IMMUNOREGULATION IN HUMAN STRONGYLOIDIASIS

描述(由申请人提供)：弓形虫病在秘鲁是一个严重的医学问题。虽然在免疫能力强的宿主中，弓形虫病的症状可能较轻，但在免疫功能低下的个体中，它可能表现为严重的播散性形式(似圆线虫高度感染)。在秘鲁，我们越来越多地观察到类圆线虫的高度感染，特别是在合并感染人类T淋巴细胞嗜淋巴病毒1型(HTLV-1)的人中。有趣的是，高度感染类圆线虫很少出现在艾滋病毒/艾滋病晚期患者中。导致这些不同疾病表现的免疫学过程尚不完全清楚。在我们的初步数据中，我们做了一个新的观察，即圆线虫/HTLV-1混合感染的患者不能产生IL-5来响应圆线虫幼虫抗原。基于这些数据，我们假设Th1或HTLV-1注意到的调节反应干扰Th2反应，防止过度感染。其具体目的是：1)测试假设，即与正常人群相比，HTLV-1感染患者对特定线虫幼虫抗原的免疫反应抑制与循环中Th1、T调节细胞和/或调节性细胞因子的数量增加有关；2)测试艾滋病毒患者中高感染率是由于对线虫幼虫抗原的特异性Th2型反应被保存的假设；以及3)表征HIV/HTLV-1双重感染患者的临床表现和对线虫幼虫抗原的免疫反应，以检验HTV-1增强HIV免疫抑制效应的假设。我们将通过前瞻性研究细胞因子对类圆线虫幼虫抗原的反应来实现这些目标。我们将通过流式细胞术进一步确定负责细胞因子产生的细胞的特征。在完成这些研究的过程中，我们将促进对人类逆转录病毒感染的免疫调节作用的了解。我们将更好地了解临床和免疫学反应，为以免疫和疫苗开发为重点的进一步研究奠定基础。对弓形虫病免疫调节的研究也可能带来解决肠道线虫负担所需的见解，这些线虫影响着数十亿人。

DESCRIPTION (provided by applicant): Strongyloidiasis is a significant medical problem in Peru. Although strongyloidiasis symptoms may be mild in immunocompetent hosts, it may present as a severe disseminated form in immunocompromised individuals (Strongyloides hyperinfection). In Peru we are increasingly observing Strongyloides hyperinfection, especially in persons co-infected with the Human T-cell-lymphotropic virus 1 (HTLV-1). Interestingly, Strongyloides hyperinfection rarely presents in persons with advanced HIV/AIDS. The immunological processes leading to these different disease manifestations are not completely understood. In our preliminary data, we made the novel observation that Strongyloides/HTLV-1 co-infected patients failed to produce IL-5 in response to Strongyloides larval antigens. Based on these data, we hypothesize that the Th1 or regulatory responses noted with HTLV-1 interfere with the Th2 responses preventing hyperinfection. The specific aims are: 1) to test the hypothesis that suppressed immune responses to specific Strongyloides larval antigens in HTLV-1 infected patients with strongyloidiasis correlate with a higher number of circulating Th1, T-regulatory cells and/or regulatory cytokines when compared to normal subjects with strongyloidiasis, 2) To test the hypothesis that the low rate of Strongyloides hyperinfection in HIV patients is due to a preserved specific Th2 type response to Strongyloides larval antigen; and 3) to characterize the clinical presentation and immune responses to Strongyloides larval antigen in patients with dual HIV/HTLV-1 infection to test the hypothesis that HTLV-1 enhances the immunosuppressive effects of HIV. We will accomplish these goals by prospectively studying cytokine responses to Strongyloides larval antigen. We will further characterize cells responsible for cytokine production by flow cytometry. In accomplishing these studies, we will advance knowledge of the immunoregulatory effects of human retroviral infections. We will better understand the clinical and immunological responses to strongyloidiasis and set the basis for further studies focusing on immunity and vaccine development. Studies of immunoregulation in strongyloidiasis may also lead to insights needed for addressing the burden of intestinal nematodes, which affect billions of people.