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

IL-7/IL-7R 通路在斑秃中的功能研究

基本信息

批准号：
9314845
负责人：
Zhenpeng Dai
金额：
$ 12.6万
依托单位：
COLUMBIA UNIVERSITY HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9314845
关键词：
Address Adolescent Alopecia Areata Autoimmune Diseases Autoimmunity Blood C3H/HeJ Mouse CD8B1 gene Cell Survival Cell physiology Cells Child Clinical Complex Cytokine Gene Data Development Disease Disease Progression Disease model Effector Cell Environment Exhibits Experimental Autoimmune Encephalomyelitis FDA approved Feedback Frequencies Genetic Transcription Goals Hair Hair follicle structure Homeostasis Human IL7 gene IL7R gene Immune Immune response Immunosuppressive Agents Inflammatory Influentials Innovative Therapy Insulin-Dependent Diabetes Mellitus Interferon Type II Interleukin-7 Knock-out Knockout Mice Knowledge Ligands Light Link Lymphocyte Mediating Modeling Molecular Molecular Profiling Morbidity - disease rate Multiple Sclerosis Mus Organ Pathogenesis Pathogenicity Pathway interactions Patients Peripheral Peripheral Blood Mononuclear Cell Pharmacology Play Production Research Research Personnel Role Safety Scalp structure Serum Severity of illness Signal Pathway Signal Transduction Skin System T cell response T memory cell T-Cell Activation T-Cell Development T-Lymphocyte Testing Therapeutic Therapeutic Intervention Tissue Sample clinical investigation cytokine effective therapy genetic signature humanized mouse improved in vivo mouse model novel therapeutics patient subsets peripheral tolerance prevent psychosocial receptor research clinical testing skin lesion targeted treatment transcriptome treatment response

项目摘要

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.

项目概要斑秃 (AA) 是最常见的自身免疫性疾病之一，会导致毁容性脱发，由于没有FDA，它会带来显着的心理社会发病率，特别是在儿童和青少年中。 AA 的治疗方法已获批准，因此确定具有改进的安全性的靶向疗法将是一个重要的问题我们最近发现 CD8+NKG2D+ T 细胞是 AA 中指导我们研究的关键致病细胞。以确定驱动其激活和功能的炎症细胞因子。分析数据显示，白细胞介素 7 (IL-7) 及其受体 (IL-7Rα) 在 AA 病变中上调 IL-7 是淋巴细胞发育和存活所必需的细胞因子，尽管 IL-7 及其受体具有。虽然 IL-7 与其他几种自身免疫性疾病有关，但 IL-7 在 AA 发病机制中的作用尚不清楚。我们的初步数据表明，IL-7 在 AA 中发挥着关键作用，这通过治疗益处得到了强调尽管 IL-7 的作用已在 AA 的 C3H/HeJ 小鼠模型中得到了充分研究。 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 AA 中的疾病环境和致病性 T 细胞反应，特别是在体内，在该提案的具体目标 1 中，我们将评估 IL-7 与脱发之间的联系。体内 T 细胞使用逆转录 TCR 系统在野生型或 IL-7 敲除中诱导自发 AA 尽管 AA 中 IL-7 的表达上调，但对其机制知之甚少。调节 AA 中皮肤 IL-7 的产生。在具体目标 1 中，我们假设产生 IFN-γ 的反馈循环。毛囊浸润 T 效应细胞，进而促进皮肤 IL-7 的产生和 T 细胞的存活实际上，我们发现IL-7Rα阻断增加了免疫抑制的表达。 T 效应细胞上的受体 PD-1，而 IL-7 则抑制 T 细胞上 PD-1 的表达。 PD-1 在 AA 发病机制中的作用尚未得到研究。该提案的具体目标 2，我们将首先通过 PD-1 通路阻断来解决 PD-1 在 AA 中的作用。鉴于 IL-7 阻断在治疗人类 AA 中的治疗潜力，我们将确定 IL-7 的作用通过确定血清 IL-7 是否与疾病参数相关，研究人类 AA 发病机制中的 7 评估特定目标 3 中 IL-7 诱导的细胞因子产生。最重要的是，我们将定义一个子集由于 AA 分子环境，患者的 AA 头皮转录组和 IL-7 基因特征 AA 的情况很复杂，具有相似 AA 表现的患者对治疗的反应也不同。总体而言，拟议的研究与申请人成为独立研究人员的目标高度一致皮肤自身免疫性疾病领域的研究者这项研究的结果将增进我们的理解。 AA 的发病机制，评估 IL-7 在毛囊终末器官耐受性丧失中所起的作用，并帮助我们评估针对 AA 中 IL-7/IL-7R 通路的治疗干预措施。