权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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(由申请人提供)：微孢子虫感染仍然是艾滋病毒感染者的一个问题，并与这些人持续腹泻和系统性疾病的原因有关。最近的研究还表明，这些制剂会导致旅行者和免疫能力强的老年人等艾滋病毒阴性群体患病。楔形脑孢子虫是一种可以在实验室轻松培养的微孢子虫，现有的有限研究表明T细胞在预防这种寄生虫方面的重要性。在T细胞亚群中，CD_8~+T细胞是主要的保护性免疫效应细胞，CD_4~+和�~+T细胞起着重要的辅助作用。缺乏这两个亚群中任何一个的敲除动物表现出对楔形艾美耳球虫感染的次优CD8+T细胞免疫力。我们实验室最近的研究表明，IL-21是一种由CD4T细胞和�T细胞产生的细胞因子，在诱导多功能CD8+T细胞对病原体的反应中起重要作用。中和IL-21反应会导致多功能CD8+T细胞反应减少，单功能CD8+T细胞反应增加，导致它们的保护性降低，宿主不能有效地清除感染。最近，多功能或多功能CD8+T细胞的重要性与增强对病毒病原体的保护有关，尽管这种直接联系尚未建立。由此可见，IL-21介导的多功能CD8+T细胞应答是预防人类免疫缺陷病毒(HIV)感染的关键。该提案包括三个具体目标。在第一个特定目标中，我们将评估�和CD4+T细胞群对白介素21应答的动力学。IL-21的产生和CD8+T细胞对病原体应答的启动机制将被检测。在第二个特定目标中，将确定IL-21在多功能CD8+T细胞效应反应发展中的作用。此外，还将分析多功能性在发展强有力的长期反应中的重要性。在第三个也是最后一个特定目标中，将测试在免疫受损(如HIV感染)宿主中诱导和维持多功能CD8+T细胞反应的各种策略，并评估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深远影响，在这些病原体中，发展强大的CD8+T细胞反应对于宿主保护至关重要。