Approaches To Immunological Intervention In Schistosomiasis

血吸虫病的免疫干预方法

基本信息

批准号：
9563873
负责人：
Thomas Wynn
金额：
$ 101.05万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
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/9563873
关键词：
ARG2 gene Affect Allergens Amino Acids Area Arginine Asparagine Biochemical Biochemistry Cell Nucleus Cell physiology Cells Cessation of life Chronic Collagen Degradation Pathway Deposition Development Disease Failure Family Fibrosis Goals Granuloma Granulomatous Halofuginone Hepatocyte Hepatomegaly Human Hydrolase Immune Tolerance Immune response Immunity Immunologics In Vitro Individual Infection Inflammation Inflammatory Interleukin-10 Interleukin-13 Interleukin-4 Interleukin-5 Interleukin-9 Intestines Knockout Mice Leukemic Cell Link Liver Liver Fibrosis Lung Malignant Neoplasms Measures Mediating Medical Molecular Morbidity - disease rate Mus Myeloid Cells Nitrogen Nutrient Oxidases Parasites Pathogenesis Pathogenicity Pathology Pathway interactions Portal Hypertension Portal Venous System Process Production Recruitment Activity Regulatory T-Lymphocyte Research Resolution Risk Role STAT6 gene Schistosoma Schistosoma mansoni Schistosomiasis Site Starvation Structure of parenchyma of lung System T cell response T-Cell Proliferation T-Lymphocyte Tissues Transgenic Mice Tryptophan Urea Work amino acid metabolism arginase asparaginase base biological adaptation to stress cell growth cytokine deprivation egg experimental study immunological intervention immunopathology indoleamine intravenous administration macrophage monocyte mortality mouse model novel strategies pathogen prevent programs proline-tRNA receptor repaired response tumor urea cycle

项目摘要

In schistosomiasis and other diseases associated with type-2 immunity, the pathology resulting from chronic infection or chronic allergen exposure is predominantly induced by the host immune response. The chronic type-2 immune response eventually triggers significant fibrosis, which is the primary cause of morbidity and mortality in many chronic infectious and inflammatory diseases. Our work is focused on elucidating the mechanisms of granulomatous inflammation, fibrosis, portal hypertension, and death following infection with S. mansoni and to devise novel strategies to slow or reverse the progression of liver fibrosis. Progress was made in the following area: Modulation of T cell responses in both normal and inflamed tissue prevents immunopathology and horror autotoxicus self-reactivity. Among the many interlocking pathways that can suppress T cell proliferation and activity, myeloid cell-mediated amino acid deprivation is a key checkpoint in preventing immunopathology. For example, both tryptophan and arginine are essential for T cell growth and function, and their local degradation by indoleamine oxidases (IDO1 and IDO2) or arginase 1 (Arg1) and possibly arginase 2 (Arg2) expressed in myeloid cells restrains T cell proliferation, limits tissue damage, and contributes to immunologic tolerance. Amino acid starvation is also a medically important strategy to target cells auxotrophic for specific amino acids. For example, asparaginase deprives leukemic cells of their exogenous supply of asparagine, and the fungal metabolite halofuginone blocks pathogenic TH17 responses by interfering with the glutamyl-prolyl tRNA synthase causing an amino acid stress response. Arginine and tryptophan degradation pathways are linked to malignancy and chronic infections, where tumors and pathogens subvert the host's T cell control pathways to suppress productive immune responses. Amino acid metabolism is also linked to Treg development and stability at sites of infection via a process termed infectious tolerance, which is a self-reinforcing pathway aiding in tissue resolution and repair following inflammation. The liver immune response to Schistosoma mansoni eggs is an example of how myeloid cells exert control over T cells through amino acid metabolism. In murine and human schistosomiasis, worm eggs lodged in the liver drive a TH2-mediated asynchronous granulomatous response characterized by collagen deposition and fibrosis, all of which are required to wall off the eggs, which are highly toxic. The fibrotic granulomas protect the surrounding tissues from damage caused by the toxic eggs until they can be degraded. The TH2 response recruits inflammatory Ly6C+ monocytes from the blood to granulomas; there they differentiate into macrophages and become activated by IL-4 and IL-13 to the alternatively activated or M2 pathway. In this context, M2 macrophages express high amounts of the arginine hydrolase Arg1 regulated via the IL-4- and IL-13-induced STAT6 pathway. When mice lacking Arg1 specifically in macrophages were infected with schistosomes, an unregulated TH2 response occurred leading to a failure to down-regulate the pro-fibrotic response, excessive production of IL-4 and IL-13, hepatomegaly, and early lethality. However, when eggs are artificially introduced into the lung via intravenous administration, a TH2 pro-fibrotic response occurs independent of macrophage Arg1. Lung tissue contains little arginase activity, whereas liver hepatocytes express high and constitutive Arg1 as part of the urea cycle, which eliminates excess nitrogen via urea. Because Arg1 catalyzes the same biochemical degradation of arginine in hepatocytes and macrophages, and because granulomas are embedded in the Arg1-rich hepatocyte parenchyma, we hypothesized that microenvironmental arginine depletion by macrophage Arg1 close to the granuloma nucleus is the key step in restricting T cell activity, thus blocking excessive immune responses. In this study we developed an in vitro cellular biochemistry system to explore the mechanistic basis of microenvironmental arginine depletion sensing by T cells. We showed that the nutrient recognition pathway Rictor/mTORC2 is the central mechanisms by which T cells measure environmental arginine.

