Complement Signaling and Treg Cells

哮喘的发病机制是先天(方案1)和后天(方案3)相互作用的结果 免疫系统。免疫细胞的一个亚群，调节性的CD4+T细胞，在抑制中起着重要的作用 先天反应和后天反应。尽管有迹象表明，调节性T细胞参与了 哮喘，在进行治疗干预之前仍有许多需要了解的地方。的目标是 该项目的第一部分是为了更好地确定补体调节因子(CD46)激活的人类T细胞的作用， 它们似乎代表独特的适应性调节T细胞亚群。在目标1中，我们将确定是否 补体激活在哮喘中起重要作用，并在体内提供生理性刺激。 这些适应性调节性T细胞。我们会问，各种补体成分是否存在遗传缺陷 (以C3开始)调节仙台病毒诱导的急性感染和慢性哮喘表型 在小鼠身上(如项目1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的原地。在目标2中，我们将寻找具有CD46的T细胞的存在 人类哮喘患者的适应性调节性T细胞表型。我们还将确定人类CD46是否 适应性调节性T细胞抑制哮喘发病细胞(Th2细胞和B细胞)的功能。如果是这样的话，这个 将主张对使用这些适应性调节细胞治疗哮喘进行进一步研究。在……里面 本项目的第二部分，我们将补充上述关于适应性调节性T细胞和 明确自然调节性T细胞在哮喘小鼠模型中的作用。通过转向这种模式，我们可以 利用新描述的天然调节性T细胞标志物Foxp3-GFP促进天然 调节性T细胞特异性。总而言之，我们的目标是进一步解决补充制度在 哮喘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。 这两种方法都是治疗哮喘的有吸引力的治疗靶点。哮喘是一种日益严重的 这在美国是一个问题，但目前的治疗方法昂贵、慢性，而且不幸的是无法治愈。 通过探索人体的先天免疫系统和自然调节机制来抑制过度 病理学，我们希望最终可以产生不需要全球合作的根治疗法 免疫抑制。

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.