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

描述（由申请人提供）：抗体调节免疫反应，不仅通过识别外来物，而且通过调节效应细胞功能。这种latte作用是通过抗体恒定区Fc区与细胞表面受体的结合介导的。Fc受体（FcRs）是由不同的免疫细胞群体表达的，可以根据它们结合的抗体类别进行分组。结合IgG抗体的受体，Fc？受体，代表了最大的家族，并且特别感兴趣，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结构和表达在个体之间的差异是很重要的，不仅因为它们有调节免疫反应的能力，而且还因为治疗性抗体的治疗使用越来越多，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转化研究中使用治疗性人类抗体检查这些受体的作用。此外，这些差异限制了检查这些受体多态性对免疫疾病发病机制和患者对治疗性抗体反应性的影响的能力。为了解决这一问题，我们建议产生一种表达人类低亲和力家族FCGR基因的小鼠系来代替内源性小鼠基因。这些细胞系易于繁殖，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.