Model for evaluation of FCGR variants in disease and response to therapeutics

描述(申请人提供)：抗体调节免疫反应，不仅通过识别外来物质，而且还通过调节效应细胞功能。这种拿铁作用是通过抗体恒定区Fc区与细胞表面受体结合而介导的。Fc受体(FCR)由不同的免疫细胞群表达，可以根据它们结合的抗体类别进行分组。结合免疫球蛋白抗体的受体，Fc？受体是最大的家族，尤其令人感兴趣，因为抗体结合可以刺激或减弱免疫反应，这取决于激活的受体。了解这些受体的功能及其在结构和表达上的个体差异非常重要，这不仅是因为它们有调节免疫反应的能力，也是因为治疗性抗体的使用增加，特别是在癌症的治疗中。小鼠和人类的物种差异阻碍了小鼠在翻译研究中的使用，这些研究检查了治疗性人类抗体与这些受体的结合。此外，这些差异限制了研究这些受体的多态性对免疫疾病的发病机制和患者对治疗性抗体的反应性的影响的能力。为了解决这个问题，我们建议创造一种表达低亲和力的人类FCGR基因家族的小鼠株系，以取代内源性的小鼠基因。这些株系很容易培育，因此不仅适用于基础研究，也适用于新的治疗性抗体的临床前评估。

DESCRIPTION (provided by applicant): Antibodies regulate immune responses, not only by recognition of foreign agents but also through the modulation of effector cell function. This latte action is mediated through binding of the antibody constant region, the Fc region, to cell surface receptors. Fc receptors (FcRs), which are expressed by diverse populations of immune cells, can be grouped based on the antibody class they bind. The receptors that bind IgG antibodies, the Fc? receptors, represent the largest family and are of particular interest because antibody binding can either stimulate or attenuate the immune response, depending on the receptor activated. Understanding the function of these receptors and the variation between individuals in their structure and expression is important, not only because of their ability to regulate immune responses, but also because of the increased therapeutic use of therapeutic antibodies, especially in the treatment of cancer. Species differences in the mouse and human have hampered the use of the mouse in translational studies examining the engagement of these receptors by therapeutic human antibodies. In addition, these differences have limited the ability to examine the impact of polymorphisms in these receptors on the pathogenesis of immune diseases and on the responsiveness of patients to therapeutic antibodies. To address this problem we propose to generate a mouse line which expresses the low affinity family of human FCGR genes in place of the endogenous mouse genes. These lines will be easy to breed and thus will be appropriate not only for basic research studies, but also for preclinical evaluation o new therapeutic antibodies.