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

基本信息

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
项目类别：
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

项目摘要

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，其中毛囊是攻击目标并导致临床脱发。一生中患 AA 的风险约为 2%，即超过 6 美国有 100 万人在生命中的某个阶段患上这种疾病。虽然经常被虽然 AA 被认为是美容问题而被忽视，但它可以产生实质性的社会心理影响，并可以显着影响受影响个体的生活质量，尤其是那些病情较严重的个体。人口患有这种具有重大社会心理影响的毁容疾病的人代表了一个重大的未得到满足的问题医疗需要。此外，自身免疫性疾病的患病率总体上呈上升趋势，至少一项研究表明，患有创伤后退伍军人的退伍军人表现出自身免疫性疾病的风险增加应激障碍。自身免疫的共同原因假说得到特定基因关联的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其他的。许多因素使 AA 成为这方面有吸引力的研究领域：患病率高、存在一种对人类疾病高度保真的动物模型，以及目标最终的轻松便捷可以对器官进行评估和取样。尽管 AA 的患病率很高，但与其他皮肤自身免疫性疾病相比，其研究还不够深入。目前，美国 FDA 还没有批准任何治疗方法将 AA 列为适应症。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导致这种疾病的免疫细胞类型和调节回路明显落后于其他自身免疫性疾病疾病。尽管我们和其他人之前的工作已经确定了 CD4 和 CD8 T 细胞的关键作用，但它并不是已知这些细胞类型如何导致毛囊的自身免疫攻击。剖析哪个效应器 CD4 T 细胞和 CD8 T 细胞的功能对于 AA 发病机制是必要的，这将集中我们对疾病发病机制，这可以使我们更接近有针对性和特异性的治疗方法。 AA 的组织学特征是球周免疫浸润，主要由 T 细胞组成， CD4 T 细胞是数量最多的细胞类型，其次是 CD8 T 细胞。我们有兴趣调查致病性 CD4 和 CD8 T 细胞在 AA C3H/HeJ 小鼠模型中的作用，可以自发地发病或响应各种诱导方法而发病。目标是该提案旨在解决这些关键的知识空白，并提供对 CD4 作用的机制见解和 CD8 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CD4 T细胞产生干扰素γ对毛囊的影响以及 AA开发。此外，我们提出的研究将有助于确定 CD4 T 细胞效应功能的目标在我们的体内模型中。在具体目标 2 中，我们将确定 CD8 T 需要哪些效应机制 AA 发育细胞。我们希望我们的研究能够确定 T 细胞使用的致病效应功能诱发 AA 疾病。这项工作的结果将为 AA 的新型治疗策略的开发提供信息。