Development of strategy to treat allergic diseases via targeting surface molecules on lymphocytes and intracellular signaling molecules

通过靶向淋巴细胞表面分子和细胞内信号分子开发治疗过敏性疾病的策略

• 批准号: 20390282
• 负责人: OKUMURA Ko
• 金额: $ 11.9万
• 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: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20390282/
• 关键词: TIMファミリー; マスト細胞; アレルギー; アポトーシス; T cell immunoglobulin and mucin domain (TIM)ファミリー; TIM-2; B細胞; T細胞; Th1細胞; Th2細胞; Th17細胞; コラーゲン誘発性関節炎; オートファジー; インターフェロン; Liht chain(LC)3; ノックアウトマウス; 脱顆粒; IgE; CD63; Tim-3; 樹状細胞; 貪食; クロスプレゼンテーション

Members of the T-cell immunoglobulin mucin (Tim) family control a variety of immune responses including Th1 and Th2 differentiation of T cells. We found that TIM-3 was expressed on C8+ dendritic cells (DC) and TIM-3 was crucial for clearance of apoptotic cells by phagocytes. Moreover, TIM-3-dependent phagocytosis of apoptotic cells was crucial for cross-presentation of dying cell-associated antigens. On the other hand, TIM-2 was found to be expressed on B cells and induced positive signals into B cells. Therefore, administration of agonistic anti-TIM-2 antibody significantly exacerbated type II collagen-induced arthritis. We next investigated a role for autophagy in the development and function of mast cells. We found that conversion of type I to type II light chain (LC3)-II, a hallmark of autophagy, was constitutively induced in mast cells under full nutrient conditions, and LC3-II localized in secretory granules of mast cells. Although deletion of Atg7 did not impair the development of BMMCs, Atg7(-/-) BMMCs showed severe impairment of degranulation, but not cytokine production upon antigen stimulation.

T细胞免疫球蛋白粘蛋白（Tim）家族成员控制多种免疫反应，包括T细胞的Th1和Th2分化。我们发现TIM-3在C8+树突状细胞（DC）上表达，并且TIM-3对于吞噬细胞清除凋亡细胞至关重要。此外，凋亡细胞的tim -3依赖性吞噬作用对于死亡细胞相关抗原的交叉呈递至关重要。另一方面，TIM-2被发现在B细胞上表达并诱导阳性信号进入B细胞。因此，施用激动性抗tim -2抗体可显著加重II型胶原诱导的关节炎。我们接下来研究了自噬在肥大细胞发育和功能中的作用。我们发现，在充分营养条件下，肥大细胞可以组成性地诱导I型轻链(LC3)-II向II型轻链(LC3)-II的转化，这是自噬的标志，并且LC3-II定位于肥大细胞的分泌颗粒中。虽然Atg7的缺失并不影响BMMCs的发育，但Atg7(-/-) BMMCs在抗原刺激下表现出严重的脱颗粒损伤，但不影响细胞因子的产生。

项目成果

NKG2A inhibits invariant NKT cell activation in hepatic injury.

• DOI: 10.4049/jimmunol.182.1.250
• 发表时间: 2009-01-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Kawamura T;Takeda K;Kaneda H;Matsumoto H;Hayakawa Y;Raulet DH;Ikarashi Y;Kronenberg M;Yagita H;Kinoshita K;Abo T;Okumura K;Smyth MJ
• 通讯作者: Smyth MJ

RANK-RANKL signaling pathway is critically in volvedin the function of CD4+CD25+ regulatory T cells in chronic colitis.

RANK-RANKL信号通路在慢性结肠炎中关键参与CD4 CD25调节性T细胞的功能。

• 发表时间: 2009
• 期刊: J. Immunol. 182
• 作者: Totsuka T;Okamoto R;Nakamura T;Watanabe M(他8名、5番目)
• 通讯作者: Watanabe M(他8名、5番目)

T-cell immunoglobulin mucin-3 determines severity of liver ischemia/reperfusion injury in mice in a TLR4-dependent manner.

• DOI: 10.1053/j.gastro.2010.07.003
• 发表时间: 2010-12
• 期刊: Gastroenterology
• 影响因子: 29.4
• 作者: Uchida Y;Ke B;Freitas MC;Yagita H;Akiba H;Busuttil RW;Najafian N;Kupiec-Weglinski JW
• 通讯作者: Kupiec-Weglinski JW

NF-κB2(p100)limits TNF-alpha-induced osteoclastogenesis

NF-κB2(p100)限制TNF-α诱导的破骨细胞生成

• 发表时间: 2009
• 期刊: J Clin Invest 119
• 作者: Tanaka;S.;Nakano;H.
• 通讯作者: H.

TRAF2 phosphorylation modulates tumor necrosis factor α-induced gene expression and cell resistance to apoptosis

TRAF2磷酸化调节肿瘤坏死因子α诱导的基因表达和细胞对凋亡的抵抗

• 发表时间: 2009
• 期刊: Mol Cell Biol 29
• 作者: Blackwell;K.;et al.
• 通讯作者: et al.