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关键作用，其失调导致免疫相关疾病，包括过敏感染和AUD自身免疫性。我们在该项目中获得了以下成就：1）建立抑制性Fcγ受体FcγRIIB的重要性，在免疫调节和自身免疫性抑制疾病中，例如自动免疫性肾小球肾炎（例如）通过使用免疫型thee thee thee theee theee theee theee theee theee theee theee theee theee theee theee theee theee theee theee theee theee theee theee theee theee theee theee theee theee thee。通过使用SV40LT-转基因小鼠，永生化的生长和免疫功能。特别是，我们已经确定了激活型Fcγ受体的关键作用，而不是抑制性FCγRIB，但没有在NOD小鼠的自身免疫糖尿病的发展中。人类中的1型糖尿病（T1D）是一种有机特异性的自身免疫性疾病，其中胰岛胰岛β细胞被自动反应性T细胞破裂。 NOD小鼠是T1D的最常用动物模型，显示出EA…胰岛（胰岛炎）中白细胞的更加渗透，导致胰岛破坏和糖尿病。 NOD小鼠产生了各种胰岛细胞特异性自身抗体，尽管它仍然是关于这些自身抗体是否有助于T1D发展的辩论主题。为了研究FcγR在NOD小鼠中的可能作用，我们产生了几种无FCγR的NOD线，即FCR常见γ链（FCRγ） - 缺陷型（（（（nod.γ^<-/ - >），FcγRiiiiii-缺乏努力（nod.null）我们在糖尿病中表现出明显的保护。小鼠对糖尿病更容易敏感的γ^< - / - >动物表明，在NK细胞上激活FcγRIII的情况触发了抗体依赖性效应子功能和炎症

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.