Innate Immune regulation of helminth-induced inflammation

蠕虫引起的炎症的先天免疫调节

基本信息

批准号：
9078287
负责人：
Mark Christopher Siracusa
金额：
$ 39.75万
依托单位：
RBHS-NEW JERSEY MEDICAL SCHOOL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-01-01 至 2020-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9078287
关键词：
Address Affect Agonist Carbonic Anhydrase Inhibitors Cells Cessation of life Characteristics Chronic Data Development Dichloromethylene Diphosphonate Disease Enzyme Activation Enzyme Inhibition Enzyme Inhibitor Drugs Enzyme Inhibitors Enzymes Epilepsy Equilibrium Event Exhibits FDA approved Family Family member Glaucoma Goblet Cells Helminths Hematopoietic Human Hyperplasia Immune Immune response Immune system Immunity In Vitro Infection Inflammation Intestines Kinetics Liposomes Literature Mediating Metabolic Molecular Morbidity - disease rate Mucous body substance Mus Parasites Pathologic Pathology Pathway interactions Patients Peripheral Population Prevalence Production Public Health Recruitment Activity Regulation Role Stem cells Testing Th2 Cells Therapeutic Tissues Trichinella Trichinella spiralis Ulcer Wound Healing base carbonate dehydratase combat cytokine enzyme activity health economics in vivo macrophage mast cell monocyte novel prevent public health relevance response stem

项目摘要

DESCRIPTION (provided by applicant): Helminth infections, including Trichinella spiralis, infect approximately 2 billion people worldwide and represent a significant public health concern. To combat these parasites the mammalian immune system has evolved mechanisms to maintain a delicate balance between promoting beneficial inflammation needed to reduce parasitic burdens and limiting pathologic inflammation in order to maintain tissue integrity. The importance of maintaining this balance is evident by the severe pathology that presents in patients exhibiting dysregulated immune responses to helminthes. Despite the importance of balancing protective and pathologic responses in the context of helminth infections, the cellular and molecular events that regulate these pathways remain unknown. It is well established that type 2 responses, characteristic of helminth-induced immune responses in humans and mice, are required to both promote worm clearance and limit infection- induced tissue damage. Our recent studies have demonstrated that specialized helminth-induced hematopoietic stem/progenitor cells (HSPCs) enter peripheral tissues, develop into mast cells and promote TH2 cytokine-dependent immunity to Trichinella spiralis. In addition, our novel preliminary data reveal that helminth-induced HSPCs upregulate Carbonic anhydrase enzymes, a family of enzymes that regulate pH and are targeted therapeutically to treat epilepsy and glaucoma. Further, blocking Car enzyme activity via treatment with FDA approved pan Car inhibitors was sufficient to prevent murine and human mast cell development in vitro and mast cell responses, TH2 cytokine production and protective immunity to Trichinella in vivo. Moreover, our preliminary studies indicate that Car-dependent mast cells promote monocyte responses and the presence of intestinal alternatively activated macrophage populations. These data indicate that pharmacologic manipulation of Car enzyme activation could be employed to regulate mast cell development, TH2 cytokine- mediated inflammation and wound healing responses in the context of helminth infections. Based on our new data, two specific aims will address the following questions: (i) Can pharmacologic inhibition or activation of specific Car enzyme family members be employed to regulate Trichinella-induced mast cell responses and TH2 cytokine-mediated inflammation? (ii) Do monocytes cooperate with Car-dependent mast cells to promote intestinal wound healing responses following Trichinella infection? Collectively, these studies will interrogate novel aspects of innate immune mechanisms through which TH2 cytokine-mediated immunity and inflammation are initiated. We anticipate that defining the mechanisms through which Car enzymes regulate helminth- induced mast cell responses, Th2 cytokine production and intestinal pathology will significantly inform new immune therapeutic strategies to treat helminth infections and their associated morbidities.

描述（由申请人提供）：包括旋毛虫在内的蠕虫感染感染了全世界约 20 亿人，是一个重大的公共卫生问题。为了对抗这些寄生虫，哺乳动物的免疫系统已经进化出机制来维持促进有益炎症和所需的微妙平衡。减少寄生虫负担并限制病理性炎症以维持组织完整性尽管平衡很重要，但对蠕虫表现出免疫反应失调的患者所表现出的严重病理学证明了维持这种平衡的重要性。蠕虫感染背景下的保护性和病理性反应，调节这些途径的细胞和分子事件仍然未知，众所周知，2 型反应是人类和小鼠中蠕虫诱导的免疫反应的特征，是促进蠕虫生长所必需的。我们最近的研究表明，特殊的蠕虫诱导的造血干/祖细胞 (HSPC) 进入外周组织，发育成肥大细胞并促进对旋毛虫的 TH2 细胞因子依赖性免疫。此外，我们新的初步数据表明，蠕虫诱导的 HSPC 会上调碳酸酐酶，碳酸酐酶是调节 pH 值的酶家族，可用于治疗癫痫和青光眼，此外，通过 FDA 批准的 pan Car 治疗可阻断 Car 酶活性。抑制剂足以阻止小鼠和人类肥大细胞的体外发育以及肥大细胞的反应、TH2细胞因子的产生和体内对旋毛虫的保护性免疫。此外，我们的初步研究表明，Car依赖性肥大细胞。这些数据表明，在蠕虫感染的情况下，可以采用 Car 酶激活的药理学操作来调节肥大细胞发育、TH2 细胞因子介导的炎症和伤口愈合反应。根据我们的新数据，两个具体目标将解决以下问题：（i）能否通过药理学抑制或激活特定的 Car 酶家族成员来调节旋毛虫诱导的肥大细胞反应和 TH2 细胞因子介导的炎症？与 Car 依赖性肥大细胞合作促进旋毛虫感染后肠道伤口愈合反应？总的来说，这些研究将探讨 TH2 细胞因子介导的免疫和炎症启动的先天免疫机制的新方面。酶调节蠕虫诱导的肥大细胞反应、Th2 细胞因子的产生和肠道病理学将为治疗蠕虫感染及其相关疾病的新免疫治疗策略提供重要信息。