Schistosome egg induced Th2 responses

血吸虫卵诱导Th2反应

• 批准号: 8239542
• 负责人: EDWARD J. PEARCE
• 金额: $ 37.24万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-11-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239542
• 关键词: Acute; Antigens; Asthma; Biological Assay; Bromodeoxyuridine; CD4 Positive T Lymphocytes; Cell Count; Cell Separation; Cell physiology; Cells; Chronic; Commit; Coupled; Dendritic Cells; Development; Disease; Environment; Functional disorder; Genetic Transcription; Granuloma; Helminthiasis; Helminths; Human; Hypersensitivity; Immune response; Immune system; In Situ; In Vitro; Infection; Interleukin-10; Interleukin-13; Interleukin-4; Intervention; Life; Measures; Mediating; Molecular Profiling; Mus; Parasites; Pathologic; Pharmaceutical Preparations; Phase; Physiologic pulse; Play; Process; Production; Proliferating; Property; Proteins; Regulation; Regulatory T-Lymphocyte; Reporter; Reporting; Resistance; Role; Schistosoma; Schistosoma mansoni; Schistosomiasis; Signal Transduction; Staging; Surface; T-Cell Proliferation; Testing; Th2 Cells; Time; Tissues; Tropical Disease; Ulcerative Colitis; Work; base; cytokine; egg; falls; immunopathology; immunoregulation; in vivo; insight; macrophage; pathogen; research study; response

DESCRIPTION (provided by applicant): The helminth parasite Schistosoma mansoni is long lived, causing chronic infections in its natural human and experimental mouse hosts. It is recognized that during schistosomiasis the parasite-induced Th2 response, as measured by in vitro antigen-stimulated T cell proliferation or cytokine secretion assays, peaks early and then declines despite ongoing infection, a process that is referred to as immunomodulation. Immunomodulation in schistosomiasis appears to play a vital role in minimizing immunopathology in a setting where the immune system is incapable of eliminating the pathogen. Here we propose to explore the underlying basis and functional significance of the diminished Th2 responses that characterize chronic schistosomiasis. We hypothesize that chronic schistosome infection leads to a state of Th2 cell dysfunction akin to adaptive tolerance. We propose to test this hypothesis through three specific aims: 1. To use IL-4 reporter mice to characterize Th2 cells throughout infection. 2. To establish whether Th2 cells from chronically infected mice are irreversibly dysfunctional or whether ongoing environmental signals are required to maintain them in this state. 3. To identify the mechanism responsible for immunomodulation during chronic infection. Recently, using 4get and KN2 IL-4 reporter mice, in which IL-4 transcription and protein production are reported by the expression of GFP and surface human CD2 respectively, we have been able to unequivocally identify CD4 T cells that have responded during infection and committed to Th2 differentiation by becoming capable of making IL-4. These cells can be detected immediately ex-vivo, and indeed in situ, and have allowed us to make significant steps forward in understanding what is happening during chronic schistosomiasis. Together, our studies promise to generate new insights into the processes that allow the regulation of Th2 responses during chronic schistosomiasis and are likely to be of relevance to other chronic helminth infections where Th2 cell hyporesponsiveness has been documented. We believe that our work has the potential to identify targets for intervention in important diseases of the developed world, such as asthma, allergy and ulcerative colitis, that are mediated by chronic, poorly controlled Th2 responses. Schistosomiasis is an important chronic tropical disease caused by long-lived parasitic worms. During the chronic stage of infection with this parasite, the immune response is controlled and diminishes through mechanisms that are poorly understood and which will be investigated in details as part of this proposal. We believe that our work has the potential to identify targets for intervention in important diseases of the developed world, such as asthma, allergy and ulcerative colitis, that are mediated by chronic, poorly controlled Th2 responses.

描述（由申请人提供）：曼氏血吸虫是一种长寿的寄生虫，可在其天然宿主人和实验小鼠中引起慢性感染。人们认识到，在血吸虫病期间，通过体外抗原刺激的T细胞增殖或细胞因子分泌测定，寄生虫诱导的Th2反应在早期达到峰值，然后在持续感染时下降，这一过程被称为免疫调节。在免疫系统无法消除病原体的情况下，血吸虫病的免疫调节似乎在最大限度地减少免疫病理方面起着至关重要的作用。在这里，我们建议探索慢性血吸虫病特征Th2反应减弱的潜在基础和功能意义。我们假设慢性血吸虫感染导致Th2细胞功能障碍的状态类似于适应性耐受。我们建议通过三个具体目标来检验这一假设：1。利用IL-4报告小鼠在整个感染过程中表征Th2细胞。2. 确定慢性感染小鼠的Th2细胞是否存在不可逆的功能失调，或者是否需要持续的环境信号来维持这种状态。3. 确定慢性感染期间免疫调节的机制。最近，使用4get和KN2 IL-4报告小鼠，其中IL-4的转录和蛋白的产生分别通过GFP和表面人类CD2的表达来报道，我们已经能够明确地识别CD4 T细胞在感染期间做出反应，并通过能够制造IL-4而致力于Th2分化。这些细胞可以在离体和原位立即检测到，并使我们在了解慢性血吸虫病期间发生的情况方面取得了重大进展。总之，我们的研究有望对慢性血吸虫病期间Th2反应的调节过程产生新的见解，并可能与其他慢性蠕虫感染相关，其中Th2细胞反应低下已被记录在案。我们相信，我们的工作有潜力确定发达国家重要疾病的干预靶点，如哮喘、过敏和溃疡性结肠炎，这些疾病是由慢性、控制不良的Th2反应介导的。血吸虫病是由寿命较长的寄生虫引起的一种重要的热带慢性疾病。在