Novel models for defining function of the BAFF/APRIL cytokine family

描述(申请人提供)：Baff及其同系物APRIL是支持B细胞存活和分化的肿瘤坏死因子样细胞因子。BAFF与三种受体BAFF-R、TACI和BCMA结合，而APRIL仅与TACI和BCMA结合，这三种受体表达于不同发育阶段的B细胞。在动物模型中，BAFF的过度表达会导致狼疮样疾病，在几种自身免疫性疾病中也发现了高水平的BAFF。因此，BAFF/APRIL家族在过去十年中一直是广泛药物开发的目标，最终在2011年批准了抗BAFF抗体belimumab用于治疗狼疮。尽管在过去的十年里，关于这一家族的细胞因子已经有了很多的了解，但关于BAFF抑制的作用机制，APRIL的确切作用，以及三种受体，特别是TACI的相对作用，仍然是一个重要的问题。这里提出的实验旨在为我们提供工具，这些工具将对BAFF和APRIL及其受体的基本生物学产生新的见解，从而提出以这些细胞因子为治疗靶点的方法可能对患者最有益。因此，我们将产生两个新的模型，一个是APRIL报告小鼠，它允许我们可视化APRIL蛋白的制造地点，另一个是条件缺陷TACI小鼠，它允许我们确定TACI对特定细胞类型的作用。这些小鼠，加上我们已经拥有的工具，将使我们能够更好地定义BAFF和APRIL在动态平衡和免疫激活期间表达的微环境，并更好地了解TACI在调节B细胞反应中的相对重要性。

DESCRIPTION (provided by applicant): BAFF and its homolog APRIL are TNF-like cytokines that support the survival and differentiation of B cells. BAFF binds to three receptors, BAFF-R, TACI, and BCMA that are expressed on B cells at different developmental stages, whereas APRIL binds only to TACI and BCMA. Overexpression of BAFF causes a lupus-like illness in animal models and high levels of BAFF are found in several autoimmune diseases. Therefore the BAFF/APRIL family has been a target of extensive drug development over the last decade, culminating in the approval in 2011 of the anti-BAFF antibody belimumab for the treatment of lupus. Although much has been learned about this family of cytokines over the last decade, important questions remain about the mechanism of action of BAFF inhibition, the precise role of APRIL and the relative role of each of the three receptors, especially TACI. The experiments proposed here are designed to give us tools that will yield new insights into the basic biology of BAFF and APRIL and their receptors and thereby suggest ways in which therapeutic targeting of these cytokines may be most beneficial for patients. We will therefore generate two new models, an APRIL reporter mouse that allows us to visualize where APRIL protein is being made and a conditionally deficient TACI mouse that allows us to determine the role of TACI on specific cell types. These mice, together with tools we already have, will allow us to better defin the microenvironments in which BAFF and APRIL are expressed during homeostasis and during immune activation, and to better understand the relative importance of TACI in regulating B cell responses.