Dendritic Cell Response to Microsporidians

描述（由申请人提供）：微孢子虫感染仍然是免疫功能低下患者的一个问题，特别是艾滋病患者，导致腹泻和体重减轻等症状。然而，在艾滋病毒阴性和免疫功能正常的患者（包括旅行者腹泻患者）和老年人中也发现了这种感染引起的并发症。老年人对微孢子虫感染的易感性增加可以解释为伴随年龄增长的免疫反应性下降。然而，对衰老人类或动物模型中针对微孢子虫的先天免疫应答的深入分析尚未开展，与先天免疫应答相关的研究几乎不存在。我们的实验室已经证明，与幼鼠相比，来自9个月大的动物的树突状细胞（dc）不能启动抗原特异性T细胞反应来对抗网丘脑虫。然而，用重组IL-15治疗可以恢复老年dc产生T细胞免疫的能力。此外，给老年动物注射外源性IL-15可以使它们在口腔棘球绦虫攻击中存活下来。因此，在衰老开始时，原发性免疫缺陷似乎发生在dc失去启动T细胞反应对抗感染的能力，而不是改变T细胞功能。了解DC反应下调的机制和能够恢复其功能的因素对于开发成功的老年人群寄生虫免疫治疗剂至关重要。该应用程序有三个特定目的：1)将执行与年龄相关的牙周炎杆菌感染期间DC反应动力学。将确定小鼠DC开始发展这种缺陷的年龄，并分析老年小鼠DC反应抑制的机制。2)研究IL-15在恢复正常DC抗棘球绦虫应答中的作用。将确定这种细胞因子逆转DC群体缺陷的机制，并评估IL-15在用纯化的弓形芽胞杆菌蛋白成功接种老年小鼠中的重要性。3)小鼠实验结果与人类和非人类dc对B类原虫产生的先天免疫应答的相关性。这一特定目的将确定衰老是否导致先天性DC对E. cucuuli的不良反应，以及IL-15是否可以恢复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.