Schistosome egg induced Th2 responses

描述(申请人提供)：蠕虫寄生虫曼氏血吸虫活得很长，在其自然的人类和实验小鼠宿主中引起慢性感染。人们认识到，在血吸虫病期间，寄生虫诱导的Th2反应，如体外抗原刺激的T细胞增殖或细胞因子分泌试验所测量的那样，在持续感染的情况下提前达到峰值，然后下降，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学方面发挥着至关重要的作用。在这里，我们建议探索Th2反应减弱的潜在基础和功能意义，这些反应是慢性血吸虫病的特征。我们假设慢性血吸虫感染会导致类似适应性耐受的Th2细胞功能障碍状态。我们建议通过三个特定的目标来验证这一假设：1.使用IL-4报告小鼠来表征Th2细胞在整个感染过程中的特征。2.确定慢性感染小鼠的Th2细胞是否存在不可逆转的功能障碍，或者是否需要持续的环境信号来维持这种状态。3.明确慢性感染过程中的免疫调节机制。最近，使用4get和KN2IL-4报告小鼠，其中IL-4的转录和蛋白产生分别通过GFP和表面人CD2的表达来报告，我们已经能够明确地识别在感染期间做出反应并通过能够产生IL-4而致力于Th2分化的CD4T细胞。这些细胞可以立即在体外被检测到，甚至可以在原位被检测到，并使我们在理解慢性血吸虫病期间发生的事情方面取得了重大进展。总之，我们的研究有望对允许调节慢性血吸虫病期间Th2反应的过程产生新的见解，并可能与其他已记录Th2细胞低反应的慢性蠕虫感染相关。我们相信，我们的工作有可能确定发达国家重要疾病的干预目标，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。血吸虫病是由长寿寄生虫引起的一种重要的慢性热带疾病。在.期间 感染这种寄生虫的慢性阶段，免疫反应受到控制并减弱 通过鲜为人知的机制，并将作为这一过程的一部分进行详细调查 求婚。我们认为，我们的工作有可能确定重要的干预目标 发达国家的疾病，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。

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.