Functional analysis and the molecular mechanism of CCR5 in the CTL induction.
CCR5在CTL诱导中的功能分析及分子机制。
基本信息
- 批准号:14370108
- 负责人:
- 金额:$ 9.54万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (B)
- 财政年份:2002
- 资助国家:日本
- 起止时间:2002 至 2003
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
1. Chemokine receptors in the immunological synapse regulate the sensitivity of antigen recognition : CCR5 is predominantly expressed on resting memory T cells of which expression is enhanced on activated T cells. Although CCR5 is known as, a coreceptor of HIV, it has been suggested that CCR5 has also a function as a costimulatory molecule for leukocyte activation in vitro other than chemotaxis. To extend this idea, we have shown that CCR5 accumulated and actually was activated in the immunological synapse after TCR stimulation by evaluating BRET (Bioluminescence Resonance Energy Transfer) signals. Furthermore, a CCR5 antagonist, TAK-779 strongly inhibited human CD8+T cell proliferation by CD3 and CD28 coated plates and also LFA-1 inside-out signaling through Rapt after TCR stimulation. We confirmed that CCR5 and CXCR3 function as costimulatory molecules of T cells in vivo by developing double CCR5 and CXCR3 knockout mouse. Taken together, CCR5 and CXCR3 on CD8+T cells have a costimulatory signal or boosting signal with T cell receptor mediated-signal to regulate LFA-1 activation through Rapl in the immunological synapse. These findings explain a mechanism of recent report describing complete acceptance of kidney transplants in recipients with CCR5delta32 mutation.2.Blockade of GVHD by targeting chemokines and development of a way to selectively induce GVL/T : In an acute GVHD model, donor CD8T cells proliferated and differentiated in the secondary lymphoid organs and apoptosis of intestinal epithelium was induced at the crypts. Surprisingly, neutralizing antibodies against Fractalkine/MAdCAM-1 inhibited intestinal injury. When tumor cells P815 (H-2^d) were injected into BDF-1 (H-2^<bd>) and the splenocytes from C57BL/6 (H-2^b) were transferred to recipient mice, elongation of the survival of recipients was observed preserving GVL effect. Thus we propose a therapy for GVHD by targeting CX3CR-1-Fractalkine and a4b7-MadCAM-1 keeping GVL/T effect.
1.免疫突触中的趋化因子受体调节抗原识别的敏感性:CCR 5主要在静息记忆T细胞上表达,其表达在活化T细胞上增强。尽管CCR 5被认为是HIV的共受体,但已经提出CCR 5除了趋化性之外还具有作为体外白细胞活化的共刺激分子的功能。为了扩展这一想法,我们已经通过评估BRET(生物发光共振能量转移)信号表明,在TCR刺激后,CCR 5在免疫突触中积累并实际上被激活。此外,CCR 5拮抗剂TAK-779通过CD 3和CD 28包被平板强烈抑制人CD 8 +T细胞增殖,并在TCR刺激后通过Rapt强烈抑制LFA-1由内而外的信号传导。我们通过建立CCR 5和CXCR 3双基因敲除小鼠,证实了CCR 5和CXCR 3在体内作为T细胞的共刺激分子发挥作用。总之,CD 8 +T细胞上的CCR 5和CXCR 3具有与T细胞受体介导的信号的共刺激信号或增强信号,以通过免疫突触中的Rapl调节LFA-1活化。这些发现解释了最近报道的CCR 5delta 32突变受者完全接受肾移植的机制。2.通过靶向趋化因子阻断GVHD和选择性诱导GVL/T的方法的开发:在急性GVHD模型中,供体CD 8 T细胞在次级淋巴器官中增殖和分化,并在隐窝处诱导肠上皮细胞凋亡。令人惊讶的是,针对Fractalkine/MAdCAM-1的中和抗体抑制肠损伤。将肿瘤细胞P815(H-2_d)注射入BDF-1(H-2_b)中<bd>,并将来自C57 BL/6(H-2_b)的脾细胞转移至受体小鼠,观察到受体存活的延长,保留了GVL效应。因此,我们提出了通过靶向CX 3CR-1-Fractalkine和a4 b7-MadCAM-1保持GVL/T效应来治疗GVHD。
项目成果
期刊论文数量(40)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Toyoda N, et al.: "Analysis of mRNA with microsomal frectionation using a SAGE-based DNA microarray system facilitates identification of the genes encoding secretory proteins."Genome Res.. 13. 1728-1736 (2003)
