Physiological and pathological functions of TNF/TNF receptor family molecules.

TNF/TNF受体家族分子的生理和病理功能。

• 批准号: 14370117
• 负责人: YAGITA Hideo
• 金额: $ 8.64万
• 依托单位: Juntendo University
• 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 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370117/
• 关键词: FasL; Fas; TRAIL; DR5; TWEAK; Fn14; OX4OL; 0X40; 4-1BBL; 4-1BB; CD70; CD27; CD30L; CD30; TRANCE; RANK; TNF; 腫瘍免疫; 移植; 自己免疫; GVHD; 細胞死

(1)We have identified a novel transcriptional activator named BSAC, which suppresses TNF-induced cell death. We have also revealed that TRAF-mediated NF-κB activation suppresses TNF-induced ROS accumulation, which leads to prolonged JNK activation and necrotic cell death.(2)We have revealed that FasL mediates immunosuppression induced by high-dose antigen administration or T. cruzi infection. We have also revealed the involvement of FasL in pathogenesis of colitis and pneumonia. Moreover, we have identified monkey FasL and established its detection system.(3)We have revealed critical role for TRAIL in immune surveillance against tumor development and metastasis, and GVT effect after BMT. We have also demonstrated that blockade of NF-κB activation can sensitize various tumor cells to TRAIL-induced apoptosis. Moreover, we have found that TRAIL can act immunosuppressive by inducing apoptosis in immature dendritic cells and plasma cells.(4)We have found that agonistic mAb against death-ind … More ucing mouse TRAIL receptor (DR5) can not only induce regression of TRAIL-sensitive tumors transiently but also induce tumor-specific CTL, which can also eradicate TRAIL-resistant variants, via recruitment of host antigen-presenting cells by its Fc portion.(5)We have revealed that a new member of TNF receptor family, Fn14, can mediate TWEAK-induced cell death. We have also found pro-inflammatory function of TWEAK/Fn14 against endothelial and epithelial cells. Moreover, we have characterized the expression and function of mouse TWEAK/Fn14 by using newly generated mAbs.(6)We have found that CD27-mediated NK cell activation by CD70 on tumor cells can induce tumor-specific T cell responses in IFN-γ-dependent manner. We have also revealed that CD70 plays critical role in CD4 T cell-independent CTL induction by activated dendrific cells and in CD28-independent cardiac allograft rejection by CD8 T cells.(7)We have found that OX40L plays critical role in allograft rejection and pathogenesis of GVHD, colotis, and asthma.(8)We have characterized the expression and function of mouse 4-1BBL by using newly generated mAbs.(9)We have revealed critical role of CD30L in pathogenesis of CD4 T cell-mediated GVHD and protective immunity to M.avium.(10)We have characterized the expression and function of mouse TRANCE/RANK by using newly generated mAbs. We have also found potent activity of TRANCE-expressing plasmid as a genetic adjuvant. Less

(1)我们发现了一种名为BSAC的新型转录激活剂，它可以抑制TNF诱导的细胞死亡。我们还发现TRAF介导的NF-κB激活抑制TNF诱导的ROS积累，从而导致JNK激活延长和坏死细胞死亡。(2)我们发现FasL介导高剂量抗原施用或克氏锥虫感染诱导的免疫抑制。我们还揭示了 FasL 参与结肠炎和肺炎的发病机制。此外，我们还鉴定了猴FasL并建立了其检测系统。(3)我们揭示了TRAIL在针对肿瘤发展和转移的免疫监视中的关键作用以及BMT后的GVT效应。我们还证明，阻断 NF-κB 激活可以使各种肿瘤细胞对 TRAIL 诱导的细胞凋亡敏感。此外，我们发现 TRAIL 可以通过诱导未成熟树突状细胞和浆细胞凋亡来发挥免疫抑制作用。(4)我们发现，针对小鼠 TRAIL 受体 (DR5) 的死亡诱导激动性单克隆抗体 (DR5) 不仅可以诱导 TRAIL 敏感肿瘤短暂消退，还可以诱导肿瘤特异性 CTL，从而通过招募宿主来根除 TRAIL 抗性变体。 (5)我们发现TNF受体家族的新成员Fn14可以介导TWEAK诱导的细胞死亡。我们还发现 TWEAK/Fn14 对内皮和上皮细胞具有促炎功能。此外，我们利用新产生的mAbs对小鼠TWEAK/Fn14的表达和功能进行了表征。(6)我们发现肿瘤细胞上CD70介导的CD27介导的NK细胞激活可以以IFN-γ依赖性方式诱导肿瘤特异性T细胞应答。我们还发现，CD70 在活化的树突细胞诱导的 CD4 T 细胞依赖性 CTL 以及 CD8 T 细胞的 CD28 依赖性心脏同种异体移植排斥中起关键作用。(7)我们发现 OX40L 在同种异体移植排斥和 GVHD、结肠炎和哮喘的发病机制中起关键作用。(8)我们通过使用新的方法表征了小鼠 4-1BBL 的表达和功能。 (9)我们揭示了CD30L在CD4 T细胞介导的GVHD发病机制和对M.avium的保护性免疫中的关键作用。(10)我们通过使用新生成的mAb来表征小鼠TRANCE/RANK的表达和功能。我们还发现 TRANCE 表达质粒作为遗传佐剂的有效活性。较少的

项目成果

Miura, Y.: "TRAIL induces neuronal death in a murine model of HIV central nervous system infection."Proc.Natl.Acad.Sci.USA. 100. 2777-2782 (2003)

Miura, Y.：“TRAIL 在 HIV 中枢神经系统感染的小鼠模型中诱导神经元死亡。”Proc.Natl.Acad.Sci.USA。

Miyahira, Y.: "A potent adjuvant effect of RANK ligand gene for inducing antigen-specific CD8+T cell response by DNA and viral vector vaccination"J.Immunol. 171. 6344-6348 (2003)

Miyahira, Y.：“RANK 配体基因通过 DNA 和病毒载体疫苗接种诱导抗原特异性 CD8 T 细胞反应的有效佐剂作用”J.Immunol。

Tian, L.: "Association of the CD134/CD134L constimulatory pathway with acute rejection of small bowel allograft"Transplantation. 74. 133-138 (2002)

Tian, L.：“CD134/CD134L 刺激通路与小肠同种异体移植急性排斥反应的关联”移植。

Yuan, X.: "Role of CD134-CD134 ligand costimulatory pathway in atloimmune response in vivo."J.Immunol. 170. 2949-2955 (2003)

袁X.：“CD134-CD134配体共刺激途径在体内阿洛免疫反应中的作用”，J.Immunol。

Takeda, K.: "Critical role for tumor necrosis factor-related apoptosis-inducing ligand in immune surveillance against tumor development"J.Exp.Med.. 195. 171-179 (2002)

Takeda, K.：“肿瘤坏死因子相关凋亡诱导配体在针对肿瘤发展的免疫监视中的关键作用”J.Exp.Med.. 195. 171-179 (2002)