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

描述（由申请方提供）：抗体不仅通过识别外源因子，而且通过调节效应细胞功能来调节免疫应答。这种间接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（FcR）由不同的免疫细胞群体表达，可以基于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，并且特别令人感兴趣，因为抗体结合可以刺激或减弱免疫应答，这取决于所激活的受体。了解这些受体的功能以及个体之间在其结构和表达方面的差异是重要的，这不仅是因为它们调节免疫应答的能力，而且还因为治疗性抗体的治疗用途增加，特别是在癌症治疗中。小鼠和人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中多态性对免疫疾病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，我们提出产生一种小鼠系，其表达人FCGR基因的低亲和力家族代替内源性小鼠基因。这些品系将易于繁殖，因此不仅适用于基础研究，而且适用于新治疗性抗体的临床前评价。

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.