Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Centre for Innovation, Canadian Blood Services, Toronto, Ontario, Canada.
Pharmacology. 2020;105(11-12):618-629. doi: 10.1159/000508239. Epub 2020 Jun 22.
Rheumatoid arthritis (RA) is a chronic autoimmune disease that causes inflammation, swelling, and pain in the joints and involves systemic complications. Mouse models of RA have been extensively used to model the pathogenesis of RA and to develop effective therapies. Although many components of the immune system have been studied in these models, the role of crystallizable fragment (Fc) gamma receptors (FcγRs) in RA has been sorely neglected. The aim of this review was to introduce the different mouse models of RA and to describe the different drug development strategies that have been tested in these models to target FcγR function, with the focus being on drugs that have been made from the Fc of immunoglobulin G (IgG).
Evidence suggests that FcγRs play a major role in immune complex-induced inflammation in autoimmune diseases, such as RA. However, there is limited knowledge on the importance of FcγRs in the human disease even though there has been extensive work in mouse models of RA. Numerous mouse models of RA are available, with each model depicting certain aspects of the disease. Induced models of RA have nonspecific immune activation with cartilage-directed autoimmunity, whereas spontaneous models of RA develop without immunization, which results in a more chronic form of arthritis. These models have been used to test FcγR-targeting monoclonal antibodies, intravenous immunoglobulin (IVIg), subcutaneously administered IVIg, and recombinant Fcs for their ability to interact with and modify FcγR function. Recombinant Fcs avidly bind FcγRs and exhibit enhanced therapeutic efficacy in mouse models of RA. Key Message: The therapeutic utility of targeting FcγRs with recombinant Fcs is great and should be explored in human clinical trials for autoimmune diseases, such as RA.
类风湿关节炎（RA）是一种慢性自身免疫性疾病，可导致关节炎症、肿胀和疼痛，并涉及全身并发症。RA 的小鼠模型已被广泛用于模拟 RA 的发病机制和开发有效的治疗方法。尽管这些模型已经研究了许多免疫系统的组成部分，但 Fc 段γ受体（FcγRs）在 RA 中的作用却被严重忽视。本综述的目的是介绍不同的 RA 小鼠模型，并描述在这些模型中测试的针对 FcγR 功能的不同药物开发策略，重点是针对 IgG Fc 开发的药物。
有证据表明，FcγRs 在免疫复合物诱导的自身免疫性疾病（如 RA）中的炎症中起主要作用。然而，尽管在 RA 的小鼠模型中已经进行了广泛的研究，但人们对 FcγRs 在人类疾病中的重要性知之甚少。有多种 RA 的小鼠模型，每种模型都描绘了该疾病的某些方面。RA 的诱导模型具有非特异性免疫激活和针对软骨的自身免疫，而自发性 RA 模型则无需免疫接种即可发展，从而导致更慢性的关节炎。这些模型已被用于测试针对 FcγR 的单克隆抗体、静脉注射免疫球蛋白（IVIg）、皮下给予 IVIg 和重组 Fc 以评估它们与 FcγR 相互作用和改变 FcγR 功能的能力。重组 Fc 可与 FcγRs 强烈结合，并在 RA 的小鼠模型中表现出增强的治疗效果。
用重组 Fc 靶向 FcγRs 的治疗效用很大，应该在针对 RA 等自身免疫性疾病的人类临床试验中进行探索。
