Preventing and Curing Persistent Infections with Transient FTY720 Treatment

了解急性和慢性感染之间的差异对于发展 治疗和治愈慢性病的疗法。我们发现淋巴细胞被戏剧性地隔离到 继发性类淋巴组织在急性LCMV阿姆斯特朗感染后早期出现，但不在后面 感染慢性LCMV克隆-13，我们假设在慢性过程中缺乏早期隔离 LCMV有助于建立隔离药物短暂给药的感染性 FTY720在感染时，增强免疫力，防止慢性LCMV的建立。 此外，我们发现FTY720治疗清除了先前确定的Done-13感染。FTY720 没有抗病毒特性，因此其治疗导致依赖于 CD4T细胞、结节细胞和巨噬细胞。 这项资助的目标是进一步了解FTY720的免疫增强作用并应用研究结果 开发慢性病的治疗方法。我们假设，FTY720的短暂治疗直接改变淋巴细胞与APC的位置和相互作用，从而增强免疫活性，同时间接防止慢性感染的建立。这笔拨款将研究FTY720逆转功能失调的免疫反应的机制。本研究的三个目的是：1)了解和探讨CD8-I-T细胞在FTY720治疗过程中增强CD8-I-T细胞功能的作用。2)了解FTY720治疗过程中对树突状细胞和巨噬细胞的影响，以及FTY720对免疫结构的总体维持作用。3)通过确定先天免疫激活的动力学以及FTY720治疗如何加速后天免疫反应的激活来衡量免疫反应的协调性，这是控制感染的关键。

Understanding differences bptween acute and chronic infections is important for the development of therapies to treat and cure chronic diseases. We found that dramatic sequestration of lymphocytes into secondary lympohoid tissues occurs early following acute LCMV Armstrong infection, though not following infection with chronic LCMV clone-13, We hypothesized that the lack of early sequestration during chronic LCMV contributes to the establishment of the infectioa Transient administration of the sequestration drug FTY720 at the time of infection, enhanced immunity and prevented the establishment of chronic LCMV. Additionally, we found that FTY720 treatment cleared a previously established done-13 infection. FTY720 has no antiviral properties therefore its treatment led to immune mediated clearance that is dependent on CD4 T cells, dendetric cells and macrophages. This grants goal is to further understand the immune enhancing effects of FTY720 and apply the findings towards developing therapies for chronic diseases. We hypothesize that transient treatment with FTY720 directly alters the location and interaction of lymphocytes with APCs ¿at leads to enhanced immune activation, while indirectly preventing the establishment of chronic infection. This grant will study the mechanism of FTY720s reversion of a dysfunctional immune response. The three aims are: 1) to understand and explore the role of CD4-I- T cells in the enhancement of CD8-I- T cell function during FTY720 treatment. 2) To understand the effects of FTY720 on dendritic cells and macrophages during FTY720 treatment, and on the general maintenance of immune architecture. 3) To measure the coordination of the immune response by determining the kinetics of innate immune activation and how treatment with FTY720 accelerates the activation of the acquired immune response that is key to controlling the infection.