Toyoda N 等人:“使用基于 SAGE 的 DNA 微阵列系统通过微粒体筛选分析 mRNA,有助于识别编码分泌蛋白的基因。”Genome Res.. 13. 1728-1736 (2003)
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Yoneyama H, et al.: "Pivotal role of dendritic cell-derived CXCL10 in the retention of T helper cell 1 lymphocytes in secondary lymph nodes."J Exp Med. 195. 1257-1266 (2002)
Yoneyama H 等人:“树突状细胞衍生的 CXCL10 在辅助性 T 细胞 1 淋巴细胞保留在二级淋巴结中的关键作用。”J Exp Med。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Ishida T, et al.: "Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma : its close association with skin involvement and unfavorable outcome."Clin.Cancer Res.. 9(10 Pt 1). 3625-3634 (2003)
Ishida T 等人:“成人 T 细胞白血病/淋巴瘤中 CCR4 表达的临床意义:其与皮肤受累和不良结果密切相关。”Clin.Cancer Res.. 9(10 Pt 1)。
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
Murai M, et al.: "Peyer's patch is the essential site in initiating murine acute and lethal graft-versus-host reaction."Nat Immunol. 4. 154-160 (2003)
Murai M 等人:“派尔氏集结是引发小鼠急性和致命的移植物抗宿主反应的重要部位。”
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
分子予防環境医学研究会: "分子予防環境医学 -生命科学研究の予防・環境医学への統合-"(株)本の泉社. 768 (2003)
分子预防环境医学研究组:“分子预防环境医学-将生命科学研究融入预防和环境医学”本能船社768(2003)
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
- 作者:
- 通讯作者:
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
MATSUSHIMA Kouji其他文献
Osteopontin identifies a novel profibrotic population of fibroblasts
骨桥蛋白鉴定出一种新型的促纤维化成纤维细胞群
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:0
- 作者:
ABE Jun;SHICHINO Shigeyuki;HASHIMOTO Shin-ichi;SHIMAOKA Takeshi;TOMURA Michio;INAGAKI Yutaka;MATSUSHIMA Kouji - 通讯作者:
MATSUSHIMA Kouji
Delayed and aberrant immune reconstitution due to destruction of hematological and immunological niches in the acute and chronic phases of GVHD
由于 GVHD 急性期和慢性期血液学和免疫学生态位的破坏导致免疫重建延迟和异常
- DOI:
- 发表时间:
2011 - 期刊:
- 影响因子:0
- 作者:
野竹剛;瀧伸介;MATSUSHIMA Kouji - 通讯作者:
MATSUSHIMA Kouji
Proposal for the breakdown of increased cancer health care cost and its improvement
关于增加的癌症医疗费用的细分及其改进的建议
- DOI:
10.1093/jjco/hyt015 - 发表时间:
2012 - 期刊:
- 影响因子:2.4
- 作者:
野竹剛;瀧伸介;MATSUSHIMA Kouji;鳥谷部真一;Koinuma N - 通讯作者:
Koinuma N
An anti-CD4 depleting antibody induces transient CD80/CD86 up-regulation on dendritic cells in tumor-bearing mice
抗 CD4 耗竭抗体诱导荷瘤小鼠树突状细胞瞬时 CD80/CD86 上调
- DOI:
- 发表时间:
2016 - 期刊:
- 影响因子:0
- 作者:
UEHA Satoshi;OGIWARA Haru;SHAND Francis;KAKIMI Kazuhiro;ITO Satoru;MATSUSHIMA Kouji - 通讯作者:
MATSUSHIMA Kouji
MATSUSHIMA Kouji的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('MATSUSHIMA Kouji', 18)}}的其他基金
Visualization of osteoblast impairments during bone marrow GVHD
骨髓 GVHD 期间成骨细胞损伤的可视化
- 批准号:
24659216 - 财政年份:2012
- 资助金额:
$ 9.54万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Elucidation of the molecular bases of the generation and maintenance of CTL memory by next generation DNA sequencer
下一代DNA测序仪阐明CTL记忆产生和维持的分子基础
- 批准号:
22390095 - 财政年份:2010
- 资助金额:
$ 9.54万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Studies on molecular mechanisms and therapeutic targets of bone marrow GVHD
骨髓GVHD分子机制及治疗靶点研究
- 批准号:
22659095 - 财政年份:2010
- 资助金额:
$ 9.54万 - 项目类别:
