Complement Signaling and Treg Cells

补体信号传导和 Treg 细胞

• 批准号: 7150335
• 负责人: John Atkinson
• 金额: $ 24.27万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7150335
• 关键词: CD antigens; DNA binding protein; T cell receptor; T lymphocyte; acute bronchitis; asthma; biological signal transduction; complement; complement pathway regulation; disease /disorder etiology; disease /disorder proneness /risk; helper T lymphocyte; host organism interaction; human subject; immune response; immunogenetics; immunoregulation; laboratory mouse; lung lavage; parainfluenza virus type 1; respiratory infections; transcription factor; virus infection mechanism

The pathogenesis of asthma results from interactions between the innate (Project 1) and adaptive (Project 3) immune systems. A subset of immune cells, regulatory CD4+ T cells, play an important role in suppression of both innate and adaptive responses. Although there are indications that regulatory T cells participate in asthma, much remains to be learned before therapeutic interventions can be entertained. The goal of the first part of this Project is to better define the role of complement regulator (CD46) activated human T cells, which appear to represent a unique adaptive regulatory T cell subset. In Aim 1, we will determine if complement activation plays an important role in asthma, as well as providing a physiologic in vivo stimulus for these adaptive regulatory T cells. We will ask if genetic deficiency in various complement components (beginning with C3) modulates the Sendai virus-induced acute infection and the chronic asthma phenotype in mice (as described in Project 1). We will also determine whether markers of altered complement activation occur in situ in human patients with asthma. In Aim 2, we will look for the presence of T cells with the CD46 adaptive regulatory T cell phenotype in human patients with asthma. We will also determine if human CD46 adaptive regulatory T cells inhibit the function of pathogenic cells in asthma (Th2 cells and B cells). If so, this would argue for further studies into the use of these adaptive regulatory cells for the treatment of asthma. In the second part of this Project, we will complement the above studies on adaptive regulatory T cells and define the role of natural regulatory T cells in a mouse model of asthma. By moving to this model, we can utilize a newly described marker Foxp3-GFP for natural regulatory T cells to facilitate studies of natural regulatory T cell specificity. In summary, our goal is to further address the role of the complement system in asthma and whether adaptive or natural regulatory T cells participate in controlling the severity of asthma. Both avenues represent attractive therapeutic targets for the treatment of asthma. Asthma is a growing problem in the United States, but current therapies are expensive, chronic, and, unfortunately not curative. By exploring the body's innate immune system and natural regulatory mechanisms that inhibit excessive pathology, our hope is that curative therapies can eventually be generated not requiring global immunosuppression.

哮喘的发病机制是先天性（项目1）和适应性（项目3）之间相互作用的结果 免疫系统免疫细胞的一个亚群，调节性CD 4 + T细胞，在抑制肿瘤细胞增殖中发挥重要作用。 先天和适应性反应。尽管有迹象表明调节性T细胞参与了 哮喘，在治疗干预可以被接受之前，还有很多事情要了解。的目标 本项目的第一部分是更好地定义补体调节因子（CD 46）激活的人T细胞的作用， 它们似乎代表了一种独特的适应性调节性T细胞亚群。在目标1中，我们将确定 补体激活在哮喘中起重要作用，以及提供生理性体内刺激 这些适应性调节性T细胞。我们会问，如果遗传缺陷，在各种补体成分， （从C3开始）调节仙台病毒诱导的急性感染和慢性哮喘表型 在小鼠中（如项目1中所述）。我们还将确定补体激活改变的标志物 发生在人类哮喘患者体内。在目标2中，我们将寻找具有CD 46的T细胞的存在。 哮喘患者的适应性调节性T细胞表型。我们还将确定人类CD 46 适应性调节性T细胞抑制哮喘中致病细胞（Th 2细胞和B细胞）的功能。如果是这样， 将进一步研究这些适应性调节细胞用于治疗哮喘。在 在本项目的第二部分，我们将补充上述关于适应性调节性T细胞的研究， 定义自然调节性T细胞在哮喘小鼠模型中的作用。通过这个模型，我们可以 利用新描述的天然调节性T细胞的标志物Foxp 3-GFP，以促进天然调节性T细胞的研究。 调节性T细胞特异性。总之，我们的目标是进一步解决补体系统在 以及适应性或自然调节性T细胞是否参与控制哮喘的严重程度。 这两种途径都代表了治疗哮喘的有吸引力的治疗靶点。哮喘是一种 这个问题在美国，但目前的治疗是昂贵的，慢性的，不幸的是没有治愈。 通过探索人体的先天免疫系统和抑制过度免疫的自然调节机制， 病理学，我们的希望是，治愈性疗法最终可以产生不需要全球 免疫抑制