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