Grant-in-Aid for Challenging Exploratory Research
Analysis of generation and control mechanism of CD8+ T cells by chemokines
趋化因子对CD8 T细胞产生及控制机制的分析
- 批准号:
18209016 - 财政年份:2006
- 资助金额:
$ 9.54万 - 项目类别:
Grant-in-Aid for Scientific Research (A)
Molecular dynamics of chemokine receptors in memory T cells
记忆T细胞趋化因子受体的分子动力学
- 批准号:
16390143 - 财政年份:2004
- 资助金额:
$ 9.54万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Dynamism of immune cells in immune-tissue formation
免疫细胞在免疫组织形成中的动态
- 批准号:
15078203 - 财政年份:2003
- 资助金额:
$ 9.54万 - 项目类别:
Grant-in-Aid for Scientific Research on Priority Areas
Pathophysiological and pharmacological studies on chemokines
趋化因子的病理生理学和药理学研究
- 批准号:
08044263 - 财政年份:1996
- 资助金额:
$ 9.54万 - 项目类别:
Grant-in-Aid for international Scientific Research
Molecular analysis of inflammation and immune response
炎症和免疫反应的分子分析
- 批准号:
08457104 - 财政年份:1996
- 资助金额:
$ 9.54万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Humanization of mouse anti-human IL-8 antibody and development of anti-inflammatory agent against cytokine regulatory factor, NFkB
小鼠抗人IL-8抗体的人源化和针对细胞因子调节因子NFkB的抗炎剂的开发
- 批准号:
07557031 - 财政年份:1995
- 资助金额:
$ 9.54万 - 项目类别:
Grant-in-Aid for Scientific Research (A)
Establishment of pathophysiological role of interleukin 8 and development of its inhibitors
白细胞介素8病理生理学作用的确立及其抑制剂的开发
- 批准号:
06454218 - 财政年份:1994
- 资助金额:
$ 9.54万 - 项目类别:
Grant-in-Aid for General Scientific Research (B)
相似海外基金
Immunological Synapse Restricted Metabolic Reprogramming Drives Driectional Cytokine Synthesis
免疫突触限制代谢重编程驱动定向细胞因子合成
- 批准号:
10156024 - 财政年份:2022
- 资助金额:
$ 9.54万 - 项目类别:
Regulation of immunological synapse by co-receptors
共受体对免疫突触的调节
- 批准号:
22H00448 - 财政年份:2022
- 资助金额:
$ 9.54万 - 项目类别:
Grant-in-Aid for Scientific Research (A)
Developing next generation bioimaging/biophotonics tools to dissect the immunological synapse in single cells, one molecule at a time
开发下一代生物成像/生物光子学工具来剖析单细胞中的免疫突触,一次一个分子
- 批准号:
2444554 - 财政年份:2020
- 资助金额:
$ 9.54万 - 项目类别:
Studentship
Defining STIM1 function at the Immunological Synapse
定义免疫突触处的 STIM1 功能
- 批准号:
10589756 - 财政年份:2020
- 资助金额:
$ 9.54万 - 项目类别:
Molecular basis of recognition in the Immunological Synapse
免疫突触识别的分子基础
- 批准号:
10613479 - 财政年份:2020
- 资助金额:
$ 9.54万 - 项目类别:
Molecular basis of recognition in the Immunological Synapse
免疫突触识别的分子基础
- 批准号:
10386851 - 财政年份:2020
- 资助金额:
$ 9.54万 - 项目类别:
Defining STIM1 function at the Immunological Synapse
定义免疫突触处的 STIM1 功能
- 批准号:
10369054 - 财政年份:2020
- 资助金额:
$ 9.54万 - 项目类别:
Developing next generation bioimaging/biophotonics tools to dissect the immunological synapse in single cells, one molecule at a time
开发下一代生物成像/生物光子学工具来剖析单细胞中的免疫突触,一次一个分子
- 批准号:
2279374 - 财政年份:2019
- 资助金额:
$ 9.54万 - 项目类别:
Studentship
Rapid super-resolution optical imaging of immunological synapse formation initiated by holographic optical tweezers
全息光镊启动免疫突触形成的快速超分辨率光学成像
- 批准号:
415832635 - 财政年份:2019
- 资助金额:
$ 9.54万 - 项目类别:
Research Grants
The effect of acidic pH within tumor microenviornment on the molecular regulation involved in the immunological synapse formation
肿瘤微环境中酸性pH值对免疫突触形成分子调节的影响
- 批准号:
18K15259 - 财政年份:2018
- 资助金额:
$ 9.54万 - 项目类别:
Grant-in-Aid for Early-Career Scientists