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: 10006640
• 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/10006640
• 关键词: 20 year old; Address; Adoptive Transfer; Affect; Alopecia Areata; Animal Model; Antigens; Area; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; 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; Epithelial; Epithelium; FDA approved; GTP-Binding Protein alpha Subunits, Gs; Genes; Goals; Hair; Hair follicle structure; Hashimoto Disease; High Prevalence; Histologic; Human; Immune; Immune response; Immune system; Individual; Interferon Type II; Interferons; Invaded; Knock-out; Knowledge; Lead; Mediating; Medical; Methods; Mus; Organ; Pathogenesis; Pathogenicity; Pathologic; Patients; Population; Post-Traumatic Stress Disorders; Prevalence; Production; Publishing; Quality of life; Risk; Role; Sampling; Skin; T cell response; T-Lymphocyte; Tissues; Translating; Tumor-infiltrating immune cells; United States; Veterans; Work; autoreactivity; base; cell type; combat; comorbidity; cytokine; effector T cell; human disease; immunoregulation; in vivo; in vivo Model; insight; interest; lifetime risk; 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.

斑秃（AA）是一种常见的自身免疫性疾病，毛囊是攻击的目标 并在临床上导致脱发。发展AA的终生风险约为2%，转化为超过6%。 在美国，有100万人在生命的某个阶段患上了这种疾病。虽然经常被 作为一个化妆品的关注，AA可以有实质性的心理社会影响，并可以显着影响 受影响个体的生活质量，特别是那些较严重的形式。人口 患有这种具有显著心理社会后果的毁容疾病的人， 医疗需求。此外，自身免疫性疾病的患病率普遍上升，至少有一项研究表明， 退伍军人已经显示出，在那些患有创伤后疾病的退伍军人中， 应激障碍自身免疫的共同原因假说，由特定基因的关联支持 一系列自身免疫性疾病，意味着一种自身免疫性疾病的进展可能适用于 他人许多因素使AA成为这方面有吸引力的研究领域：高患病率， 一种对人类疾病高度逼真的动物模型，以及目标结束的容易和方便- 可以对器官进行评估和取样。 尽管其患病率很高，但相对于其他皮肤自身免疫性疾病， 疾病，并且没有美国FDA批准的治疗将AA列为适应症。尽管新的兴趣 和数据到免疫机制调节AA的发展，我们的理解的致病性 驱动这种疾病的免疫细胞类型和调节回路明显滞后于其他自身免疫性疾病。 疾病尽管我们和其他人先前的工作已经确定了CD 4和CD 8 T细胞的关键作用，但事实并非如此。 我们知道这些细胞类型是如何导致毛囊的自身免疫攻击的。解剖哪个效应器 CD 4 T细胞和CD 8 T细胞的功能是AA发病机制所必需的， 疾病的发病机制，这可以使我们更接近有针对性的和具体的治疗。 AA的组织学特征是球周免疫浸润，主要由T细胞组成， CD 4 T细胞是最多的细胞类型，其次是CD 8 T细胞。我们有兴趣调查 致病性CD 4和CD 8 T细胞在C3 H/HeJ小鼠AA模型中的作用， 自发发病或对各种诱导方法作出反应而发病。的目标 该提案旨在解决这些关键性的知识缺口，并对CD 4的作用提供机理性的见解 和CD 8 T细胞在AA发病机制中的作用。我们将通过追求两个具体目标来实现我们的目标。在 具体目标1，我们将剖析干扰素γ对毛囊的CD 4 T细胞产生的影响， AA发展。此外，我们提出的研究将有助于确定CD 4 T细胞效应功能的靶点。 in our in vivo体内model模型.在具体目标2中，我们将确定CD 8 T细胞需要哪些效应机制， AA发育的细胞我们希望我们的研究能够确定T细胞所使用的致病效应功能， 在AA中诱发疾病。这项工作的结果将为AA的新治疗策略的发展提供信息。