PGI2 augments Treg function

PGI2 增强 Treg 功能

• 批准号: 10582610
• 负责人: Ray Stokes Peebles
• 金额: $ 53.56万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-20 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10582610
• 关键词: Address; Adoptive Transfer; Allergens; Allergic; Allergic Disease; Allergic inflammation; Antigens; Asthma; Cell surface; Cells; Clinical; Data; Defect; Development; Epoprostenol; Equilibrium; FDA approved; FOXP3 gene; Goals; Human; Hypersensitivity; Immune Tolerance; Immune response; Immunosuppression; Impairment; Inflammatory; Interleukin-10; Interleukin-13; Interleukin-2; Interleukin-5; Link; Lung; Maintenance; Maps; Mediating; Modeling; Mus; Pathogenicity; Patients; Phenotype; Production; Publishing; Pulmonary Hypertension; Receptor Signaling; Regulatory T-Lymphocyte; Reporter; Reporting; Respiratory Disease; Signal Transduction; Surface; Testing; Therapeutic; Thymus Gland; Transforming Growth Factor beta; analog; clinically significant; cytokine; experimental study; immune system function; in vivo; in vivo Model; model organism; novel; pathogen; pharmacologic; prevent; receptor; response; restraint

An optimally functioning immune system requires a balance between protective responses against environmental pathogens and tolerogenic responses to innocuous environmental antigens. The breakdown of tolerance to harmless environmental antigens results in antigens becoming allergens that induce allergic inflammation and disease. Regulatory T cells (Treg) are central to the development and maintenance of tolerance to allergens; however, the mechanisms by which Treg fail to support tolerance in patients with allergic disease are not fully defined. In this application, our preliminary data strongly support that a host's inability to signal through the prostaglandin (PG)I2 receptor impedes immune tolerance and that treatment with PGI2 analogs promotes tolerance. Specifically, we found that defective PGI2 signaling in thymic Treg (tTreg) resulted in decreased Foxp3 expression, reduced suppressive function, inhibited IL-10 production, and downregulated inducible Treg (iTreg) differentiation. We also showed that Treg from mice deficient in the PGI2 receptor IP (IP KO) mice did not suppress type 2 cytokine production in an in vivo adoptive transfer model of allergic inflammation compared to Treg from WT mice. Therefore, our overarching hypothesis is that PGI2 promotes the immunosuppressive functions of Treg. To test this hypothesis, we have two specific aims. Specific Aim 1 is to determine the ability of endogenous PGI2 signaling to promote Treg function. In this aim we hypothesize that: a) antigen-specific Treg that have deficient PGI2 signaling have inhibited suppression of the cardinal features of asthma compared to antigen-specific WT Treg, b) PGI2 signaling promotes Treg stability in the setting of allergen challenge, and c) PGI2 signaling restrains ST2 expression on Treg, and that a deficiency of PGI2 signaling corrupts Treg function promoting the development of pathogenic IL-13 expressing ST2+ Treg. Specific Aim 2 is to determine the ability of exogenous PGI2 signaling to promote Treg function. In this aim we hypothesize that: a) PGI2 analog treatment of Treg ex vivo enhances the ability of iTreg to restrain allergic inflammation, b) exogenous administration of a PGI2 analog increases Treg function to suppress allergic inflammation, and c) PGI2 analogs enhance IL-10 production and suppressive function by human iTreg in response to activation with IL-2 and TGF-β. These studies are paradigm shifting because there are currently no known pharmacologic agents which promote Treg function and our preliminary data strongly supports that PGI2 may be the first described. The proposed experiments using human cells and mice will advance the field in that they will further define the mechanisms by which Treg function is regulated. The current availability of PGI2 for human treatment highlights the clinical significance of our studies as this therapy could be immediately repurposed for the treatment of allergic respiratory diseases such as asthma.

最佳运行的免疫系统需要在保护反应和预防 环境病原体和对无害环境抗原的耐受性反应。的细目 对无害环境抗原的耐受会导致抗原变成过敏原，从而引起过敏 炎症和疾病。调节性T细胞(Treg)是发育和维持的中心。 对过敏原的耐受性；然而，Treg未能支持患者对过敏原的耐受性的机制 过敏性疾病还没有完全定义。在此应用程序中，我们的初步数据有力地支持了主机的 无法通过前列腺素(PG)I2受体发出信号会阻碍免疫耐受，而治疗 PGI2类似物促进耐受性。特别是，我们发现胸腺Treg(TTreg)中有缺陷的PGI2信号 导致Foxp3表达减少，抑制功能降低，抑制IL-10产生，以及 下调诱导的Treg(ITreg)分化。我们还发现，来自PGI2缺陷小鼠的Treg 受体IP(IP KO)小鼠在体内过继转移模型中不抑制2型细胞因子的产生 与来自WT小鼠的Treg相比，过敏性炎症。因此，我们的首要假设是PGI2 促进Treg的免疫抑制功能。为了检验这一假设，我们有两个具体目标。 具体目的1是确定内源性PGI2信号促进Treg功能的能力。在这 目的我们假设：a)具有缺陷的PGI2信号的抗原特异性Treg抑制了抑制 在哮喘与抗原特异性的WT Treg相比的基本特征中，b)PGI2信号促进Treg 在变应原攻击设置中的稳定性，以及c)PGI2信号抑制Treg上ST2的表达，并且a PGI2信号通路缺陷破坏Treg功能促进致病IL-13表达 ST2+Treg.具体目的2是确定外源PGI2信号促进Treg的能力 功能。为此，我们假设：a)PGI2类似物体外处理Treg可增强 ITreg可抑制过敏性炎症，b)外源性给予PGI2类似物可增加Treg功能以 抑制过敏性炎症，以及c)PGI2类似物通过以下途径增强IL-10的产生和抑制功能 人iTreg对IL-2和转化生长因子-β激活的反应。这些研究正在转变范式，因为 目前还没有已知的促进Treg功能的药理药物和我们的初步数据 强烈支持PGI2可能是第一个被描述的。拟议中的实验使用了人类细胞和小鼠 将推动这一领域的发展，因为他们将进一步定义Treg功能的调节机制。这个 目前PGI2用于人类治疗的可用性突出了我们研究的临床意义，因为 治疗方法可以立即改变用途，用于治疗哮喘等过敏性呼吸道疾病。