Interrogating innate immunity to helminth parasites

询问对蠕虫寄生虫的先天免疫力

基本信息

批准号：
8679561
负责人：
Mark Christopher Siracusa
金额：
$ 16.2万
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：
2015
资助国家：
美国
起止时间：
2015-03-01 至 2017-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8679561
关键词：
Address Allergens Allergic Allergic Disease Allergic inflammation Antigens Area B-Lymphocytes Basophilia Basophils CD4 Positive T Lymphocytes Cell Differentiation process Cells Chronic Clinical Coculture Techniques Communities Coupled Data Dendritic Cells Dendritic cell activation Developed Countries Development Economic Burden Epithelial Cells Future Goblet Cells Growth Helminths Human Hyperplasia IgE IgG1 Immune Immune response Immunity Immunoglobulin Class Switching In Vitro Individual Infection Inflammation Interleukin-13 Interleukin-3 Interleukin-4 Interleukin-5 Interleukin-9 Lead Life Mediating Modeling Molecular Mucous body substance Mus Natural Immunity Nematoda Parasites Pathway interactions Population Predisposition Prevalence Production Publishing Regulation Reporting Resistance Resistance to infection Role STAT6 gene Signal Transduction Smooth Muscle Soil Testing Th2 Cells Therapeutic Time Tissues Trichuris Work adaptive immunity base cellular targeting cytokine disability gastrointestinal granulocyte human TSLP protein in vivo pandemic disease prevent public health relevance response

项目摘要

DESCRIPTION (provided by applicant): The global prevalence of soil transmitted helminth infections is currently estimated at two billion individuals infected worldwide, with an estimated one billion people infected with Trichuris. Helminth infections can lead to significant malnutritio, growth retardation and long-term disability. In addition, infections of live stock populations in endemic areas exert enormous economic burdens on the local communities. Given the global prevalence of helminth infections coupled with the pandemic of allergic diseases in industrialized countries, it is critical to gain a better understanding of the pathways that contro TH2 cytokine-mediated immunity and inflammation. CD4+ TH2 cells produce IL-4, IL-5, IL-9 and IL-13, and their development is dependent on IL-4R, STAT6 and GATA3. In addition, B cells activated in the context of a TH2 cytokine response primarily class switch to produce antigen-specific IgG1 and IgE. Type 2 cytokine-driven inflammation in tissues results in goblet cell hyperplasia, mucus production, increased smooth muscle contractility, and the influx of granulocyte populations. Despite significant developments in our understanding of the pathways that control the differentiation and regulation of TH2 cells, the molecular and cellular pathways that initiate helminth- or allergen-specific TH2 cell responses remain poorly defined. My previous work demonstrates that TSLP promotes the population expansion of a phenotypically and functionally distinct, IL-3-independent basophil population and that TSLP-elicited basophils are sufficient to partially restore CD4+ TH2 cell responses and protective immunity to Trichuris in normally susceptible TSLPR-deficient mice. In addition, my new preliminary studies indicate, for the first time, that TSLP-elicited basophils cooperate with DCs to promote CD4+ TH2 cell responses and that TSLP-elicited basophils can directly alter the activation state of DC populations. Collectively, these data provoke the hypothesis that TSLP-elicited basophils promote TH2 cytokine-mediated inflammation and protective immunity to Trichuris by influencing the activation status of DC populations. Based on my new data, two specific aims will address the following questions: (i) Do TSLP-elicited basophils promote protective immunity to Trichuris? (ii) Do TSLP-elicited basophils regulate DC populations in a manner that promotes TH2 cytokine responses and protective immunity to Trichuris? Collectively, these studies will interrogate the innate immune mechanisms through which TSLP promotes protective immunity to Trichuris. I anticipate that defining the mechanisms through which TSLP and basophils promote protective immunity will direct future clinical efforts to prevent and treat soil transmitted helminth infectins.

描述（由申请人提供）：目前估计全球有 20 亿人感染土壤传播的蠕虫感染，其中估计有 10 亿人感染鞭虫。蠕虫感染可导致严重营养不良、生长迟缓和长期残疾。此外，流行地区牲畜感染给当地社区带来巨大的经济负担。鉴于全球蠕虫感染的流行以及工业化国家过敏性疾病的流行，更好地了解控制 TH2 细胞因子介导的免疫和炎症的途径至关重要。 CD4+ TH2 细胞产生 IL-4、IL-5、IL-9 和 IL-13，其发育依赖于 IL-4R、STAT6 和 GATA3。此外，在 TH2 细胞因子反应的背景下激活的 B 细胞主要类别转换以产生抗原特异性 IgG1 和 IgE。组织中 2 型细胞因子驱动的炎症导致杯状细胞增生、粘液产生、平滑肌收缩力增加以及粒细胞群涌入。尽管我们对控制 TH2 细胞分化和调节的途径的理解取得了重大进展，但启动蠕虫或过敏原特异性 TH2 细胞反应的分子和细胞途径仍然不清楚。我之前的工作表明，TSLP 促进表型和功能独特、不依赖 IL-3 的嗜碱性粒细胞群体的群体扩张，并且 TSLP 诱导的嗜碱性粒细胞足以部分恢复通常易感 TSLPR 缺陷的鞭毛虫的 CD4+ TH2 细胞反应和保护性免疫老鼠。此外，我的新初步研究首次表明，TSLP诱导的嗜碱性粒细胞与DC合作促进CD4+ TH2细胞反应，并且TSLP诱导的嗜碱性粒细胞可以直接改变DC群体的激活状态。总的来说，这些数据提出了这样的假设：TSLP 诱导的嗜碱性粒细胞通过影响 DC 群体的激活状态来促进 TH2 细胞因子介导的炎症和对鞭毛虫的保护性免疫。根据我的新数据，两个具体目标将解决以下问题：（i）TSLP 诱导的嗜碱性粒细胞是否能促进对鞭毛虫的保护性免疫？ (ii) TSLP 诱导的嗜碱性粒细胞是否以促进 TH2 细胞因子反应和对鞭虫的保护性免疫的方式调节 DC 群体？总的来说，这些研究将探讨 TSLP 促进鞭虫保护性免疫的先天免疫机制。我预计，确定 TSLP 和嗜碱性粒细胞促进保护性免疫的机制将指导未来预防和治疗土壤传播的蠕虫感染的临床工作。