CD8+ T cell effectors against microsporidia

对抗微孢子虫的 CD8 T 细胞效应

基本信息

批准号：
8892976
负责人：
IMTIAZ AHMED KHAN
金额：
$ 39.92万
依托单位：
GEORGE WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-17 至 2018-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8892976
关键词：
AIDS/HIV problem Acquired Immunodeficiency Syndrome Adopted Albendazole Animals Biological Assay Blood Body Weight decreased CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell Communication Cells Child Clinical Data Defect Development Diagnosis Diarrhea Effector Cell Elderly Encephalitozoon cuniculi Encephalitozoon hellem Enterocytozoon bieneusi Exhibits Generations Geographic Locations Goals HIV HIV Infections Hand Health Heterogeneity Human Immune Immune response Immunity Immunocompromised Host Immunotherapeutic agent Impairment Individual Infection Interferons Kinetics Knock-out Laboratories Lead Link Maintenance Mediating Memory Methods Microsporidia Microsporidiosis Modeling Mono-S Mus Opportunistic Infections Organ Transplantation Organism Parasite Control Parasites Patients Persons Pharmaceutical Preparations Play Population Population Study Predisposition Prevalence Production Risk Role Septata intestinalis Source Symptoms System Systemic disease T cell response T-Lymphocyte T-Lymphocyte Subsets Testing Therapeutic Transplant Recipients Vaccines Viral adaptive immunity base cytokine fumagillin improved interest novel therapeutic intervention oral infection pathogen perforin response socioeconomics

项目摘要

DESCRIPTION (provided by applicant): Microsporidial infection continues to be a problem for HIV infected individuals and are associated as a cause of persistent diarrhea and systemic disease in these people. Recent studies have also implicated these agents in causing illness to HIV- negative groups like travelers and immuno-competent elderly individuals. The limited studies available with Encephalitozoon cuniculi, a microsporidia that can be easily cultured in the laboratory have demonstrated importance of T cells in protection against the parasite. Amongst the T cell subsets, CD8+ T lymphocytes are primary effector cells responsible for protective immunity with CD4+ and ?� T playing an important helper role. Knock out animals lacking either of the two subsets exhibit sub-optimal CD8+ T cell immunity to E.cuniculi infection. Recent studies from our laboratory suggest that IL- 21, a cytokine produced by both CD4 and ?� T cells, is important for the induction of multifunctional CD8+T cell response against the pathogen. Neutralization of IL-21 response leads to decreased polyfunctional and increased mono-functional CD8+ T cell response as a result of which they are less protective and the host is unable to clear infection in an efficient manner. Importance of poly or multifunctional CD8+ T cells has recently been associated with increased protection against viral pathogens, although the direct link has yet to established. Thus it appears that IL-21 mediated polyfunctional CD8+ T cell response is key to protection against E.cuniculi infection which poses a risk to HIV infected population. The proposal comprises of three specific aims. In the first specific aim the kinetics o IL-21 response by ?� and CD4+ T cell population in response to E.cuniculi infection will be evaluated. The mechanism of IL-21 production and priming of CD8+ T cell response against the pathogen will be assayed. In the second specific aim role of IL-21 in the development of polyfunctional CD8+ T cell effector response will be determined. Further, importance of polyfunctionality in the development of robust long-term response will be analyzed. In the third and final specific aim various strategies which can lead to induction and maintenance of polyfunctional CD8+ T cell response in immunocompromised (like HIV-infected) host will be tested and therapeutic role of IL-21 in this situation will be evaluated. These studies will have fr reaching implications in other opportunistic infections and viral pathogens where development of robust CD8+ T cell response is critical for host protection.

描述（由适用提供）：对于艾滋病毒感染的个体而言，微孢子虫感染仍然是一个问题，并且是这些人持续性腹泻和全身性疾病的原因。最近的研究还实施了这些药物，导致疾病引起艾滋病毒负面群体，例如旅行者和竞争者的老年人。可以在实验室中很容易培养的微型孢子虫脑肺炎脑的有限研究表明，T细胞在保护寄生虫中的重要性。在T细胞子集中，CD8+ T淋巴细胞是负责用CD4+和？t扮演重要辅助作用的免疫学细胞的主要效应细胞。敲除缺乏两种亚群的动物，表现出对大肠杆菌感染的最佳CD8+ T细胞免疫学。我们实验室的最新研究表明，IL-21是CD4和CD4产生的细胞因子？ T细胞对于针对病原体的多功能CD8+T细胞反应很重要。 IL-21响应的中和导致多功能和单功能CD8+ T细胞反应的提高，因此它们受到较少保护，并且宿主无法有效地清除感染。尽管直接连接尚未建立，但聚或多功能CD8+ T细胞的重要性最近与对病毒病原体的保护增加有关。看来IL-21介导的多功能CD8+ T细胞反应是防止大肠杆菌感染的关键，这对HIV感染人群构成风险。该提案包括三个具体目标。在第一个特定目的中，将评估？将分配IL-21产生和CD8+ T细胞反应的启动的机制。在第二个特定目标中，IL-21在多功能CD8+ T细胞效应子响应中的发展中。此外，将分析多功能在稳健的长期反应发展中的重要性。在第三个也是最后的特定目的中，将测试各种策略，这些策略可以导致在免疫功能低下（如HIV感染）宿主中进行多功能CD8+ T细胞反应的诱导和维持，并将评估IL-21在这种情况下的治疗作用。这些研究将对其他机会性感染和病毒病原体产生影响，在这些机会感染和病毒病原体中，鲁棒CD8+ T细胞反应的发展对于宿主保护至关重要。