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cd26介导的T细胞共刺激被含有小窝蛋白-1 (Cav-Ig) n端结构域的可溶性Fc融合蛋白阻断，不仅减少了对抗原的初级和次级增殖反应，而且减少了对不相关的异体抗原呈递细胞的初级和次级增殖反应。为了将体外研究结果扩展到体内系统，我们在异种GVHD （xGVHD）小鼠模型中检测了cd26依赖性器官损伤。人源化抗人CD26单克隆抗体（mAb）在hu- ppl - nog小鼠中降低了xGVHD的严重程度并延长了生存期，但没有丧失人T细胞的植入，而增加CTLA4-Ig剂量则减少了人淋巴细胞的植入。重要的是，抗cd26单抗治疗保留了移植物抗白血病的效果。总之，我们的研究结果表明CD26在GVHD的调节中发挥作用，并指出CD26是治疗干预这种疾病的新靶点。

项目成果

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

Localization of CD26/DPPIV in nucleus and its nuclear translocation enhanced by anti-CD26 monoclonal antibody with anti-tumor effect.

• DOI: 10.1186/1475-2867-9-17
• 发表时间: 2009-06-26
• 期刊: Cancer cell international
• 影响因子: 5.8
• 作者: Yamada K;Hayashi M;Du W;Ohnuma K;Sakamoto M;Morimoto C;Yamada T
• 通讯作者: Yamada T

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