Modulation of cellular and humoral immune response to third party antigens in nematode-infected mice

三分之一的人口感染了寄生虫。为了避免被驱逐并限制病理，蠕虫已经发展出复杂的策略来抑制和调节宿主的免疫反应。当这种免疫抑制溢出到不相关的第三方抗原时，先前存在的蠕虫感染可能会干扰疫苗接种的效果。我们之前的研究表明，鼠形圆线虫的短暂感染诱导小鼠对模型抗原接种的抗体反应转向2型表型，而长时间感染s形齿毛线虫导致所有类型抗体反应的普遍抑制。观察到的抗体反应的抑制不是通过直接干扰产生抗体的B细胞介导的，而是主要通过干扰辅助性T细胞功能介导的。在当前的应用中，我们将使用L. sigmodonis感染的小鼠来阐明导致线虫诱导的对T细胞功能和T细胞依赖性B细胞反应的干扰的分子机制。在这个应用程序的第一部分，我们集中在线虫感染期间调节抗体反应。我们打算比较在感染象形乳杆菌不同阶段、感染自然清除后和感染药物流产后小鼠对模型抗原接种的抗体反应。我们打算寻找佐剂，使疫苗的功能，尽管预先存在的乙形乳杆菌感染，我们将详细分析滤泡T辅助细胞的表型。在这个应用程序的第二部分，我们集中在线虫感染期间的调节T细胞反应。我们将比较过继转移T细胞受体转基因卵清蛋白特异性CD4+ T辅助细胞（OT-II）和CD8+细胞毒性T细胞（OT-I）在naïve和sigmodontis感染小鼠体内的增殖和效应功能。因此，我们打算分析调节细胞因子、调节受体和调节细胞群在线虫诱导的T细胞抑制中的作用。总之，我们期望解开从确定的线虫感染到降低疫苗接种效力的一系列事件。基于获得的信息，我们打算开发在小鼠模型中预先存在的蠕虫感染背景下有效的疫苗接种制度。这些结果也可能有助于开发针对寄生虫流行地区人群的功能性疫苗。

One third of the human population is infected with helminth parasites. To avoid their expulsion and to limit pathology, helminths have developed sophisticated strategies to suppress and modulate the immune response of their hosts. As this immune suppression spills over to unrelated third-party antigens, a preexisting helminth infection may interfere with vaccination efficacy. We have shown before that transient infection of mice with Strongyloides ratti induced a diversion of antibody responses to model antigen vaccination towards a type 2 phenotype whereas a long lasting infection with Litomosoides sigmodontis led to a generalized suppression of all types of antibody responses. The observed suppression of antibody response was not mediated by direct interference with antibody-producing B cells but predominantly by interference with T helper cell function. In the current application we will use L. sigmodontis-infected mice to elucidate the molecular mechanisms leading to nematode-induced interference with T cell function and T cell dependent B cell responses. In the first part of this application we focus on modulated antibody response during nematode infection. We intend to compare the antibody response to model antigen vaccination in mice at different stages of L. sigmodontis infection, after spontaneous clearance of infection and after drug induced abortion of infection. We intend to search for adjuvants that render vaccinations functional despite a preexisting L. sigmodontis infection and we will analyze the phenotype of follicular T helper cells in detail. In the second part of this application we focus on the modulated T cell response during nematode infection. We will compare the proliferation and the effector functions of adoptively transferred T cell receptor transgenic ovalbumin-specific CD4+ T helper cells (OT-II) and CD8+ cytotoxic T cells (OT-I) within naïve and L. sigmodontis infected mice. Thereby we intend to analyze the role of regulatory cytokines, regulatory receptors and regulatory cell populations in the mediation of nematode-induced T cell suppression. In conclusion we expect to unravel the chain of events leading from established nematode infection to reduced vaccination efficacy. Based on the information gained, we intend to develop vaccination regimes that are functional on the background of preexisting helminth infections in the mouse model. These results may also be useful to develop functional vaccinations for the human population in helminth endemic areas.