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.

项目摘要尽管现代免疫抑制疗法，但全身性红斑狼疮（SLE）的患者仍在进行性器官损害的高风险，强调需要对这种疾病进行更好的目标治疗。除了生产致病性自身抗体外，最近的研究表明，B细胞可以通过引发免疫耐受性破裂并促进产生，促进狼疮发病机理自发生发中心（GC）。在这种情况下，不同的共刺激受体家族已连接自身免疫的发病机理。然而，尽管SLE和临床益处具有令人信服的临床前数据在其他自身免疫性疾病中，CTLA4-IG（Abatacept）的co刺封锁未能控制疾病狼疮临床试验。这些数据强调，我们对细胞中性机制的理解 B7：CD28共刺激信号会影响狼疮中的自动反应性B细胞激活。在这个项目中，我们将使用特征良好的鼠狼疮模型以及嵌合抗原受体（CAR）T的新颖应用细胞技术剖析开始，传播和细胞输出的背后的免疫机制 SLE中的狂热外（EF）与GC B细胞活化途径。在AIM 1中，我们将研究致病性自身抗体可以通过T细胞依赖性的EF B细胞激活途径生成，但是CD28 独立，方式。在AIM 2中，我们将测试B细胞共求信号是否促进了启动或维护自身免疫性GC响应。最后，在AIM 3中，我们将测试是否另一种共同刺激受体对，ICO：ICOS配体，补偿狼疮发病机理期间CD28信号的损失。一起，这些研究有望促进我们对狼疮发病机理的理解，并可能告知 SLE和其他体液自身免疫性疾病中的共刺激性阻滞的未来人类临床试验。