Dendritic Cell Response to Microsporidians

描述(申请人提供)：微孢子虫感染仍然是免疫功能低下的患者的一个问题，特别是那些患有艾滋病的患者，导致腹泻和体重减轻等症状。然而，在艾滋病毒阴性和免疫能力强的患者中也发现了这种感染引起的并发症，包括旅行者腹泻患者和老年人。老年人群对微孢子虫感染的易感性增加，可以解释为伴随着衰老而导致的免疫反应性的恶化。然而，对老年人或动物模型中针对微孢子虫的先天免疫反应的深入分析还没有进行，与先天免疫反应相关的研究几乎不存在。用鼠脑微孢子虫作为模型微孢子虫，我们的实验室发现，与幼鼠相比，9月龄小鼠的树突状细胞(DC)不能激发抗原特异性T细胞应答。然而，用重组IL-15治疗可以恢复较老的DC产生针对病原体的T细胞免疫的能力。此外，给年长的动物注射外源性IL-15使它们能够在口服楔形艾美耳球虫的挑战中存活下来。因此，在衰老开始时，初级免疫缺陷似乎发生了，树突状细胞失去了启动T细胞应对感染的能力，而不是改变了T细胞功能。了解DC反应下调的机制以及能够恢复其功能的因素对于为老年人群开发成功的寄生虫性免疫治疗药物至关重要。这项应用需要三个特定的目标：1)将进行与年龄相关的动力学反应的DC在感染楔形埃希氏菌。小鼠DC开始出现这种缺陷的年龄将被确定，并将分析在老年小鼠中DC反应被抑制的机制。2)研究IL-15在恢复正常DC免疫应答中的作用。将确定这种细胞因子逆转DC群体内缺陷的机制，并将评估IL-15在成功用纯化的楔形埃希氏菌蛋白接种老年小鼠方面的重要性。3)从小鼠身上获得的结果与在人类和非人类DC中针对这种B类原虫产生的先天免疫反应的相关性。这一特定的目的将决定衰老是否导致先天性DC对楔形艾美耳球虫的反应不良，以及IL-15是否能恢复ARC功能。

DESCRIPTION (provided by applicant): Microsporidial infections continue to be a problem for immunocompromised patients, particularly those with AIDS, leading to symptoms like diarrhea and weight loss. However, complications due to this infection have also been identified in patients who are HIV negative and immunocompetent, including individuals with traveler's diarrhea, and in the elderly. Increased susceptibility of the elderly population to microsporidial infection can be explained by the deterioration in immune responsiveness that accompanies aging. However, in depth analysis of innate immune responses against microsporidians in aging humans or in animal models have not been performed and studies related to innate immune response almost non-existent. Using Encephalitozoon cuniculi as the model microsporidian, our laboratory has shown that compared to young mice, dendritic cells (DCs) from 9-month-old animals are unable to prime antigen-specific T cell response against E. cuniculi. However, treatment with recombinant IL-15 restores the ability of older DCs to generate T cell immunity against the pathogen. Moreover, administration of exogenous IL-15 to older animals enables them to survive an oral E. cuniculi challenge. Thus on the onset of aging, a primary immune defect seems to occur with DCs losing their ability to prime a T cell response against infection rather than altered T cell function. Understanding the mechanism involved in the down-regulation of DC response and factors which are able to restore their function is critical for generating successful parasitic immunotherapeutic agents for the aged population. This application entails three specific aims: 1) Age related kinetics of DC response during E. cuniculi infection will be performed. The age at which murine DCs begin to develop this defect will be determined and the mechanism involved in the suppression of DC response in the older mice will be analyzed. 2) The role of IL-15 in the restoration of normal DC response against E. cuniculi will be studied. The mechanism by which this cytokine reverses the defect within the DC population will be determined and importance of IL-15 in the successful vaccination of older mice with purified E. cuniculi protein will be evaluated. 3) Correlation of the results obtained from mice to the innate immune responses generated against this category B protozoon in both humans and non-human DCs. This specific aim will determine if aging results in poor innate DC response to E. cuniculi and whether IL-15 can restores ARC function.