Pre-Translational Approaches to the Conquest of Immune Disorders by Targeting Fcγ Receptors

通过靶向 Fcγ 受体征服免疫性疾病的翻译前方法

• 批准号: 17209017
• 负责人: TAKAI Toshiyuki
• 金额: $ 19.55万
• 依托单位: Tohoku University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (A)
• 财政年份: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17209017/
• 关键词: Immune regulation; Autoimmune disease; Immunoglobulin; Autoantibodies; Intravenous immunoglobulin; Fc receptor; 自己免疫性糖尿病; 大量免疫グロブリン療法; NODマウス; 膵島炎; 樹状細胞; NK細胞; シグナル伝達; 免疫学; アレルギー・ぜんそく; 糖尿病; 自己免疫

Fc receptors play pivotal roles in immune regulation, and their dysregulation leads to immune-related diseases including allergic inflammationand aud autoimmunity. We have obtained in this project the following accomplishments:1) Establishment of the importance of inhibitory Fcγ receeptor, FcγRIIB, in immune regulation and autoimmune dieseases, such as autoimmune glomerulonephritis.2) Establishment of animal models for immune disorders by the use of Feγ receptor gene-targeted mice.3) Establishment of immune cells with the immortalized growth and immune functions by the use of SV40LT-transgenic mice.Among these, in particular, we have identified the pivotal roles of activating-type Fcγ receptors, but not inhibitory FcγRIB, in the development of autoimmune diabetes of NOD mice. Type 1 diabetes mellitus (T1D) in humans is an organ-specific autoimmune disease in which pancreatic islet β cell are ruptured by autoreactive T cells. NOD mice, the most commonly used animal model of T1D, show ea … More rly infiltration of leukocytes in the islets (insulitis), resulting in islet destruction and diabetes later. NOD mice produce various islet β cell-specific autoantibodies, although it remains a subject of debate regarding whether these autoantibodies contribute to the development of T1D or not. To investigate the possible role of FcγRs in NOD mice, we have generated several FcγR-less NOD lines, namely FcR common γ chain (FcRγ)-deficient ((NOD.γ^<-/->), FcγRIII-deficient (NOD.III^<-/->), FcγRIIB-deficient (NOD.IIB^<-/->), and both FcRγ and Fcγ and FcγRIIB-deficient NOD (NOD.null) mice. We have shown significant protection from diabetes in NOD.γ^<-/->, NOD.III^<-/->, and NOD.null but not in NOD.IIB^<-/-> mice even with grossly comparable production of autoantibodies among them. Insulitis in NOD.γ^<-/-> mice was also alleviated. Adoptive transfer of bone marrow-derived dendritic cells or NK cells from NOD mice rendered NOD.γ^<-/-> animals more susceptible to diabetes, suggesting a possible scenario in which activating FcγRIII on NK cells trigger antibody-dependent effector functions and inflammation. These findings highlight the critical roles of activating FcγRs in the development of T1D, and indicate that FcγRs are novel targets for therapies for T1D. Less

Fc受体在免疫调节中起着关键作用，其失调会导致包括过敏性炎症和自身免疫在内的免疫相关疾病。1)建立了抑制性Fcγ受体FcγRIIB在免疫调节和自身免疫性疾病(如自身免疫性肾炎)中的重要性。2)利用Feγ受体基因靶向小鼠建立了免疫紊乱的动物模型。3)利用SV40LT转基因小鼠建立了具有永生化生长和免疫功能的免疫细胞。其中，我们特别确定了活化型Fcγ受体而不是抑制性FcγRIB在NOD小鼠自身免疫性糖尿病发生发展中的关键作用。人类1型糖尿病(T1D)是一种器官特异性自身免疫性疾病，胰岛β细胞被自身反应性T细胞破坏。NOD小鼠是T1D最常用的动物模型，表现为EA…胰岛内有更多的白细胞渗入(胰岛炎症)，导致胰岛破坏和后来的糖尿病。NOD小鼠产生各种胰岛β细胞特异性自身抗体，尽管这些自身抗体是否有助于T1D的发展仍是一个争论的主题。为了研究Fcγ受体在NOD小鼠中的可能作用，我们建立了几个FcγR缺失的NOD系，即Fcr CommonγChain(FcRγ)缺陷((Nod.γ^&lt；-/-&gt；)，FcγRIII缺陷(NOD.III^&lt；-/-&gt；)，FcγRIIB缺陷(NOD.IIB^&lt；-/-&gt；)，以及Fcrγ和FCγ和FcγRIIB缺陷(NOD.NULL)小鼠。我们已经在NOD.γ^&lt；-/-&gt；，NOD.IIB^&lt；-/-&gt；-/-&gt；和NOD.Null中显示了对糖尿病的显著保护，但在NOD.IIB^&lt；-/-&gt；小鼠身上没有，即使它们之间产生的自身抗体大致相同。NOD.γ^&lt；-/-&gt；小鼠的胰岛素炎症也得到缓解。来自NOD小鼠的骨髓来源的树突状细胞或NK细胞过继转移使NOD.γ^&lt；-/-&gt；动物更容易患糖尿病，这表明激活NK细胞上的Fc-γRIII可能会触发抗体依赖的效应功能和炎症。这些发现强调了激活Fc-γ受体在T1D发生中的关键作用，并表明Fc-γ-R是治疗T1D的新靶点。较少

项目成果

Vav1 controls DAP10-mediated natural eytotoxicity by regulating actin and microtubule dynamics.

Vav1 通过调节肌动蛋白和微管动力学来控制 DAP10 介导的天然细胞毒性。

• 发表时间: 2006
• 期刊: J. Immunol 177(4)
• 作者: Graham DB ;et. al.
• 通讯作者: et. al.

Fcγ receptor regulation of Citrobacter rodentium infection

• DOI: 10.1128/iai.01493-07
• 发表时间: 2008-04-01
• 期刊: INFECTION AND IMMUNITY
• 影响因子: 3.1
• 作者: Masuda, Atsuhiro;Yoshida, Masaru;Azuma, Takeshi
• 通讯作者: Azuma, Takeshi

Plexin-Al and its interaction with DAP12 in immune responses and bone homeostasis.

Plexin-Al 及其与 DAP12 在免疫反应和骨稳态中的相互作用。

• 发表时间: 2006
• 期刊: Nat. Cell Biol 8(6)
• 作者: Takegahara N ;et. al.
• 通讯作者: et. al.

Hydronephrosis associated with anti-urothelial and anti-nuclear autoantibodies inBALB/c-Fcgr2b^<-/->lPdcdlh^<-/-> mice

BALB/c-Fcgr2b^<-/->lPdcdlh^</-/-> 小鼠中与抗尿路上皮和抗核自身抗体相关的肾积水

• 发表时间: 2005
• 期刊: J. Exp. Med 202
• 作者: Okazaki T;et. al.
• 通讯作者: et. al.

A CD200 receptor-like protein CD200R3 functions. as an activating rece ptor expressed exclusively on basophils and mast cells

CD200 受体样蛋白 CD200R3 发挥作用。

• 发表时间: 2007
• 期刊: J. Immunol 179
• 作者: Kojima T;et. al.
• 通讯作者: et. al.