Selective Aryl Hydrocarbon Receptor Modulators and T cell Effector Function

项目摘要 转录因子芳香烃受体(AhR)与小分子相互作用，调节T 辅助性T细胞分化和细胞因子分泌。然而，AhR可以与激动剂相互作用，纯 拮抗剂或选择性AhR调节剂(SAhRm)，它们对Th细胞功能有不同的影响。 慢性呼吸道炎症性疾病影响全球超过3亿人，高达11% 仅在美国的人口中。目前慢性气道炎是可以控制的 治愈，使它们成为发达国家医疗保健系统最昂贵的疾病之一。 慢性气道炎的一个特征是Th细胞因子、白介素4、5、13或 IL17A、IL17F和IL22影响肺部炎症和呼吸道高反应性。当前 治疗主要围绕使用皮质类固醇来抑制炎症，虽然 有效，有显著的副作用。最近针对哮喘的这些细胞因子的研究使用 单抗正在通过临床，但一种潜在的有效方法 可能是在炎症过程中对Th细胞因子反应的小分子操纵。我们 提示AhR配体的这种功能差异可能被利用来操纵T辅助分子 呼吸道炎症中的细胞因子，从而减少炎症。因此，此应用程序的目标是 确定AhR配体、激动剂、SAhRM和拮抗剂调节Th的机制 细胞因子分泌与呼吸道炎症。我们将检验假设，不同类别的芳基 碳氢受体配体差异调节AhR功能以调节T辅助细胞分化和 功能，从而调节呼吸道炎症。我们的具体目标是：1)确定 AHR配体和SAhRM调节呼吸道炎症，以及2)确定AhR配体的作用 和SAhRms在调节T细胞分化中的作用。这项工作极具创新性，因为我们有 一种令人兴奋的假设，即不同类别的AhR配体能够不同地调节AhR 功能，从而在呼吸道炎症过程中调控Th的分化。我们还提出了 研究这些选择性AhR配体改变Th分化的机制的新方法。 此外，我们还组建了一支独特的团队，在免疫分析方面拥有深厚的专业知识 呼吸道炎症的基础，以及在AhR和配体研究方面的杰出专业知识，如 SAHRMS。这种结合为Th细胞因子中AhR的研究带来了无与伦比的协同作用 回应。因此，我们的工作对治疗慢性呼吸道疾病的方法有直接的影响 人类的炎症性疾病，如哮喘和过敏性肺炎，如 AHR的小分子调节剂对T细胞的应答可能会影响这些疾病。

Project Summary The transcription factor Aryl Hydrocarbon receptor (AhR) interacts with small molecules and modulates T helper (Th) cell differentiation and cytokine secretion. However, the AhR can interact with agonists, pure antagonists, or Selective AhR Modulators (SAhRMs), which have different effects on Th cell function. Chronic airway inflammatory diseases affect greater than 300 million people worldwide, with up to 11% of the population of the United States alone. Currently chronic airway inflammation can be controlled not cured, making them among the most expensive diseases for healthcare systems in developed countries. A hallmark of chronic airway inflammation is the increase in Th cytokines, Interleukins (IL) 4, 5, 13, or IL17A, IL17F and IL22 that affect inflammation in the lung and airways hyper responsiveness. Current therapies largely revolve around the use of corticosteroids for suppression of inflammation, which while effective, have significant side effects. More recent efforts targeting these cytokines in asthma using monoclonal antibodies are moving their way through the clinic, but one potentially powerful approach would be small molecule manipulation of the Th cytokine response during the inflammatory process. We suggest that such functional differences in AhR ligands may be exploited to manipulate T helper cytokines in airway inflammation, thus reducing it. The objective of this application is therefore to determine the mechanism by which AhR ligands, agonist, SAhRM and antagonist, act to modulate Th cell cytokine secretion and airway inflammation. We will test the hypothesis that different classes of Aryl hydrocarbon Receptor ligands differentially regulate AhR function to tune T helper cell differentiation and function, thereby modulating airway inflammation. Our specific aims are to: 1) determine the ability of AhR ligands and SAhRMs to modulate airway inflammation, and 2) determine the role of AhR ligands and SAhRMs in modulating T cell differentiation. This work is extremely innovative because we have an exciting hypothesis that different classes of AhR ligands are able to differentially regulate AhR function, and thus manipulate Th differentiation during airway inflammation. We have also proposed novel approaches to study the mechanism by which these selective AhR ligands alter Th differentiation. Furthermore, we have assembled a unique team, with deep expertise in analysis of the immunological basis for airway inflammation, and outstanding expertise in the study of the AhR and ligands such as SAhRMs. This combination brings incomparable synergy to the study of the AhR in Th cytokine responses. Our work therefore has immediate implications on approaches to treat chronic airway inflammatory diseases such as asthma and Hypersensitivity pneumonitis in humans, as manipulation of the T cell response with small molecule modulators of the AhR may be able to affect these diseases.