Scientific research of transplantation tolerance targeting CD26/caveolin-1 costimulation pathway

CD26/caveolin-1共刺激通路移植耐受的科学研究

• 批准号: 21679005
• 负责人: OHNUMA Kei
• 金额: $ 41.18万
• 依托单位: Juntendo University (2012-2013)The University of Tokyo (2009-2011)
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (S)
• 财政年份: 2009
• 资助国家: 日本
• 起止时间: 2009 至 2013
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-21679005/
• 关键词: 移植片対宿主病; 造血幹細胞移植; T細胞; 共刺激; CD26/DPPIV; Caveolin-1; CD26; DPPIV; 骨髄移植; CD8; CTLA4-Ig; 移植免疫

In our research, we demonstrated in in vitro experiments that blockade of CD26-mediated T cell costimulation by soluble Fc fusion proteins containing the N-terminal domain of caveolin-1 (Cav-Ig) diminished primary and secondary proliferative responses not only to recall antigen, but also to unrelated allogeneic antigen-presenting cell. To expand the in vitro findings to an in vivo system, we examined CD26-dependent organ injury in a xenogeneic GVHD (xGVHD) murine model. Administration of humanized anti-human CD26 monoclonal antibody (mAb) decreased xGVHD severity and prolonged survival in hu-PBL-NOG mice without loss of engraftment of human T cells, while increasing doses of CTLA4-Ig diminished engraftment of human lymphocytes. Importantly, anti-CD26 mAb treatment preserved the graft-versus-leukemia effects. Altogether, our findings indicate a role for CD26 in the regulation of GVHD and point to CD26 as a novel target for therapeutic intervention in this disease.

在我们的研究中，我们在体外实验中证明了通过可溶性FC融合蛋白阻断CD26介导的T细胞共刺激，其中含有Caveolin-1（Cav-ig）的N末端结构域（CAV-IG）减少了原发性和继发性增殖反应，不仅对回忆抗原，而且对无与伦比的抗原抗原性抗原性细胞均减少。为了将体外发现扩展到体内系统，我们检查了异构GVHD（XGVHD）鼠模型中CD26依赖性器官损伤。人源化抗人CD26单克隆抗体（MAB）的给药降低了XGVHD的严重程度，并在Hu-Pbl-Nog小鼠中延长了生存率，而不会损失人类T细胞的植入，同时增加了CTLA4-IG剂量的人类淋巴细胞的施加。重要的是，抗CD26 mAb治疗保留了移植物与白血病的作用。总的来说，我们的发现表明CD26在调节GVHD中的作用，并将CD26指向该疾病治疗干预的新靶标。

项目成果

DIPEPTIDYL PEPTIDASE IN AUTOIMMUNE PATHOPHYSIOLOGY

• DOI: 10.1016/s0065-2423(11)53003-3
• 发表时间: 2011-01-01
• 期刊: ADVANCES IN CLINICAL CHEMISTRY, VOL 53
• 作者: Ohnuma, Kei;Hosono, Osamu;Morimoto, Chikao
• 通讯作者: Morimoto, Chikao

A Novel Function of CD26-Mediated Costimulation in the cytotoxic activity of human CD8^+ T cells in xenogeneic graft-versus-host disease mice model

CD26 介导的共刺激在异种移植物抗宿主病小鼠模型中人 CD8^ T 细胞细胞毒活性中的新功能

• 发表时间: 2010
• 作者: Hatano R;Ohnuma K;et al
• 通讯作者: et al

CD26 expression of vascular endothelium and its role in inflammatory endothelial cell injury

血管内皮细胞CD26的表达及其在炎性内皮细胞损伤中的作用

• 发表时间: 2009
• 作者: 高澤渉;大沼圭;他
• 通讯作者: 他

Inhibition of dipeptidyl peptidase 4 regulates microvascular endothelial growth induced by inflammatory cytokines.

• DOI: 10.1016/j.bbrc.2010.08.112
• 发表时间: 2010-10
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Wataru Takasawa;K. Ohnuma;R. Hatano;Y. Endo;N. Dang;C. Morimoto

CD26 expression of vascular endothelium and its role in inflammatory endothelial cell injury.

血管内皮细胞CD26的表达及其在炎性内皮细胞损伤中的作用

• 发表时间: 2009
• 作者: 高澤渉、大沼圭;他
• 通讯作者: 他