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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，其中毛囊是攻击的目标