyake S,et al.Stimulation of host NKT cells by synthetic glycolipid regulates acute graft-versus-host disease by inducing Th2 polarization of donor T cells.J Immunol.2005,174(l):551-6.
[94]Minami K,Yanagawa Y,Iwabuchi K,et al.Negative feedback regulation of T helper type 1(Thl)/Th2 cytokine balance via dendritic cell and natural killer T cell interactions.Blood.2005,106(5):1685-93.
[95]Haraguchi K,Takahashi T,Matsumoto A,et al.Host-residual invariant NKT cells attenuate graft-versus-host immunity.J Immunol.2005,175(2):1320-8.
[96]Ho LP,Urban BC,Jones L,et al.CD4(-)CD8alphaalpha subset of CD1d-restricted NKT cells controls T cell expansion.J Immunol.2004,172(12):7350-8.
[97]Novak J,Beaudoin L,Griseri T,et al.Inhibition of T Cell differentiation into effectors by NKT cells requires cell contacts.J Immunol.2005,174(4):1954-61.
© 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 |