Determining the role of T cell effector functions in Alopecia Areata

确定 T 细胞效应功能在斑秃中的作用

• 批准号: 10664944
• 负责人: Ali Jabbari
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10664944
• 关键词: 20 year old; Address; Adoptive Transfer; Affect; Alopecia Areata; Animal Model; Antigens; Area; Autoimmune Diabetes; Autoimmune Diseases; Autoimmunity; C3H/HeJ Mouse; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell-Mediated Cytolysis; Cells; Clinical; Cosmetics; Cutaneous; Data; Development; Disease; Disease remission; Disease susceptibility; Epithelium; FDA approved; Genes; Goals; Hair; Hair follicle structure; Hashimoto Disease; High Prevalence; Histologic; Human; Immune; Immune response; Immune system; Individual; Interferon Type II; Invaded; Knock-out; Knowledge; Lead; Mediating; Medical; Methods; Mus; Organ; Pathogenesis; Pathogenicity; Pathologic; Patients; Persons; Population; Post-Traumatic Stress Disorders; Prevalence; Production; Publishing; Quality of life; Risk; Role; Sampling; Skin; T cell response; T-Lymphocyte; Tissues; Translating; United States; Veterans; Work; autoimmune pathogenesis; autoreactivity; cell type; combat veteran; comorbidity; cytokine; effector T cell; efficacious treatment; human disease; immune cell infiltrate; immunoregulation; in vivo; in vivo Model; insight; interest; lifetime risk; military veteran; mouse model; novel; pathogen; prevent; psychosocial; response; self esteem; side effect; targeted treatment; tool; treatment strategy; 20 year old; Address; Adoptive Transfer; Affect; Alopecia Areata; Animal Model; Antigens; Area; Autoimmune Diabetes; Autoimmune Diseases; Autoimmunity; C3H/HeJ Mouse; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell-Mediated Cytolysis; Cells; Clinical; Cosmetics; Cutaneous; Data; Development; Disease; Disease remission; Disease susceptibility; Epithelium; FDA approved; Genes; Goals; Hair; Hair follicle structure; Hashimoto Disease; High Prevalence; Histologic; Human; Immune; Immune response; Immune system; Individual; Interferon Type II; Invaded; Knock-out; Knowledge; Lead; Mediating; Medical; Methods; Mus; Organ; Pathogenesis; Pathogenicity; Pathologic; Patients; Persons; Population; Post-Traumatic Stress Disorders; Prevalence; Production; Publishing; Quality of life; Risk; Role; Sampling; Skin; T cell response; T-Lymphocyte; Tissues; Translating; United States; Veterans; Work; autoimmune pathogenesis; autoreactivity; cell type; combat veteran; comorbidity; cytokine; effector T cell; efficacious treatment; human disease; immune cell infiltrate; immunoregulation; in vivo; in vivo Model; insight; interest; lifetime risk; military veteran; mouse model; novel; pathogen; prevent; psychosocial; response; self esteem; side effect; targeted treatment; tool; treatment strategy

