Role of basophils in the immune response to filariae

嗜碱性粒细胞在丝虫免疫反应中的作用

• 批准号: 7479961
• 负责人: EDWARD E MITRE
• 金额: $ 5.4万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-15 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7479961
• 关键词: Address; Allergic; Antigens; Area; Arthropods; Automobile Driving; B-Lymphocytes; Basophils; Blood specimen; CD4 Positive T Lymphocytes; Cells; Communicable Diseases; Data; Development; Disease; Eosinophilia; Flow Cytometry; Frequencies; Functional disorder; Goals; Helminths; Human; Hypersensitivity; IgE; Immune; Immune response; Immune system; Infection; Interleukin-13; Interleukin-4; Interleukin-5; Knowledge; Laboratories; Leukocytes; Measures; Mediating; Memory; Methods; Patients; Peripheral; Phenotype; Physiological; Play; Postdoctoral Fellow; Production; Range; Research; Research Personnel; Research Project Grants; Role; Serum; Source; T memory cell; T-Lymphocyte; Testing; Vaccines; Whole Blood; Work; base; burden of illness; enzyme linked immunospot assay; expectation; filaria; immunoregulation; innovation; programs; response; vaccine development

Filariae are arthropod-bornetissue-dwelling helminths that are a majorworldwide burden of disease. They typically cause a type 2 immune responsecharacterizedby eosinophilia, elevated serum levels of Ag- specific and polyclonal IgE, and increases in T-cell production of IL-4, IL-5, and IL-13. This type 2 response is likely helpful in controlling helminth infections. While it is clear that IL-4 plays a central role in driving type 2 responses, the exact factors responsible for triggering and maintaining prolonged type 2 immune responses in filarial infections remain unknown. These gaps in our knowledge are problematic becausethey impair our ability to develop helminth-specific vaccinesthat produce long-standing type 2 immune responses with high titers of Ag-specific IgE. Because they are the least common peripheral leukocyte andbecause they are difficult to work with, the role basophils play in the immune response to infectious diseases has largely gone unstudied. However,recent evidence demonstratesthat basophils are major contributorsto the IL-4 pool in ftlaria-infected humans, suggesting they may play an important role in the immune response to filarial infections. The objective of this appliation is to characterize the role basophils play in initiating and maintaining type 2 responses in filarial infections. The central hypothesis being tested is: sustained production of filarial-specific IgE by B cells enables basophils to coordinate a rapid Type 2 memoryresponse following filarial exposure by releasing large quantities of IL-4 and by driving naive T-cells toward a type 2 phenotype. This hypothesis will be addressed by pursuing the following aims. Specific Aim 1: To determine whether basophils can be activated by filarial antigen to release IL-4 non-specifically. Specific Aim 2: To determine whether Ag-specific IgE production and Ag-specific IgE-mediated basophil activation persists in the context of treated filarial infections. Specific Aim 3: To determine the role basophils play in driving naive T cells toward a type 2 phenotype.

丝虫是节肢动物出生组织寄生的蠕虫，是世界范围内主要的疾病负担。他们 典型地引起以嗜酸性粒细胞增多症为特征的2型免疫反应，血清中Ag- 特异性和多克隆性IgE，增加T细胞产生IL-4、IL-5和IL-13。此类型2响应 可能有助于控制蠕虫感染。虽然很明显，IL-4在驾驶类型中起着核心作用 2反应，触发和维持持久的2型免疫的确切因素 对丝虫感染的反应仍不清楚。我们知识中的这些差距是有问题的，因为它们 削弱我们开发产生长期2型免疫反应的蠕虫特异性疫苗的能力 高滴度的抗原特异性免疫球蛋白E。因为它们是最不常见的外周血细胞 它们很难处理，嗜碱性细胞在传染病免疫反应中所起的作用 很大程度上没有人研究过。然而，最近的证据表明，嗜碱性粒细胞是导致 Ftlaria感染者体内的IL-4池，提示它们可能在免疫应答中发挥重要作用 丝虫病。这项应用的目的是表征嗜碱性细胞在启动和 在丝虫病感染中维持II型反应。正在测试的中心假设是：持续 B细胞产生丝虫特异性IgE使嗜碱性粒细胞能够协调快速的2型记忆反应 丝虫病暴露后，通过释放大量IL-4和驱动幼稚T细胞向2型转化 表型。这一假设将通过追求以下目标来解决。具体目标1：确定 嗜碱性粒细胞能否被丝虫抗原激活而非特异性地释放IL-4。具体目标2： 确定Ag-特异性IgE产生和Ag-特异性IgE介导的嗜碱性细胞激活是否持续存在 治疗丝虫病的背景。具体目标3：确定嗜碱性细胞在驱使幼稚方面所起的作用 T细胞向2型表型转化。