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

(1)我们发现了一种名为BSAC的新型转录激活因子，它可以抑制tnf诱导的细胞死亡。我们还发现traf介导的NF-κB活化抑制tnf诱导的ROS积累，从而导致JNK活化时间延长和坏死细胞死亡。(2)我们发现FasL介导高剂量抗原给药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，我们还鉴定了猴子FasL并建立了检测系统。(3)我们揭示了TRAIL在肿瘤发展和转移的免疫监视以及BMT后GVT作用中的关键作用。我们还证明，阻断NF-κB活化可以使多种肿瘤细胞对trail诱导的凋亡敏感。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的凋亡来发挥免疫抑制作用。(4)我们已经发现，针对死亡和死亡的小鼠TRAIL受体（DR5）的激动性单抗不仅可以诱导TRAIL敏感肿瘤的短暂消退，还可以诱导肿瘤特异性CTL， CTL也可以通过其Fc部分募集宿主抗原呈递细胞来根除TRAIL耐药变体。(5)我们发现TNF受体家族的一个新成员Fn14可以介导tweak诱导的细胞死亡。我们还发现TWEAK/Fn14对内皮细胞和上皮细胞具有促炎功能。此外，我们利用新生成的单克隆抗体对小鼠TWEAK/Fn14的表达和功能进行了表征。(6)我们发现cd27介导的NK细胞在肿瘤细胞上被CD70激活，可以以IFN-γ依赖的方式诱导肿瘤特异性T细胞反应。我们还发现CD70在活化树突状细胞诱导CD4 T细胞不依赖CTL和cd28不依赖CD8 T细胞的心脏移植排斥反应中起关键作用。(7)我们发现OX40L在同种异体移植排斥反应和GVHD、结肠炎和哮喘的发病机制中起关键作用。(8)我们利用新生成的单克隆抗体对小鼠4-1BBL的表达和功能进行了表征。(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）我们利用新生成的单克隆抗体对小鼠TRANCE/RANK的表达和功能进行了表征。我们还发现表达trance的质粒作为遗传佐剂具有很强的活性。少

(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