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受体在免疫调节中发挥着关键作用，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。我们在该项目中取得了以下成果：1）确立了抑制性Fcγ受体FcγRIIB在免疫调节中的重要性。 2）利用Feγ受体基因靶向建立免疫性疾病动物模型3）利用SV40LT转基因小鼠建立具有永生化生长和免疫功能的免疫细胞。其中，特别是，我们已经确定了激活型Fcγ受体而非抑制性FcγRIB在免疫反应中的关键作用。人类 1 型糖尿病 (T1D) 是一种器官特异性自身免疫性疾病，其中胰岛 β 细胞被破坏。自身反应性 T 细胞，最常用的 T1D 动物模型，显示出胰岛中白细胞的早期浸润（胰岛炎），导致胰岛破坏，随后 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 的发展仍然是一个争论的话题。为了研究 FcγR 在 NOD 小鼠中的可能作用，我们已经产生了几种。 FcγR-less NOD系，即FcR共同γ链(FcRγ)缺陷((NOD.γ^<-/->)、FcγRIII缺陷(NOD.III^<-/->)、FcγRIIB缺陷(NOD.γRIII缺陷(NOD.III^<-/->))。 IIB^<-/->)，以及 FcRγ 和 Fcγ 以及 FcγRIIB 缺陷型 NOD (NOD.null) 小鼠，我们都显示出显着的结果。在 NOD.γ^<-/->、NOD.III^<-/-> 和 NOD.null 小鼠中具有预防糖尿病的保护作用，但在 NOD.IIB^</-/-> 小鼠中没有作用，即使它们之间的自身抗体产生量大致相当NOD.γ^<-/-> 小鼠的胰岛炎也得到缓解，NOD 小鼠的骨髓来源的树突状细胞或 NK 细胞使 NOD.γ^</-/-> 动物的胰岛素炎得到缓解。这些发现强调了激活 FcγR 在 T1D 发展中的关键作用，并表明 FcγR 是 T1D 治疗的新靶点。

项目成果

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

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.

Dual assemblies of an activating immune receptor, MAIR-II, with ITAM-bearing adaptors DAP12 and FcRγ chain on peritoneal macrophages

激活免疫受体 MAIR-II 与腹膜巨噬细胞上带有 ITAM 的适配器 DAP12 和 FcRγ 链的双重组装

• 发表时间: 2007
• 期刊: J. Immunol 178(2)
• 作者: Nakahashi C;et. al.
• 通讯作者: et. al.

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.

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.