Helminth-Induced Immune Tolerance in Asthma

蠕虫引起的哮喘免疫耐受

• 批准号: 6928575
• 负责人: Joel N Kline
• 金额: $ 22.13万
• 依托单位: UNIVERSITY OF IOWA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6928575
• 关键词: Nematoda; asthma; cytokine; genetically modified animals; helminthic antigen; helper T lymphocyte; immune tolerance /unresponsiveness; immunoregulation; inflammation; laboratory mouse; lung; parasitism; pathologic process

DESCRIPTION (provided by applicant): Asthma, a disease of increasing prevalence and severity, is characterized by eosinophilic airway inflammation induced by excessive and inappropriate Th2 responses to environmental antigens. The "hygiene hypothesis" suggests that reduced rates of atopy and asthma in non-industrialized populations are due to protective "anti-atopic" responses to microbes. Although microbe-induced Th1 responses have been invoked as a mechanism of this protection, non-atopic individuals do not have elevated Th1 cytokines, and excessive Th1-type responses can be equally deleterious as Th2 responses. Moreover, even infections characterized by Th2 patterns, as is the case with helminths, are associated with reduced prevalence and severity of asthma and atopy. Recent studies have suggested that helminth infections induce regulatory-type immune responses; these responses may promote long-term tolerance against the development of atopic sensitization. The overall goal of this proposal is to investigate the mechanisms through which intestinal helminthes modulate atopic sensitization and airway inflammation in asthma. The central hypothesis is that intestinal helminthes can inhibit airway inflammation in asthma by induction of regulatory T-lymphocytes and/or regulatory dendritic cells. We will explore this hypothesis using a murine model of asthma in the following specific aims: Aim 1. Determine whether and how intestinal helminths prevent aberrant Th2 immune responses in the airway. A. Study the effect of intestinal worm exposure on a murine model of atopic asthma. B. Investigate if IL-10 or other soluble immunoregulatory cytokines are induced locally in the gut or in regional lymphoid tissues and mediate the protective process. C. Determine the cellular sources of these regulatory cytokines. Aim 2. Ascertain if helminths induce formation of regulatory T cells that mediate protection against atopic asthma. A. Identify and characterize regulatory T cells that appear in the lung after worm exposure. B. Study mechanisms leading to development of regulatory T cells. C. Determine if these regulatory T cells are sufficient to protect mice from Th2-mediated atopic asthma. In Aim I, we will examine the effects of helminths on manifestations of atopic asthma in a murine model, including the development of pulmonary Th2 cytokine production, airway eosinophilia, bronchial hyperresponsiveness, and antigen-specific immunoglobulin induction. We will study the induction of immunoregulatory cytokines, and identify the source of these mediators. Aim II will expand on these observations by testing the hypothesis that intestinal helminths induce regulatory cells (dendritic cells and/or regulatory T-lymphocytes) in the gut that migrate to the lung; we will determine how such regulatory cells limit pulmonary Th2 responses, study mechanisms leading to development of these cells and explore whether these cells can suffice to protect from asthma. Although completion of the second Aim is almost certainly beyond the scope of this two-year developmental research grant, these studies will be continued and extended through an R01 grant application.

描述(由申请人提供)：哮喘是一种发病率和严重性不断增加的疾病，其特征是由于Th2对环境抗原的过度和不适当的反应而引起的嗜酸性呼吸道炎症。“卫生假说”表明，非工业化人群中过敏症和哮喘发病率的降低是由于对微生物的保护性“抗过敏性”反应。尽管微生物诱导的Th1反应已被用作这种保护的一种机制，但非特应性个体并不具有升高的Th1细胞因子，过度的Th1型反应可能与Th2反应一样有害。此外，即使是以Th2模式为特征的感染，如蠕虫，也与哮喘和特应性疾病的患病率和严重性降低有关。最近的研究表明，蠕虫感染诱导调节型免疫反应；这些反应可能促进对特应性致敏发展的长期耐受性。这项建议的总体目标是研究肠道蠕虫调节哮喘特应性致敏和呼吸道炎症的机制。中心假设是肠道蠕虫可以通过诱导调节性T淋巴细胞和/或调节性树突状细胞来抑制哮喘患者的呼吸道炎症。我们将使用哮喘的小鼠模型来探索这一假设，具体目的如下：1.确定肠道蠕虫是否以及如何阻止呼吸道中异常的Th2免疫反应。A.研究肠道蠕虫暴露对特应性哮喘小鼠模型的影响。B.调查IL-10或其他可溶性免疫调节细胞因子是否在肠道或局部淋巴组织中局部诱导，并介导保护过程。C.确定这些调节性细胞因子的细胞来源。目的2.确定蠕虫是否诱导调节性T细胞的形成，从而介导对特应性哮喘的保护。A.识别和表征暴露于蠕虫后出现在肺内的调节性T细胞。B.研究调节性T细胞发育的机制。C.确定这些调节性T细胞是否足以保护小鼠免受Th2介导的特应性哮喘的影响。在目标I中，我们将在小鼠模型中检测蠕虫对特应性哮喘表现的影响，包括肺Th2细胞因子的产生、呼吸道嗜酸性粒细胞增多、支气管高反应性和抗原特异性免疫球蛋白诱导。我们将研究免疫调节性细胞因子的诱导，并确定这些介质的来源。目的II将通过测试肠道蠕虫诱导肠道中的调节性细胞(树突状细胞和/或调节性T淋巴细胞)迁移到肺的假设来扩展这些观察；我们将确定这些调节性细胞如何限制肺内Th2反应，研究导致这些细胞发育的机制，并探索这些细胞是否足以预防哮喘。虽然完成第二个目标几乎肯定超出了这项为期两年的发展研究补助金的范围，但这些研究将通过R01补助金申请继续和延长。