Functional Studies of the IL-7/IL-7R Pathway in Alopecia Areata

项目摘要 斑秃(AA)是最常见的导致脱发的自身免疫性疾病之一， 患有严重的社会心理疾病，特别是在儿童和青少年中。因为没有食品和药物管理局 对于已批准的再生障碍性贫血的治疗，确定具有更好安全性的靶向治疗将是 有很大的进步。我们最近发现CD8+NKG2D+T细胞是再生障碍性贫血的关键致病细胞 努力确定推动其激活和功能的炎性细胞因子。我们的基因转录 资料显示，白介素7(IL-7)及其受体(IL-7Rα)在AA皮损中表达上调 皮肤。IL-7是淋巴细胞发育和存活所必需的细胞因子。尽管IL-7及其受体 IL-7与其他几种自身免疫性疾病有关，但其在再障发病机制中的作用尚不清楚。 我们的初步数据显示，IL-7在再生障碍性贫血中起着关键作用，这一点得到了治疗益处的强调 IL-7对再障C3H/HeJ小鼠模型的阻断作用。尽管IL-7的作用已经在 T细胞的发育、稳态增殖和存活，IL-7/IL-7R的机制 信号通路影响再生障碍性贫血的疾病设置和致病性T细胞反应，特别是在体内。 没有得到充分的解决。在本提案的具体目标1中，我们将评估IL-7和脱发之间的联系 利用逆转录TCR系统在体内诱导野生型或IL-7基因敲除的自发性再生障碍性贫血 背景资料。尽管再生障碍性贫血患者IL-7的表达上调，但其机制尚不清楚。 调节再生障碍性贫血患者皮肤IL-7的产生。在具体目标1中，我们假设了一个产生干扰素-γ的反馈循环 通过毛囊渗透T效应细胞，进而促进皮肤IL-7的产生和T细胞的存活 淋巴细胞。有趣的是，我们发现IL-7Rα阻断增加了免疫抑制的表达 受体PD-1在T效应细胞上表达，而IL-7抑制T细胞上PD-1的表达。PD-1扮演着中心角色 在外周耐受性中的作用。PD-1在再生障碍性贫血发病机制中的作用尚未得到研究。在……里面 本提案的具体目标2，我们将首先通过阻断PD-1通路来探讨PD-1在再障中的作用。最后， 鉴于IL-7阻断在治疗人类再障中的治疗潜力，我们将确定IL-7的作用。 7通过确定血清IL-7是否与疾病参数相关，从而在人类再障的发病机制中发挥作用 评估IL-7诱导的细胞因子产生的特定目的3。最重要的是，我们将定义一个子集 患者中AA头皮转录组和IL-7基因的签名是因为AA的分子环境 是复杂的，具有相似AA表现的患者对治疗的反应各不相同。 总体而言，拟议的研究与申请者成为独立人士的目标非常一致 皮肤自身免疫性疾病领域的研究人员。这项研究的结果将促进我们的理解 在再生障碍性贫血的发病机制中，评估IL-7在毛囊终器耐受性丧失中所起的作用， 并帮助我们评估针对再障患者IL-7/IL-7R途径的治疗干预措施。

Project Summary Alopecia areata (AA) is one of the most common autoimmune diseases resulting in disfiguring hair loss, and carries significant psychosocial morbidity especially in children and adolescents. Since there are no FDA approved treatments for AA, the identification of targeted therapies with an improved safety profile would be a substantial advance. We recently identified CD8+NKG2D+ T cells as the key pathogenic cells in AA guiding our efforts to identify inflammatory cytokines that drive their activation and function. Our gene transcriptional profiling data showed that interleukin-7 (IL-7) as well as its receptor (IL-7Rα) are upregulated in AA lesional skin. IL-7 is a cytokine essential for lymphocyte development and survival. Although IL-7 and its receptor have been implicated in several other autoimmune diseases, the role of IL-7 in the pathogenesis of AA is unknown. Our preliminary data show that IL-7 plays a critical role in AA which was underscored by the therapeutic benefit of IL-7 blockade in C3H/HeJ mouse model of AA. Although the role of IL-7 has been well studied in development, homeostatic proliferation, and survival of T cells, the mechanism by which the IL-7/IL-7R signaling pathway influences disease settings and pathogenic T cell responses in AA, particularly in vivo, has not been fully addressed. In Specific Aim 1 of this proposal, we will assess the link between IL-7 and alopecic T cells in vivo using a retrogenic TCR system to induce spontaneous AA in wild type or IL-7 knockout background. Although the expression of IL-7 is upregulated in AA, little is known about the mechanisms that regulate skin IL-7 production in AA. In Specific Aim 1, we postulate a feedback loop in which IFN-γ is produced by hair follicle infiltrating T effector cells, which in turn promotes skin IL-7 production and the survival of T lymphocytes. Interestingly, we have found that IL-7Rα blockade increases the expression of immune inhibitory receptor PD-1 on T effector cells, whereas IL-7 inhibits the expression of PD-1 on T cells. PD-1 plays a central role in peripheral tolerance. The role of PD-1 in the pathogenesis of AA has not been yet investigated. In Specific Aim 2 of this proposal, we will first address the role of PD-1 in AA by PD-1 pathway blockade. Lastly, given the therapeutic potential of IL-7 blockade in the treatment for human AA, we will determine the role of IL- 7 in pathogenesis of human AA by determining if serum IL-7 correlates with parameters of disease, by evaluating the IL-7-induced cytokine production in Specific Aim 3. Most importantly, we will define a subset of patients in which the AA scalp transcriptome and IL-7 gene signature because the AA molecular environment is complex and patients with seemingly similar AA presentations have heterogeneous responses to treatment. Overall, the proposed research is strongly aligned with the applicant’s goal of becoming an independent investigator in the field of skin autoimmune diseases. The results of this study will advance our understanding of the pathogenesis of AA, evaluate the role that IL-7 plays in the loss of tolerance in the hair follicle end-organ, and aid us in evaluating therapeutic interventions that target the IL-7/IL-7R pathway in AA.