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）是异基因造血细胞移植后最重要的临床问题。在GVHD的发展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的严重性。本研究采用急性GVHD模型小鼠C57 BL/6（供体）和（C57 BL/6 X DBA/2）F1（B6 D2 F1）（受体），通过分析趋化因子在GVHD靶器官中的表达情况，尝试通过趋化因子拮抗剂及其受体进行治疗。B6 D2 F1小鼠接受13戈伊照射。在GVHD发生发展过程中，Th 1相关趋化因子（Mig/CXCL 9和IP-10/CXCL 10）、Th 2相关趋化因子（TARC和MDC）、MIP-1α和MIP-1β、RANTES和KC在肝脏中的表达增加。相反，Th 1相关趋化因子MIP-1 α和MIP-1 β、MCP-1和MCP-3以及LTN在肠道中增加。从这一发现，高水平的表达的Th 1相关的趋化因子和它们的受体CXCR 3被观察到在肝脏和肠道的GVHD诱导的受体小鼠。接下来，我们尝试使用IP-10拮抗剂治疗急性GVHD。与对照组小鼠相比，IP-10拮抗剂显著改善了肝脏和肠道的损伤。与接受CD 4 ^+ CD 25 ^+ Foxp 3 ^+ T细胞（Treg细胞）的受体小鼠相比，接受CD 4 ^+ CD 25 ^+ Foxp 3 ^+ CXCR 3转染的T细胞（CXCR 3-Treg细胞）的受体小鼠显示出肝脏和肠道中GVHD变化的显著改善。这是由于CXCR 3-Treg细胞更明显的迁移及其在TM相关趋化因子表达器官中更长时间的定位，导致更强的抑制活性。因此，我们成功地制备了表达趋化因子受体的Treg细胞，并证明了它们在靶器官中积累后改善疾病进展的能力。该方法可能为急性GVHD的器官损害提供一种新的治疗途径。

项目成果

IK cytokine ameliorates the progression of lupus nephritis in MRL/lpr mice

• DOI: 10.1002/art.22172
• 发表时间: 2006-11-01
• 期刊: ARTHRITIS AND RHEUMATISM
• 作者: Muraoka, Masatake;Hasegawa, Hitoshi;Yasukawa, Masaki
• 通讯作者: Yasukawa, Masaki

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

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