Dendritic Cell Response to Microsporidians

树突状细胞对微孢子虫的反应

• 批准号: 7477126
• 负责人: IMTIAZ AHMED KHAN
• 金额: $ 69.32万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7477126
• 关键词: Abattoirs; Acquired Immunodeficiency Syndrome; Address; Adjuvant; Age; Age of Onset; Aging; Aging-Related Process; Albendazole; Animal Model; Animals; Antigen Presentation; Antigen-Presenting Cells; Antigens; Biological Models; Body Weight decreased; CD8B1 gene; Categories; Cell Aging; Cell physiology; Centers for Disease Control and Prevention (U.S.); Child; Clinical; Communicable Diseases; Contact Lenses; Data; Defect; Dendritic Cells; Dendritic cell activation; Depth; Deterioration; Development; Diarrhea; Down-Regulation; Elderly; Elements; Encephalitozoon; Encephalitozoon cuniculi; Encephalitozoon hellem; Exhibits; Farming environment; Functional disorder; Generations; Genes; Granulocyte-Macrophage Colony-Stimulating Factor; HIV; Host Defense; Host-Parasite Relations; Human; Immune; Immune response; Immune system; Immunity; Immunocompetent; Immunocompromised Host; Immunotherapeutic agent; Incidence; Individual; Infection; Interleukin-15; Interleukin-4; Intestines; Kinetics; Knock-out; Laboratories; Life; Life Expectancy; Measures; Mediating; Microsporidia; Microsporidiosis; Modeling; Mus; Nude Mice; Numbers; Oral; Organ Transplantation; Parasites; Patients; Persons; Pharmaceutical Preparations; Population; Predisposition; Prevalence; Primates; Proliferating; Proteins; Range; Rate; Recombinants; Relative (related person); Reporting; Research; Resistance; Role; Route; Septata intestinalis; Severities; Source; Staging; Symptoms; System; Systemic disease; T-Lymphocyte; Testing; Therapeutic; Time; Transplant Recipients; Traveler' s diarrhea; United States National Institutes of Health; Vaccination; Water; Wild Animals; age related; aged; bench to bedside; biodefense; cell age; cytokine; cytotoxic; drinking water; foodborne; fumagillin; immune function; immunosenescence; improved; microbial; monocyte; mouse model; nonhuman primate; novel; pathogen; research study; response; restoration; transmission process; vaccination strategy; waterborne

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.

描述（由申请人提供）：对于免疫功能低下的患者，尤其是患有艾滋病的患者，微孢子虫感染仍然是一个问题，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的患者中，包括旅行者腹泻的患者以及老年人中还发现了由于这种感染引起的并发症。老年人群对微孢子虫感染的敏感性增加，可以通过伴随衰老的免疫反应性恶化来解释。但是，在对人类衰老或动物模型中对微孢子虫的先天免疫反应的深入分析尚未进行，并且与先天免疫反应有关的研究几乎不存在。我们的实验室使用脑核酸脑库尼库里（Cuniculi）作为模型的微孢子虫模型，表明，与年轻小鼠相比，来自9个月大的动物的树突状细胞（DC）无法促进针对Cuniculi大肠杆菌的抗原特异性T细胞反应。但是，重组IL-15的治疗恢复了旧DC对病原体产生T细胞免疫的能力。此外，对年龄较大的动物的外源性IL-15给药使它们能够在口服E. cuniculi挑战中生存。因此，在衰老开始时，DC似乎发生了主要的免疫缺陷，而DC失去了针对感染的T细胞反应的能力，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为老年人群生成成功的寄生免疫治疗剂至关重要。该申请需要三个特定目的：1）将在大肠杆菌感染期间与年龄相关的直流反应动力学。将确定鼠DC开始发展此缺陷的年龄，并将分析老鼠DC反应抑制的机制。 2）将研究IL-15在恢复正常直流反应中针对Cuniculi的正常反应中的作用。将确定这种细胞因子逆转DC种群中缺陷的机制，并评估IL-15在成功接种纯化的小鼠中IL-15的重要性。 3）从小鼠获得的结果与人类和非人类DC中的B型原生动物产生的先天免疫反应的相关性。这个具体的目的将确定衰老是否导致对库尼库里的先天直流反应不佳，以及IL-15是否可以恢复电弧功能。