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: 6963963
• 负责人: EDWARD E MITRE
• 金额: $ 16.14万
• 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/6963963
• 关键词: antigens; clinical research; immune response; infection; motivation; play; role

DESCRIPTION (provided by applicant): Filariae are arthropod-borne tissue-dwelling helminths that are a major worldwide burden of disease. They typically cause a type 2 immune response characterized by 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 because they impair our ability to develop helminth-specific vaccines that produce long-standing type 2 immune responses with high titers of Ag-specific IgE. Because they are the least common peripheral leukocyte and because they are difficult to work with, the role basophils play in the immune response to infectious diseases has largely gone unstudied. However, recent evidence demonstrates that basophils are major contributors to the IL-4 pool in filaria-infected humans, suggesting they may play an important role in the immune response to filarial infections. The objective of this application 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 memory response 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.

描述(申请人提供)：丝虫是节肢动物传播的组织寄生蠕虫，是世界范围内主要的疾病负担。它们通常会引起以嗜酸性粒细胞增多为特征的2型免疫反应，升高血清中抗原特异性和多克隆IgE水平，并增加T细胞产生IL-4、IL-5和IL-13。这种2型反应可能有助于控制蠕虫感染。虽然很明显，IL-4在驱动2型免疫反应中起着核心作用，但在丝虫感染中触发和维持持久的2型免疫反应的确切因素仍不清楚。我们知识中的这些差距是有问题的，因为它们损害了我们开发蠕虫特异性疫苗的能力，这种疫苗产生具有高滴度抗原特异性IgE的长期存在的2型免疫反应。因为它们是最不常见的外周白细胞，而且它们很难处理，所以嗜碱性细胞在传染病免疫反应中所起的作用在很大程度上还没有被研究过。然而，最近的证据表明，嗜碱性粒细胞是丝虫感染者IL-4池的主要贡献者，这表明它们可能在丝虫感染的免疫反应中发挥重要作用。本申请的目的是描述嗜碱性粒细胞在丝虫感染中启动和维持2型反应中所起的作用。正在测试的中心假设是：B细胞持续产生丝虫特异性IgE，使嗜碱性粒细胞能够通过释放大量IL-4和驱动幼稚的T细胞向2型表型转变，来协调丝虫暴露后快速的2型记忆反应。这一假设将通过追求以下目标来解决。具体目的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：确定在治疗丝虫感染的背景下，是否存在Ag特异性IgE产生和Ag特异性IgE介导的嗜碱性细胞激活。具体目标3：确定嗜碱性粒细胞在推动幼稚T细胞向2型表型转变中所起的作用。