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: 10183173
• 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/10183173
• 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; Epithelial; 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; autoimmune pathogenesis; autoreactivity; base; cell type; combat veteran; comorbidity; cytokine; effector T cell; efficacious treatment; human disease; 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.

斑秃是一种常见的自身免疫性疾病，毛囊是其攻击的目标。 并在临床上导致脱发。患再生障碍性贫血的终生风险约为2%，相当于超过6% 美国有数百万人在一生中的某个时候患上了这种疾病。尽管经常是 作为一种美容方面的考虑，再生障碍性贫血可以产生实质性的心理社会影响，并可以显著影响 受影响个人的生活质量，特别是在那些形式更严重的人中。人口 患有这种具有重大心理社会分支的毁容疾病的人代表着一种重大的未满足的 医疗需要。此外，自身免疫性疾病的患病率总体上正在上升，至少有一项关于 退伍军人表明，患有创伤后疾病的退伍军人患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，由特定基因的关联所支持 对于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。许多因素使再生障碍性贫血成为这方面的一个有吸引力的研究领域：高患病率，存在 一种对人类疾病高度逼真的动物模型，以及目标结束时的轻松和方便- 可以对器官进行评估和取样。 尽管其发病率很高，但相对于其他皮肤自身免疫，再生障碍性贫血还没有得到广泛的研究。 疾病，而且没有被美国FDA批准的治疗方法将AA列为适应症。尽管有了新的兴趣 并将资料转化为免疫调节机制对再障的发展，我们对其致病机理的认识 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 疾病。尽管我们和其他人之前的工作已经确立了CD4和CD8 T细胞的关键作用，但它并没有 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 CD4T细胞和CD8T细胞的功能是再生障碍性贫血发病机制所必需的，我们将重点了解 疾病的发病机制，这可以使我们更接近靶向和特定的治疗方法。 再生障碍性贫血的组织学特征是球周免疫浸润，主要由T细胞组成， CD4T细胞数量最多，其次是CD8T细胞。我们有兴趣调查 致病的CD4和CD8 T细胞在再生障碍性贫血C3H/HeJ小鼠模型中的作用 自发发展疾病或因各种诱导方法而发展疾病。的目标是 这项建议旨在解决这些关键的知识差距，并提供对CD4作用的机械性见解 CD8T细胞在再障发病机制中的作用。我们将通过追求两个具体目标来实现我们的目标。在……里面 具体目标1，我们将解剖产生干扰素的CD4T细胞对毛囊和 AA开发。此外，我们提出的研究将有助于确定CD4T细胞效应器功能的目标 在我们的活体模型中。在具体目标2中，我们将确定CD8 T需要哪些效应器机制 再生障碍性贫血发育细胞。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 在再生障碍性贫血中诱发疾病。这项工作的结果将为开发新的再生障碍性贫血治疗策略提供信息。