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

Targeting the T cell immune synapse in autoimmunity

自身免疫中靶向 T 细胞免疫突触

基本信息

批准号：
9406059
负责人：
AMY S MAJOR
金额：
$ 7.9万
依托单位：
VANDERBILT UNIVERSITY MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2018-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9406059
关键词：
Affect Antibodies Antibody Formation Antigen Targeting Antigen-Presenting Cells Area Arthritis Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity B-Cell Activation B-Lymphocytes Back CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Nucleus Cells Cellular biology Cessation of life Chemosensitization Chronic Cilia Complex Custom Cyclic AMP Development Disease Embryo Erinaceidae Fab Immunoglobulins Functional disorder Future Genetic Transcription Grant Immune Targeting Immune system Immunosuppression In Vitro Individual Infection Inflammation Inflammatory Inflammatory Bowel Diseases Innovative Therapy Kidney Kidney Diseases Ligand Binding Ligation Mediating Membrane Micelles Molecular Monoclonal Antibodies Nanotechnology Nature Organ Pathology Patients Polymers Predisposition Production Property Proteins Research Rheumatoid Arthritis Scleroderma Severities Signal Transduction Surface Systemic Lupus Erythematosus T-Cell Activation T-Lymphocyte Testing Therapeutic Therapeutic Effect Time Tissues Treatment Efficacy Vertebrate Biology Viral Tumor Antigens Woman Zebrafish chronic autoimmune disease design ds-DNA experimental study extracellular heart disease risk immunological synapse immunological synapse formation in vivo inhibitor/antagonist kinetosome migration mouse model nanoparticle novel strategies novel therapeutics prevent receptor response small molecule smoothened signaling pathway subcellular targeting therapeutic target trafficking translational study

项目摘要

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects a staggering 1 out of 1,000 individuals, 90% of which are women. Unfortunately, treatment options for this debilitating disease remain limited. Most strategies involve overt immunosuppression which increases susceptibility to infection and often has off-target effects. Given the complex nature of this disease, developing effective therapeutic strategies is challenging, with new therapies emerging slowly and often times proving ineffective. Although SLE is largely thought of as an antibody-mediated disease, potentiation of the B cell response via interaction with CD4+ T helper cells is critical to autoantibody production. Central to this CD4+ T cell/B cell cooperation is their physical interaction at what has been termed the immune synapse, an area of concentrated signaling and interaction located at the point where the membranes of the CD4+ T cell and antigen presenting cell (APC) make physical contact. There are two main objectives for this R03 grant. The first is to test the hypothesis that specific inhibition of the immune synapse between T cells and APCs is a therapeutic option for SLE. The second is to develop new nanotechnology that may be used to study autoimmunity and accelerate development of future therapies for autoimmunity and other T cell-mediated diseases. This application proposes the novel approach to target the immune synapse between T and B cells to decrease autoimmune inflammation. This will be accomplished by using a newly discovered small molecule, eggmanone (Egm), which is predicted to disrupt the immune synapse between T cells and APCs. To specifically target CD4+ T cells, Egm will be loaded into polymer nanoparticles, or micelles, conjugated with the Fab fragment of a monoclonal antibody specific for CD4, a surface receptor known to be internalized upon ligation. Specific inhibition of activated CD4+ T cells will prevent T cell help to B cells and, ultimately, the production of autoantibodies that cause tissue damage and death in SLE. This research has high potential to identify an innovative therapy to specifically target CD4+ T cells in SLE. Future studies will use Egm to elucidate the molecular mechanisms involved in dysregulation of T cell activation and autoimmune inflammation.

系统性红斑狼疮（SLE）是一种慢性自身免疫性疾病，发病率高达千分之一