B cell costimulatory signals in the pathogenesis of SLE

SLE 发病机制中的 B 细胞共刺激信号

基本信息

批准号：
10208723
负责人：
Shaun William Jackson
金额：
$ 58.79万
依托单位：
SEATTLE CHILDREN'S HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-08-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10208723
关键词：
Affect Anatomy Animal Model Antigen Presentation Antinuclear Antibodies Autoantibodies Autoantigens Autoimmune Autoimmune Diseases Autoimmune Responses Autoimmunity Automobile Driving B-Cell Activation B-Cell Antigen Receptor B-Lymphocytes Biology CD19 gene CD28 gene CD4 Positive T Lymphocytes CD80 gene CD86 gene CTLA4-Ig Cell Survival Cells Chronic Chronic Childhood Arthritis Clinical Clinical Trials Complex Data Development Disease Epitopes Event FDA approved Family Future Generations Goals Human Humoral Immunities Immune Immune Tolerance Immune response Immune signaling Immunity Immunoglobulin Class Switching Immunoglobulin Somatic Hypermutation Immunohistochemistry Knowledge Ligands Link Location Longitudinal Studies Lupus Lupus Nephritis MHC Class II Genes Maintenance Modeling Modernization Mus Mutation Analysis Nuclear Antigens Organ Output Pathogenesis Pathogenicity Pathway interactions Patients Plasma Cells Production RNA Randomized Clinical Trials Research Rheumatoid Arthritis Role Serum Signal Transduction Specificity Structure of germinal center of lymph node Systemic Lupus Erythematosus T-Cell Activation T-Lymphocyte Technology Testing Therapeutic Therapeutic immunosuppression autoreactive B cell base chimeric antigen receptor T cells clinical efficacy design disorder control ds-DNA experimental study high risk improved insight migration novel novel therapeutics pathogenic autoantibodies pre-clinical preservation receptor response systemic autoimmune disease targeted treatment tool

项目摘要

Project abstract Despite modern immunosuppressive therapies, patients with systemic lupus erythematosus (SLE) remain at high risk for progressive organ damage, emphasizing the need for better, targeted treatments for this disease. In addition to the production of pathogenic autoantibodies, recent studies have demonstrated that B cells can promote lupus pathogenesis by initiating immune tolerance breaks and facilitating the generation of spontaneous germinal centers (GC). In this context, distinct costimulatory receptor families have been linked with the pathogenesis of autoimmunity. However, despite compelling preclinical data in SLE and clinical benefit in other autoimmune diseases, costimulatory blockade with CTLA4-Ig (Abatacept) failed to control disease in lupus clinical trials. These data emphasize that our understanding of the cell-intrinsic mechanisms whereby B7:CD28 costimulatory signals impact autoreactive B cell activation in lupus is incomplete. In this project, we will use well-characterized murine lupus models and the novel application of chimeric antigen receptor (CAR) T cell technology to dissect the immune mechanisms underlying the initiation, propagation and cellular output of extra-follicular (EF) vs. GC B cell activation pathways in SLE. In Aim 1, we will study whether pathogenic autoantibodies can be generated via an EF B cell activation pathway in a T cell-dependent, but CD28 independent, manner. In Aim 2, we will test whether B cell costimulatory signals promote the initiation or maintenance of autoimmune GC responses. Finally, in Aim 3, we will test whether another costimulatory receptor pair, ICOS:ICOS ligand, compensates for loss of CD28 signals during lupus pathogenesis. Together, these studies promise to advance our understanding of lupus pathogenesis and may inform the design of future human clinical trials of costimulatory blockade in SLE and other humoral autoimmune diseases.

项目摘要尽管采用现代免疫抑制疗法，系统性红斑狼疮 (SLE) 患者的病情仍处于进行性器官损伤的高风险，强调需要对该疾病进行更好的、有针对性的治疗。除了产生致病性自身抗体外，最近的研究表明 B 细胞还可以通过引发免疫耐受破坏和促进狼疮的产生来促进狼疮发病机制自发生发中心（GC）。在这种情况下，不同的共刺激受体家族被联系起来与自身免疫的发病机制有关。然而，尽管 SLE 的临床前数据和临床获益令人信服在其他自身免疫性疾病中，CTLA4-Ig（阿巴西普）的共刺激阻断未能控制疾病狼疮临床试验。这些数据强调我们对细胞内在机制的理解 B7：CD28 共刺激信号影响狼疮中自身反应性 B 细胞激活不完全。在这个项目中，我们将使用特征明确的小鼠狼疮模型和嵌合抗原受体（CAR）T的新应用细胞技术剖析免疫机制的启动、传播和细胞输出 SLE 中滤泡外 (EF) 与 GC B 细胞激活途径。在目标 1 中，我们将研究是否致病自身抗体可以通过 T 细胞依赖性的 EF B 细胞激活途径产生，但 CD28 独立，方式。在目标 2 中，我们将测试 B 细胞共刺激信号是否促进启动或维持自身免疫 GC 反应。最后，在目标 3 中，我们将测试是否有另一种共刺激受体对，ICOS：ICOS 配体，补偿狼疮发病过程中 CD28 信号的损失。一起，这些研究有望增进我们对狼疮发病机制的理解，并可能为设计未来共刺激阻断治疗系统性红斑狼疮和其他体液自身免疫性疾病的人体临床试验。