Expression of chemokines and their receptors in GVHD target organs and therapeutic target

GVHD靶器官及治疗靶点中趋化因子及其受体的表达

• 批准号: 17591045
• 负责人: HASEGAWA Hitoshi
• 金额: $ 2.24万
• 依托单位: Ehime University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17591045/
• 关键词: Chemokines; Graft-versus-host disease; Regulatory T cells

Graft-versus-host disease (GVHD) is the most significant clinical problem that arises after allogeneic hematopoietic cell transplantation. Chemokines induced during the development of GVHD promote T-cell migration into GVHD target organs and contribute to severity of GVHD. Therefore, we analyzed the expression of chemokines in GVHD target organs in an animal model and tried the therapy through chemokine antagonists and their receptors.In this study, we used acute GVHD model mouse: C57BL/6 (donor) and (C57BL/6 X DBA/2)F1 (B6D2F1) (recipient). The B6D2F1 mice were treated by 13 Gy irradiation. During the development of GVHD, expressions of Th1-associated chemokines (Mig/CXCL9 and IP-10/CXCL10), Th2-associated chemokines (TARC and MDC), MIP-1α and-1β, RANTES, and KC were increased in liver. In contrast, Th1-associated chemokines, MIP-lα and-β, MCP-1 and-3, and LTN were increased in gut. From this finding, high levels of expression of Th1-associated chemokines and their receptor CXCR3 were observed in the liver and intestines of GVHD-induced recipient mice. Next, we tried the treatment of acute GVHD by using IP-10 antagonist. Consiquently, IP-10 antagonist ameliorated the damage significantly in liver and gut, compared with control mice.Recipient mice that had undergone transfer of CD4^+CD25^+Foxp3^+ CXCR3-transfected T cells (CXCR3-Treg cells) showed significant amelioration of GVHD changes in the liver and intestines in comparison with recipient mice that had received CD4^+CD25^+Foxp3^+ T cells (Treg cells). This was due to more pronounced migration of CXCR3-Treg cells and their localization for a longer time in TM-associated chemokine-expressing organs, resulting in stronger suppressive activity. Thus we succeeded in preparing chemokine receptor-expressing Treg cells and demonstrated their ability to ameliorate disease progression upon accumulation in target organs. This method may provide a new therapeutic approach for organ damage in acute GVHD.

移植物抗宿主病（GVHD）是同种异性造血细胞移植后出现的最重要的临床问题。 GVHD发育过程中诱导的趋化因子促进T细胞迁移到GVHD靶器官中，并导致GVHD的严重程度。因此，我们在动物模型中分析了GVHD靶心器官中趋化因子的表达，并通过趋化因子拮抗剂及其接收器尝试了治疗。在这项研究中，我们使用了急性GVHD模型鼠标：C57BL/6（供体）（供体）和（C57BL/6 x DBA/2）F1（B6D2F1）（B6D2F1）（受体）。通过13 Gy辐照处理B6D2F1小鼠。在GVHD开发过程中，Th1相关趋化因子（MIG/CXCL9和IP-10/CXCL10），Th2相关趋化因子（TARC和MDC），MIP-1α和1β，RANTES，RANTES和KC的表达增加。相反，肠道中与Th1相关的趋化因子，MIP-Lα和-β，MCP-1和-3和LTN增加。从这一发现中，在GVHD诱导的受体小鼠的肝脏和肠中观察到了与Th1相关趋化因子及其受体CXCR3的高表达。接下来，我们尝试使用IP-10拮抗剂尝试治疗急性GVHD。与对照小鼠相比，IP-10拮抗剂在肝脏和肠道中显着改善了损害。接种小鼠经历了CD4^+CD25^+CD25^+Foxp3+Foxp3+CXCR3转染的T细胞（CXCR3- TREG细胞）的转移，与GVHD相比，与GVHD相比，与MOTINES相比，与MOTINE相比，与MOTINE相比，这与MOTINGE的相比有显着变化。 CD4^+CD25^+FOXP3^+T细胞（Treg细胞）。这是由于CXCR3- Treg细胞及其定位在与TM相关的表达趋化因子的器官中更长的时间迁移，从而导致更强的抑制活性。我们成功地准备了表达趋化因子受体的Treg细胞，并证明了它们在靶器官积累后改善疾病进展的能力。该方法可以为急性GVHD中器官损伤提供一种新的治疗方法。

项目成果

急性GVHDマウスモデルにおける標的臓器でのケモカインの発現様式と病態との関連。

急性GVHD小鼠模型靶器官趋化因子表达模式与病理状况的关系。

• 发表时间: 2007
• 期刊: 第29回日本造血細胞移植学会抄録
• 作者: Hatakenaka M;et al.;長谷川 均 他。
• 通讯作者: 長谷川 均 他。

Expression of chemokines in GVHD target organs and therapeutic target.

GVHD靶器官和治疗靶点中趋化因子的表达。

• 发表时间: 2006
• 期刊: Proceedings of the Japanese Society for Immunology 36
• 作者: Yamashita T;Arai K;Honda M et al.;Mihiro Yano;Nakashima Y;Hasegawa H et al.
• 通讯作者: Hasegawa H et al.

ケモカインおよびそのレセプターを分子標的にした自己免疫疾患の治療

使用趋化因子及其受体作为分子靶标治疗自身免疫性疾病

• 发表时间: 2007
• 期刊: 愛媛医学 26
• 作者: Honda M;Yamashita T;Ueda T et al.;Saegusa J.;Mihiro Yano.;長谷川均
• 通讯作者: 長谷川均

ケモカインアンタゴニストによるループス腎炎の抑制

趋化因子拮抗剂抑制狼疮性肾炎

• 发表时间: 2005
• 期刊: 臨床免疫 44
• 作者: 長谷川 均;井上 淳
• 通讯作者: 井上 淳

ケモカインおよびそのレセプクーを分子標的にした自己免疫疾患の治療

使用趋化因子及其受体作为分子靶标治疗自身免疫性疾病

• 发表时间: 2007
• 期刊: 愛媛医学 26
• 作者: Misu H;Takamura T;Matsuzawa N;Shimizu A;Ota T;Sakurai M;Ando H;Arai K;Yamashita T;Honda M;Yamashita T;Kaneko S.;長谷川 均
• 通讯作者: 長谷川 均