Novel modulation of dendritic cell response against a chronic virus infection

描述（由申请方提供）：慢性感染病毒通常逃避或抑制宿主免疫系统，以避免免疫监视并在宿主中建立持久性。淋巴细胞性脉络丛脑膜炎病毒（LCMV）克隆13（Cl 13）株感染小鼠（其天然宿主），诱导严重的免疫抑制并在宿主中持续长达100天。由LCMV C113感染引起的免疫抑制与刺激病毒特异性T细胞中最有效的抗原呈递树突状细胞（DC）应答的损害有关。因此，LCMV C113感染充当用于研究病毒-免疫系统相互作用和病毒持久性的优良动物模型。 鞘氨醇是鞘脂组的一个单位，鞘脂组是一种调节多种细胞状况的生物活性脂质介质，具有治疗自身免疫性疾病的潜力。事实上，鞘氨醇类似物FTY 720是一种很有前途的免疫抑制剂，正在III期临床试验中进行测试，用于治疗多发性硬化症，以取代目前的I型IFN（IFN-2）疗法。然而，鞘氨醇调节慢性病毒感染后宿主免疫反应的机制需要进一步澄清。 初步数据表明，与其已知的免疫抑制活性不同，鞘氨醇类似物在LCMV C1 13感染后刺激DC的表型和功能。结果表明鞘氨醇类似物可以逆转DC应答的慢性病毒抑制以扩增抗病毒T细胞。 在该提议中，将进一步探索直接作用于DC的鞘氨醇类似物的新的免疫刺激潜力：1）将使用鞘氨醇类似物处理的DC的连续转移实验来进一步评估鞘氨醇类似物介导的DC在LCMV Cl 13感染时的调节。动力学研究将阐明LCMV特异性T细胞的形成和活化以及受鞘氨醇类似物调节的DC影响的病毒清除; 2）鞘氨醇类似物处理的DC的细胞治疗潜力将通过使用LCMV C113持续感染的小鼠模型来评估; 3）此外，将通过评估生物化学和免疫学测定的性能来研究由鞘氨醇类似物在DC上触发的分子下游信号传导途径。因此，这项研究有望发现新的信号通路，重要的是增加抗原呈递DC的能力和鞘氨醇类似物在宿主DC对慢性病毒感染的反应中的作用的效力。因此，这里提出的项目应该有助于开发新的免疫疗法来治疗慢性病毒性疾病。 公共卫生相关性：多种病毒逃避或抑制树突状细胞（DC）反应，以建立持续感染。最近确定的鞘氨醇类似物作为免疫调节剂，影响宿主免疫的各个方面，促使我们研究它们在DC介导的宿主防御和免疫反应对慢性病毒感染的作用。揭示鞘氨醇类似物刺激DCs的机制，并确定类似物触发的DCs细胞内信号通路，可以为开发新型DC介导的免疫疫苗以征服持续性病毒性疾病提供基础。

DESCRIPTION (provided by applicant): Chronically infecting viruses often evade or suppress the host immune system to avoid immunological surveillance and establish persistence in the host. Lymphocytic choriomeningitis virus (LCMV) clone 13 (Cl 13) strain infects the mouse, its natural host, induces profound immune suppression and persists in the host up to 100 days. The immunosuppression caused by LCMV Cl 13 infection is associated with impairment of the most potent antigen-presenting dendritic cell (DC) response in stimulating virus-specific T cells. Thus, LCMV Cl 13 infection serves as an excellent animal model for study of the virus-immune system interaction and viral persistence. The sphingosine is one unit of the sphingolipid group, a bioactive lipid mediator regulating multiple cellular conditions with curative potential for autoimmune diseases. Indeed, the sphingosine analog FTY720 is a promising immunosuppressant that is being tested in phase III clinical trials for the treatment of multiple sclerosis to replace current type I IFN (IFN-2) therapy. However, the sphingosine's mechanism of modulating the host immune response upon chronic virus infection requires further clarification. Preliminary data indicate that, unlike its known immune-suppressive activity, a sphingosine analog stimulates the phenotype and function of DCs upon LCMV Cl 13 infection. The results indicate that sphingosine analogs could reverse chronic viral suppression of the DC response to expand anti-viral T cells. In this proposal, the new immunostimulatory potential of the sphingosine analog directly acting on DCs will be further explored: 1) Adoptive transfer experiments with the sphingosine analog-treated DCs will be employed to further assess the sphingosine analog-mediated regulation of DCs upon LCMV Cl 13 infection. Kinetic study would illuminate the formation and activation of LCMV-specific T cells and viral clearance that are influenced by the sphingosine analog-conditioned DCs; 2) The cytotherapeutic potential of sphingosine analog- treated DCs will be evaluated by using the mouse model of persistent infection with LCMV Cl 13; 3) Further, molecular downstream signaling pathways triggered by the sphingosine analog on DCs will be investigated by evaluating the performance of biochemical and immunological assays. Accordingly, this research is expected to discover novel signaling pathways important for increasing the potency of antigen-presenting DC's capacity and the role of the sphingosine analog in host DC responses to the chronic virus infection. In consequence, the project proposed here should assist in developing novel immuno-therapeutics to remedy chronic viral diseases. PUBLIC HEALTH RELEVANCE: Multiple viruses evade or suppress dendritic cell (DC) responses to establish persistent infections. Recent identification of sphingosine analogs as immune regulators affecting diverse aspects of host immunity prompted us to investigate their role in the DC-mediated host defense and immune responses against a chronic virus infection. Uncovering the mechanisms by which sphingosine analogs stimulate DCs and identifying the analog-triggered intracellular signaling pathways on DCs could provide a basis for the development of novel DC-mediated immunotherapeutic vaccines to conquer persistent viral diseases.