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

用于定义 BAFF/APRIL 细胞因子家族功能的新模型

• 批准号: 8787449
• 负责人: Anne Davidson
• 金额: $ 8.43万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8787449
• 关键词: Animal Model; Antibodies; Autoimmune Diseases; Autoimmunity; B cell differentiation; B-Lymphocytes; Binding; Biological Response Modifier Therapy; Biology; Bone Marrow; Cell Survival; Cell surface; Cells; Clinical; Development; Disadvantaged; Disease; Drug Targeting; DsRed; Evaluation; Family; Flow Cytometry; Funding; Goals; Health; Homeostasis; Homologous Gene; Human; Immune response; Immune system; Immunoglobulin A; Immunoglobulin Class Switching; Inflammation; Laboratories; Learning; Lupus; Malignant Neoplasms; Mediator of activation protein; Methods; Modeling; Mus; Patients; Phase III Clinical Trials; Plasma Cells; Relative (related person); Reporter; Rest; Role; Scientist; Serum; Source; Staging; Sum; Systemic Lupus Erythematosus; TNF gene; Testing; autoreactive B cell; belimumab; cell type; cytokine; design; drug development; human ANP32B protein; immune activation; immune function; insight; interest; lupus-like; neonate; novel; overexpression; programs; receptor; research study; response; therapeutic target; tool

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.

描述（由申请人提供）：BAFF及其同系物APRIL是支持B细胞存活和分化的TNF样细胞因子。BAFF结合三种受体，BAFF-R、TACI和BCMA，它们在不同发育阶段的B细胞上表达，而APRIL仅结合TACI和BCMA。BAFF的过表达在动物模型中引起狼疮样疾病，并且在几种自身免疫性疾病中发现高水平的BAFF。因此，在过去十年中，BAFF/APRIL家族一直是广泛药物开发的目标，最终在2011年批准抗BAFF抗体贝利木单抗用于治疗狼疮。虽然在过去的十年中已经了解了很多关于这个家族的细胞因子，重要的问题仍然是关于BAFF抑制的作用机制，APRIL的确切作用和三种受体中每一种的相对作用，特别是TACI。这里提出的实验旨在为我们提供工具，使我们对BAFF和APRIL及其受体的基础生物学产生新的见解，从而提出这些细胞因子的治疗靶向可能对患者最有益的方法。因此，我们将产生两个新的模型，一个APRIL报告小鼠，使我们能够可视化APRIL蛋白的产生位置，一个条件缺陷TACI小鼠，使我们能够确定TACI对特定细胞类型的作用。这些小鼠与我们已经拥有的工具一起，将使我们能够更好地定义BAFF和APRIL在稳态和免疫激活期间表达的微环境，并更好地理解TACI在调节B细胞应答中的相对重要性。