Functional analysis of costimulatory molecules for autoimmune diseases

自身免疫性疾病共刺激分子的功能分析

• 批准号: 18390292
• 负责人: OKUMURA Ko
• 金额: $ 11.21万
• 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: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390292/
• 关键词: autoimmune diseases; collagen-induced arthritis; experimental autoimmune uveoretinitis; murine model of asthma; experimental autoimmune encephalomyelitis; costimulatory molecules; CD28-B7 family; TNF-TNFR family; コラーゲン誘発性関節炎; B7RP-1; TWEAK

1.The role of the ICOS/B7RP-1 and OX40/OX40L in murine experimental autoimmune uveoretinitis.We examined the role of ICOSB7RP-1 and OX40/OX40L pathways in the pathogenesis of mouse experimental autoimmune uveoretinitis (EAU) , an animal model of human autoimmune uveitis. The anti-B7RP-1 monoclonal antibody (mAb)-treated or ICOS-deficient mice showed a substantial reduction of disease scores. Blockade of ICOS/B7RP-1 interaction during the effector phase ameliorated the disease, whereas its blockade during the induction phase exhibited no significant effect. Blockade of OX40/OX40L interaction during the effector phase also ameliorated the disease, whereas its blockade during the induction phase accelerated. These results suggest that ICOS/B7RP-1 and OX40/OX40L interactions play a critical role in the pathogenesis of uveitis. We also indicated that ICOS-mediated costimulation plays differential roles in EAU and experimental autoimmune encephalomyelitis, which is also a Thl disease induced … More in the same manner as EAU.2.Amelioration of collagen-induced arthritis (CIA) by anti-RANKL and anti-TWEAK mAbs treatment.We have investigated the effect of anti-RANKL and anti-TWEAK mAbs on the development of CIA, a well-established murine model of rheumatoid arthritis (RA).Anti-RANKL mAb had no effect on immune responses or inflammation, it ameliorated bone loss at the site of inflammation. Histological analyses revealed that osteoclast formation was impaired at the site of joint inflammation in anti-RANKL-treated CIA mice. These results suggest the utility of anti-RANKL mAb for the prevention of osteoporosis associated with joint inflammation in RA. Administration of anti-TWEAK mAb significantly ameliorated paw swelling, synovial hyperplasia, and infiltration of inflammatory cells. The levels of proinflammatory chemokines in serum and knee joints were reduced. Histological examination revealed that the treatment with anti-TWEAK mAb suppressed the development of small vessels in synovial tissues. These results indicated anti-inflammatory and antiangiogenic effects of the TWEAK blockade in CIA, which may be also beneficial for the treatment of RA. Less

1. ICOS/B7 RP-1和OX 40/OX 40 L在小鼠实验性自身免疫性葡萄膜视网膜炎中的作用我们研究了ICOS/B7 RP-1和OX 40/OX 40 L通路在小鼠实验性自身免疫性葡萄膜视网膜炎（EAU）发病机制中的作用，EAU是人类自身免疫性葡萄膜炎的动物模型。抗B7 RP-1单克隆抗体（mAb）处理或ICOS缺陷小鼠显示疾病评分大幅降低。在效应期阻断ICOS/B7 RP-1相互作用可改善疾病，而在诱导期阻断ICOS/B7 RP-1相互作用则无显著效果。在效应期阻断OX 40/OX 40 L相互作用也改善了疾病，而在诱导期阻断则加速了疾病。这些结果表明，ICOS/B7 RP-1和OX 40/OX 40 L相互作用在葡萄膜炎的发病机制中起关键作用。我们还表明，ICOS介导的共刺激在EAU和实验性自身免疫性脑脊髓炎中发挥不同的作用，实验性自身免疫性脑脊髓炎也是一种Thl疾病诱导的疾病。 ...更多信息 2.抗RANKL和抗TWEAK单克隆抗体对胶原诱导性关节炎（CIA）的改善我们研究了抗RANKL和抗TWEAK单克隆抗体对CIA的影响，这是一种建立良好的类风湿关节炎（RA）小鼠模型，抗RANKL单克隆抗体对免疫反应和炎症没有影响，它改善了炎症部位的骨丢失。组织学分析显示，在抗RANKL处理的CIA小鼠中，破骨细胞形成在关节炎症部位受损。这些结果表明，抗RANKL mAb可用于预防RA中与关节炎症相关的骨质疏松症。给予抗TWEAK mAb显著改善了爪肿胀、滑膜增生和炎性细胞浸润。血清和膝关节炎性趋化因子水平降低。组织学检查显示，用抗TWEAK mAb处理抑制了滑膜组织中小血管的发育。这些结果表明TWEAK阻断剂在CIA中具有抗炎和抗血管生成作用，这也可能有利于治疗RA。少

项目成果

Interleukin-12-and interferon-gamma-mediated natural killer cell activation by Agaricus blazei Murill

姬松茸介导的白介素 12 和干扰素 γ 介导的自然杀伤细胞激活

• 发表时间: 2007
• 期刊: IMMUNOLOGY 121
• 作者: 竹腰正隆;前田史子;Fukushima A;王 英正;上山 知己;Seko Y;王 英正;Nakano N;野村 哲矢;Takeda K;立石 健人;Yuminamochi E
• 通讯作者: Yuminamochi E

TGF-beta type I receptor kinase inhibitor down-regulates rheumatoid synoviocytes and prevents the arthritis induced by type II collagen antibody

TGF-β I 型受体激酶抑制剂下调类风湿滑膜细胞并预防 II 型胶原抗体诱发的关节炎

• 发表时间: 2007
• 期刊: INTERNATIONAL IMMUNOLOGY 19
• 作者: Sakurai D;Takeda K;Niyonsaba F;Chen XJ;Piao JH;Sakuma M
• 通讯作者: Sakuma M

Downregulation of c-FLIP promotes caspase-dependent JNK activation and reactiveoxveen species accumulation in tumor cells

c-FLIP 的下调促进肿瘤细胞中 caspase 依赖性 JNK 激活和反应性牛物种积累

• 发表时间: 2008
• 期刊: ONCOGENE 27
• 作者: 竹腰正隆;前田史子;Nakajima A
• 通讯作者: Nakajima A

T-cell Ig and mucin domain-containing protein(Tim)-2 regulates murine allergicconiunctivitis durine the effector phase

T细胞Ig和含粘蛋白结构域蛋白(Tim)-2在效应期调节小鼠过敏性结膜炎

• 发表时间: 2007
• 期刊: IMMUNOLOGY LETTERS 110
• 作者: Sakurai;D.;H.;Hase;Y.;Kanno;H.;Kojima;K.;Okumura;T.;Kobata;Zheng Y;Ando T;Gondokaryono SP;Takeda K;Fukushima A
• 通讯作者: Fukushima A

TNF receptor-associated factor 2-dependent canonical pathway is crucial for thedevelopment of Pever's Hatches

TNF 受体相关因子 2 依赖性经典途径对于 Pevers Hatches 的发展至关重要

• 发表时间: 2007
• 期刊: JOURNAL OF IMMUNOLOGY 178
• 作者: Sakurai;D.;H.;Hase;Y.;Kanno;H.;Kojima;K.;Okumura;T.;Kobata;Zheng Y;Ando T;Gondokaryono SP;Takeda K;Fukushima A;Seko Y;Nakano N;Yuminamochi E;Koyama K;Niyonsaba F;Chen XJ;Piao JH
• 通讯作者: Piao JH