Approaches to Immunological Intervention in Schistosomiasis

血吸虫病的免疫干预方法

• 批准号: 6099142
• 负责人: Thomas Wynn
• 金额: --
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6099142
• 关键词: Schistosoma mansoni; T lymphocyte; cytokine; host organism interaction; human subject; immunoregulation; interferons; laboratory mouse; leukocyte activation /transformation

The purpose of this research program is to elucidate the mechanisms of vaccine-induced immunity in schistosomiasis and to dissect the process of egg-induced granuloma formation. Several murine models of schistosomiasis are employed in these studies so that basic pathogenic processes can be investigated. Key findings in the murine studies are then extended to the field, where the immune responses of schistosomiasis patients exhibiting different clinical forms of the disease are examined. The ultimate goal of this research is to understand the host immune response to infection so that immunologically based strategies might be employed in the development of a highly effective vaccine for schistosomiasis. Progress was achieved in the following areas during the year: 1) The role of IL-10 in the regulation of egg-induced immunopathology during infection with S. mansoni was examined. Interleukin-10 gene knockout mice (IL-10T) were used to examine the role of endogenous IL-10 in the down-modulation of hepatic granuloma formation and lymphocyte response that occurs in chronic schistosomiasis infection. These studies showed that while IL-10 plays an important role in controlling acute granulomatous inflammation and the magnitude of the cytokine response, it plays no essential role in the process of immune down-modulation in chronic schistosome infection. 2) IL-10 was shown to play an important role in the suppression of Type-1 (IFN-) cytokine expression in both acutely and chronically infected schistosomiasis patients. The contribution of IL-10 and IFN- to the regulation of Type 1 and Type 2 cytokine responses was investigated in whole blood cultures obtained from Brazilian individuals with acute schistosomiasis or chronic intestinal disease and in the PBMCs and spleen cells of patients with hepatosplenic disease. These studies demonstrated that early or acute infection with S. mansoni is associated with a significant IFN- response and that IL-10 contributes to the suppression of that response during both early and late infection. 3) IFN-, IL-12, and TNF- were shown to play key roles in the suppression of egg-induced liver pathology in mice vaccinated with egg antigens and IL-12. Severe pathology in schistosomiasis has been linked to a dominant CD4+ Th2-type cytokine response and our previous studies showed that sensitizing animals to egg antigens in combination with IL-12, prior to infection, leads to a highly significant reduction in egg-induced immunopathology. In this study, we demonstrated that in contrast to egg/IL-12- sensitized animals which showed marked decreases in pathology, mice similarly sensitized but depleted of IFN-, IL-12, and TNF-  at the time of egg laying developed granulomas which were similar to the non-IL-12-treated control group. The mice also displayed a partial reduction in IFN- production, which suggests that multiple Th1-associated cytokines may be required to maintain polarized Th1 responses in vivo. 4) IL-13 was identified as a key effector cytokine for granuloma formation. In this study, we showed that in vivo blockade of the Th2 cytokine IL-13, using sIL-13Ra2-Fc, significantly reduced the size of pulmonary granulomas in un-sensitized as well as egg- sensitized mice. Blocking IL-13 also significantly reduced total serum IgE levels. These findings suggest that IL-13 may play a central role in the development of egg-induced immunopathology. 5) The role of inducible nitric oxide-synthase in the regulation of immunity induced by attenuated cercariae of S. mansoni was examined. Inducible nitric oxide synthase-deficient mice were shown to develop an enhanced Type-1 cellular and humoral immune response after vaccination with attenuated S. mansoni cercariae but nevertheless, displayed a partial reduction in resistance.

该研究计划的目的是阐明 疫苗诱导的血吸虫病免疫力的机制和 剖析卵引起的肉芽肿的过程。一些 在这些研究中采用了血吸虫病的鼠模型 可以研究基本的致病过程。关键发现 然后将鼠研究扩展到免疫的田野 血吸虫病患者的反应表现出不同的临床 检查了该疾病的形式。最终目标 研究是了解宿主对感染的免疫反应，因此 以免疫学为基础的策略可以采用 开发高效的血吸虫病疫苗。 在这一年中以下领域取得了进展：1） IL-10在卵诱导的调节中的作用 检查了曼氏链球菌感染期间的免疫病理学。 白介素10基因敲除小鼠（IL-10T）用于检查 内源性IL-10在肝下调中的作用 肉芽肿的形成和淋巴细胞反应发生在 慢性血吸虫病感染。这些研究表明， IL-10在控制急性肉芽肿方面起着重要作用 炎症和细胞因子反应的大小，它发挥了 在免疫下调过程中没有必要的作用 慢性血块感染。 2）IL-10显示出 在抑制1型（IFN-）中的重要作用 急性和慢性感染的细胞因子表达 血吸虫病患者。 IL-10和 IFN-调节1型和2型细胞因子 从从中获得的全血培养物进行了研究 巴西患有急性血吸虫病或慢性肠道的人 疾病以及患者的PBMC和脾细胞 肝肾病。这些研究表明，早期或 曼氏链球菌的急性感染与显着相关 IFN-响应，IL-10有助于 在早期和晚期感染期间抑制这种反应。 3） IFN-，IL-12和TNF-被证明播放键 小鼠抑制卵诱导的肝脏病理学的作用 用鸡蛋抗原和IL-12疫苗接种。严重的病理 血吸虫病已与主要的CD4+ Th2型相关 细胞因子反应和我们以前的研究表明，敏化 动物与IL-12结合卵抗原，然后 感染，导致卵诱导的高度显着降低 免疫病理学。在这项研究中，我们证明了相比之下 到鸡蛋/IL-12-敏化动物，显示出明显的减少 病理学，小鼠类似地敏化但耗尽了IFN-， IL-12和tnf-在产卵时开发 与非IL-12处理的对照相似的肉芽肿 团体。小鼠还显示了部分减少 IFN-生产，这表明多个 可能需要与Th1相关的细胞因子保持极化 Th1在体内做出反应。 4）IL-13被确定为关键效应器 细胞因子形成肉芽肿。在这项研究中，我们表明 使用SIL-13RA2-FC，Th2细胞因子IL-13的体内阻断， 显着降低了肺肉芽肿的大小 未敏化的小鼠和卵子敏化的小鼠。也阻止IL-13 显着降低了总血清IgE水平。这些发现表明 IL-13可能在发展中发挥着核心作用 卵引起的免疫病理学。 5）诱导氮的作用 氧化物合成酶在调节因衰减诱导的免疫力调节中 检查了曼氏链球菌的Cercariae。诱导一氧化氮 证明合成酶缺陷型小鼠会发展出增强的类型1 疫苗接种后的细胞和体液免疫反应 减弱了曼森cercariae的S.，但仍然显示出部分 降低电阻。