权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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：
10670450
负责人：
Shaun William Jackson
金额：
$ 60.61万
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/10670450
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 Compensation Complex Data Development Disease Epitopes Event FDA approved Family Future Generations Goals Heterozygote 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 Research Rheumatoid Arthritis Role Serum Signal Transduction Specificity Structure of germinal center of lymph node System Systemic Lupus Erythematosus T-Cell Activation T-Lymphocyte Technology Testing Therapeutic Therapeutic immunosuppression anti-dsDNA autoantibody autoreactive B cell 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 randomized, clinical trials 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.

项目摘要尽管有现代免疫抑制治疗，系统性红斑狼疮（SLE）患者仍处于高水平。进行性器官损伤的高风险，强调需要更好的，有针对性的治疗这种疾病。除了产生致病性自身抗体外，最近的研究表明，B细胞可以通过启动免疫耐受性破坏和促进自发生发中心（GC）。在这种情况下，不同的共刺激受体家族已被联系在一起，自身免疫的发病机制然而，尽管有令人信服的SLE临床前数据和临床获益，在其它自身免疫性疾病中，用CTLA 4-IG（阿巴西普）进行共刺激阻断不能控制狼疮临床试验这些数据强调了我们对细胞内在机制的理解， B7：CD 28共刺激信号影响狼疮患者自身反应性B细胞活化不完全本课题将使用充分表征的小鼠狼疮模型和嵌合抗原受体（CAR）T的新应用，细胞技术来剖析免疫机制的启动，繁殖和细胞输出 SLE中滤泡外（EF）与GC B细胞活化途径。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细胞活化途径产生，但CD 28 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性GC反应。最后，在目标3中，我们将测试另一种共刺激因子是否受体对，ICOS：ICOS配体，补偿狼疮发病过程中CD 28信号的损失。在一起，这些研究有望促进我们对狼疮发病机制的理解，并可能为设计 SLE和其他体液自身免疫性疾病中共刺激阻断的未来人类临床试验。