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

Fc受体在免疫调节中起重要作用，其调节异常可导致过敏性炎症、自身免疫等免疫相关疾病。本研究取得了以下成果：1）确定了抑制性Fcγ受体（FcγRIIB）在免疫调节和自身免疫性疾病（如自身免疫性肾小球肾炎）中的重要作用; 2）利用Feγ受体基因靶向小鼠建立了免疫性疾病的动物模型; 3）利用SV 40 LT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。人类1型糖尿病（T1 D）是一种器官特异性自身免疫性疾病，其中胰岛β细胞被自身反应性T细胞破坏。NOD小鼠是最常用的T1 D动物模型， 关于我们 白细胞在胰岛中的过度浸润（胰岛炎），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，尽管关于这些自身抗体是否有助于T1 D的发展仍然存在争议。为了研究Fcγ R在NOD小鼠中的可能作用，我们已经产生了几种Fcγ R较少的NOD系，即FcR共同γ链（FcRγ）缺陷型（NOD.γ^<-/->）、Fcγ RIII缺陷型（NOD.III^<-/->）、Fcγ RIIB缺陷型（NOD.IIB^<-/->）以及FcRγ和Fcγ以及Fcγ RIIB缺陷型NOD小鼠（NOD.null）。我们已经在NOD.γ^<-/->、NOD.III^<-/->和NOD.null小鼠中显示出对糖尿病的显著保护作用，但在NOD.IIB^<-/->小鼠中没有，即使它们之间的自身抗体产生量大体相当。NOD.γ^<-/->小鼠的胰岛炎也减轻。从NOD小鼠连续转移骨髓来源的树突状细胞或NK细胞使NOD.γ^<-/->动物更易患糖尿病，这表明可能的情况是激活NK细胞上的FcγRIII触发抗体依赖性效应子功能和炎症。这些发现强调了激活Fcγ R在T1 D发展中的关键作用，并表明Fcγ R是T1 D治疗的新靶点。少

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