Targeting the T cell immune synapse in autoimmunity

自身免疫中靶向 T 细胞免疫突触

• 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
• 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

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，1,000人中有1人患病 个人，其中90%是女性。不幸的是，这种令人衰弱的疾病的治疗选择仍然存在。 有限的。大多数策略包括公开的免疫抑制，这增加了感染的易感性，通常 有偏离目标的效果。鉴于这种疾病的复杂性质，开发有效的治疗策略是 具有挑战性，新的治疗方法出现得很慢，而且往往被证明无效。尽管SLE在很大程度上是 被认为是一种抗体介导的疾病，通过与CD4+T细胞的相互作用增强B细胞的反应 辅助细胞对自身抗体的产生至关重要。这种CD4+T细胞/B细胞合作的核心是它们的生理 在所谓的免疫突触上的相互作用，这是一个集中信号和相互作用的区域 位于CD4+T细胞和抗原提呈细胞(APC)的膜上 联系。这笔R03拨款有两个主要目标。第一个是检验特定的假设 抑制T细胞和APC之间的免疫突触是SLE的一种治疗选择。第二个是 开发可用于研究自身免疫的新纳米技术并加速未来的发展 自身免疫和其他T细胞介导性疾病的治疗。该应用程序提出了一种新的方法 靶向T和B细胞之间的免疫突触，以减少自身免疫性炎症。这将是 通过使用一种新发现的小分子蛋黄酮(EGM)来完成，这种小分子预计会破坏 T细胞和APC之间的免疫突触。为了特别针对CD4+T细胞，EGM将被加载到 聚合物纳米颗粒，或胶束，与抗病毒单抗的Fab片段结合 CD4，一种已知在结扎时内化的表面受体。特异性抑制活化的CD4+T细胞将 防止T细胞帮助B细胞，最终导致自身抗体的产生，从而导致组织损伤和 死于系统性红斑狼疮。这项研究具有很高的潜力来确定一种专门针对CD4+T细胞的创新疗法 SLE中的细胞。未来的研究将利用EGM来阐明T细胞调节失调的分子机制 细胞活化和自身免疫性炎症。