Targeting the T cell immune synapse in autoimmunity

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 其中90%是女性。不幸的是，这种使人衰弱的疾病的治疗选择仍然存在， 有限公司大多数策略涉及明显的免疫抑制，这增加了对感染的易感性， 有脱靶效应鉴于这种疾病的复杂性，开发有效的治疗策略是 新的治疗方法出现缓慢，而且往往被证明无效。尽管SLE在很大程度上 被认为是一种抗体介导的疾病，通过与CD 4 + T细胞相互作用增强B细胞应答 辅助细胞对自身抗体的产生至关重要。这种CD 4 + T细胞/B细胞合作的核心是它们的物理特性。 免疫突触是一个信号和相互作用集中的区域， 位于CD 4 + T细胞和抗原呈递细胞（APC）的膜进行物理 contact. R 03赠款有两个主要目标。第一个是检验假设， 抑制T细胞和APC之间的免疫突触是SLE的一种治疗选择。二是 开发新的纳米技术，可用于研究自身免疫和加速未来的发展 用于自身免疫和其他T细胞介导的疾病的疗法。本申请提出了一种新的方法， 靶向T细胞和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，eggmanone（Egm），这是预测破坏 T细胞和APC之间的免疫突触。为了特异性靶向CD 4 + T细胞，将Egm加载到 聚合物纳米颗粒或胶束，其与特异于以下的单克隆抗体的Fab片段缀合： CD 4，一种已知在连接时内化的表面受体。活化的CD 4 + T细胞的特异性抑制将 阻止T细胞帮助B细胞，并最终产生导致组织损伤的自身抗体， SLE死亡。这项研究具有很高的潜力，以确定一种创新的疗法，专门针对CD 4 + T细胞 SLE中的细胞未来的研究将使用Egm来阐明T细胞调节异常的分子机制。 细胞活化和自身免疫性炎症。

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.