在血吸虫病和与2型免疫相关的其他疾病中，由慢性感染或慢性过敏原暴露引起的病理主要由宿主免疫反应引起。慢性2型免疫反应最终会触发明显的纤维化，这是许多慢性传染病和炎症性疾病中发病率和死亡率的主要原因。我们的工作重点是阐明肉芽肿性炎症，纤维化，门静脉高压和死亡的机制，并在感染了曼氏链球菌后死亡，并制定了新的策略，以减缓或逆转肝纤维化的进展。在以下区域取得了进展：正常和发炎组织中T细胞反应的调节可防止免疫病理学和恐怖自毒性自我反应性。在可以抑制T细胞增殖和活性的许多互锁途径中，髓样细胞介导的氨基酸剥夺是预防免疫病理学的关键检查点。例如，色氨酸和精氨酸对于T细胞的生长和功能都是必不可少的，并且它们通过吲哚胺氧化酶（IDO1和IDO2）或精氨酸酶1（ARG1）以及在髓样细胞中表达的精氨酸酶2（ARG2）的局部降解都限制了组织损害，并限制了组织损伤，并限制了组织损害，并对免疫学耐受性有所帮助。氨基酸饥饿也是针对特定氨基酸的靶细胞靶向细胞的重要策略。例如，天冬酰胺酶剥夺了白血病细胞的外源天冬酰胺，而真菌代谢产素硫酮通过干扰谷氨酰基 - 丙基促进酶合成酶，从而阻止致病性TH17反应，从而导致氨基酸应激反应。精氨酸和色氨酸降解途径与恶性肿瘤和慢性感染有关，其中肿瘤和病原体颠覆了宿主的T细胞控制途径以抑制生产性免疫反应。氨基酸代谢还与感染部位的TREG发育和稳定性有关，该过程称为感染性耐受性，这是一种自我强化的途径，协助炎症后的组织分辨率和修复。肝脏对曼森卵的肝脏免疫反应是髓样细胞如何通过氨基酸代谢对T细胞施加控制的一个例子。在鼠类和人血吸虫病中，肝脏中产生的蠕虫卵在肝脏中驱动Th2介导的异步肉芽肿反应，其特征在于胶原蛋白沉积和纤维化，所有这些反应都需要将所有这些反应围起来，以使卵子隔离，这是有毒的卵。纤维化颗粒保护周围的组织免受有毒卵造成的损害，直到它们降解为止。 TH2反应募集了从血液到肉芽肿的炎症LY6C+单核细胞。在那里，它们将其分化为巨噬细胞，并被IL-4和IL-13激活，以替代激活或M2途径。在这种情况下，M2巨噬细胞通过IL-4和IL-13诱导的STAT6途径表达大量的精氨酸水解酶ARG1。当缺乏巨噬细胞中缺乏ARG1的小鼠被血块感染时，发生了不受管制的TH2反应，导致未能下调促纤维化反应，过度产生IL-4和IL-13，肝肿大，肝肿大和早期致死性。但是，当通过静脉内给予人为地引入卵时，TH2促纤维化反应就与巨噬细胞ARG1无关。肺组织几乎没有精氨酸酶活性，而肝肝细胞表示高，本构为尿素周期的一部分，从而消除了通过尿素的过量氮。因为Arg1催化精氨酸在肝细胞和巨噬细胞中的同样生化降解，并且由于颗粒膜嵌入了富含Arg1的肝细胞实质中过度免疫反应。在这项研究中，我们开发了一种体外细胞生物化学系统，以探索T细胞微环境精氨酸消耗感测的机械基础。我们表明，营养识别途径Rictor/mTORC2是T细胞测量环境精氨酸的中心机制。