Alopecia areata (AA) is a common autoimmune disease in which the hair follicle is the target of attack and results clinically in hair loss. The lifetime risk of developing AA is approximately 2%, translating to over 6 million people in the United States developing the disease at some point in their lives. Although often being dismissed as a cosmetic concern, AA can have a substantive psychosocial impact and can significantly affect the quality of life of affected individuals, especially among those with the more severe forms. The population that suffers from this disfiguring disease with significant psychosocial ramifications represents a significant unmet medical need. In addition, autoimmune diseases in general are rising in prevalence, and at least one study of veterans have shown an increased risk of autoimmune disease in those veterans suffering from post-traumatic stress disorder. The common cause hypothesis of autoimmunity, supported by the association of specific genes to a range of autoimmune diseases, signifies that advances in one autoimmune disease may be applicable to others. Numerous factors make AA an attractive area of study in this regard: high prevalence, the existence of an animal model with high fidelity to human disease, and the ease and convenience with which the target end- organ may be assessed and sampled. Despite its high prevalence, AA has not been as heavily studied relative to other cutaneous autoimmune diseases, and there are no treatments approved by the US FDA that list AA as an indication. Despite new interest and data into the immune mechanisms regulating the development of AA, our understanding of the pathogenic immune cell types and regulatory circuits that drive this disease significantly lags that of other autoimmune diseases. Although prior work by us and others have established a critical role for CD4 and CD8 T cells, it is not known what these cell types are doing to lead to autoimmune attack of the hair follicle. Dissecting which effector functions of CD4 T cells and CD8 T cells are necessary for AA pathogenesis will focus our understanding of disease pathogenesis, which can bring us closer to targeted and specific treatments. AA is characterized histologically by a peribulbar immune infiltrate mostly comprised of T cells, with CD4 T cells being the most numerous cell type followed by CD8 T cells. We are interested in investigating the role of pathogenic CD4 and CD8 T cells in the context of the C3H/HeJ murine model of AA, which can either develop disease spontaneously or develop disease in response to various methods of induction. The goal of this proposal is to address these critical knowledge gaps and provide mechanistic insight into the role of CD4 and CD8 T cells in the pathogenesis of AA. We will achieve our goal by pursuing two specific Aims. In Specific Aim 1, we will dissect the impact of CD4 T cell production of interferon gamma on the hair follicle and AA development. Furthermore, our proposed studies will help define the target of CD4 T cell effector functions in our in vivo model. In Specific Aim 2, we will determine which effector mechanisms are required by CD8 T cells for AA development. We expect our studies to identify the pathogenic effector functions used by T cells to induce disease in AA. Results of this work will inform the development of novel treatment strategies for AA.

脱发Areata（AA）是一种常见的自身免疫性疾病，其中毛囊是攻击的目标 并在临床上导致脱发。开发AA的终身风险约为2％，转化为6多个 在美国，有百万人在生活中的某个时刻发展这种疾病。虽然经常是 AA被视为化妆品的关注，可能会产生实质性的社会心理影响，并可能显着影响 受影响个人的生活质量，尤其是在具有更严重形式的人中。人口 这种毁容的疾病遭受了重大的社会心理后果，这是一个重要的未得到的疾病 医疗需求。此外，通常的自身免疫性疾病的患病率正在上升，至少一项研究 退伍军人在那些遭受创伤后的退伍军人中表现出增加自身免疫性疾病的风险 应力障碍。自身免疫性的共同原因假设，由特定基因的关联支持 对于一系列自身免疫性疾病，表示一种自身免疫性疾病的进步可能适用于 其他的。在这方面，许多因素使AA成为吸引人的研究领域：高流行率，存在 对人类疾病高保真的动物模型，目标最终的轻松和便利性 可以评估和采样器官。 尽管患病率很高，但相对于其他皮肤自身免疫性，AA的研究尚未进行大量研究 疾病，没有美国FDA批准的治疗方法将AA列为指示。尽管有新的兴趣 以及调节AA发展的免疫机制的数据，我们对致病性的理解 驱动该疾病的免疫细胞类型和调节回路显着滞后其他自身免疫性 疾病。尽管我们和其他人的先前工作已经确立了CD4和CD8 T细胞的关键作用，但不是 知道这些细胞类型在导致毛囊的自身免疫性攻击。解剖哪个效应子 CD4 T细胞和CD8 T细胞的功能是AA发病机理所必需的，将集中于我们对 疾病发病机理，可以使我们更接近靶向和特定治疗。 AA在组织学上的特征是由Peribulbar免疫浸润，主要由T细胞组成， CD4 T细胞是最多的细胞类型，其次是CD8 T细胞。我们有兴趣调查 致病性CD4和CD8 T细胞在C3H/HEJ鼠模型的背景下的作用 自发发展疾病或响应各种诱导方法而发展疾病。目标 该建议是解决这些关键知识差距，并提供有关CD4作用的机械洞察力 AA发病机理中的CD8 T细胞。我们将通过实现两个具体目标来实现我们的目标。在 具体的目标1，我们将剖析干扰素伽玛的CD4 T细胞产生对毛囊和 AA开发。此外，我们提出的研究将有助于定义CD4 T细胞效应子功能的目标 在我们的体内模型中。在特定的目标2中，我们将确定CD8 T需要哪些效应机制 用于AA开发的细胞。我们希望我们的研究能够确定T细胞使用的致病效应子功能 在AA中诱导疾病。这项工作的结果将为AA的新型治疗策略的发展提供信息。