权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Mechanisms of CD49a Expression and Resident Memory T Cell Formation in Skin.

皮肤中 CD49a 表达和常驻记忆 T 细胞形成的机制。

基本信息

批准号：
9302659
负责人：
SHANNON K BROMLEY
金额：
$ 41.69万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-06-23 至 2021-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9302659
关键词：
Acute Address Adhesions Adhesives Affect Allergic Disease Anti-Bacterial Agents Antigens Atopic Dermatitis Autoimmune Diseases Autoimmune Process Autoimmune Responses Bacterial Genes Basement membrane Biology CD8-Positive T-Lymphocytes CD8B1 gene Cells Collagen Collagen Receptors Cutaneous Data Dermis Development Disease E-Cadherin Environment Epidermis Epithelial Cells Extracellular Matrix Focal Infection Goals Health Herpesvirus 1 Host Defense Human Immune Immune Targeting Immune response Immune system In Situ Individual Infection Infectious Agent Inflammation Inflammatory Integrins Interleukin-4 Link Maintenance Mediating Memory Modeling Molecular Morphology Mus Organ Pathway interactions Peripheral Play Population Predisposition Recruitment Activity Recurrence Regulation Signal Transduction Simplexvirus Site Skin T memory cell T-Lymphocyte Testing Therapeutic Therapeutic Uses Tissues Transforming Growth Factor beta Vaccine Design Vaccines Viral Vitiligo adhesion receptor antigen challenge autoreactivity base cell motility clinical application cytokine integrin alpha1beta1 interstitial interstitial cell melanocyte migration mouse model novel novel therapeutics pathogen prevent receptor receptor expression response skin disorder targeted treatment

项目摘要

The immune system must defend the host at the most likely sites of pathogen encounter--the epithelial cell boundaries between barrier organs and the host's environment. Exciting recent data demonstrate that a population of memory T cells (TRM) resides long-term within peripheral tissues and provides a first line of host defense from pathogens that cause local infection. However, in some settings, the local persistence of memory T cells that provide robust response is detrimental. TRM are thought to play a key role in local, recurring inflammatory skin diseases. This proposal seeks to address significant gaps in our understanding of the mechanisms that regulate cutaneous TRM in health and disease. Defining mechanisms that control TRM precursor localization and persistence within skin will be important for optimizing vaccines to provide local protection as well as therapies to prevent unwanted inflammation. Mechanisms that direct the interstitial migration, persistence and response of cutaneous TRM will be defined in a normal immune response to HSV infection and in autoimmune vitiligo. While the local cytokine microenvironment is known to direct TRM formation, factors that inhibit TRM differentiation/persistence are unknown. This proposal will investigate the hypothesis that depending on the cytokine microenvironment TRM formation is either promoted or inhibited. Lastly, although TRM have been identified at sites of cutaneous inflammatory disease, targeting TRM is an untested therapeutic approach. We will use a mouse model of vitiligo with clinical application to investigate the novel hypothesis that autoreactive TRM maintain depigmentation, and that depletion of autoreactive TRM will prevent and/or ameliorate disease. Up-regulating pathways that promote the persistence of T cells in peripheral tissues is a critical focus of current vaccine design; it may be equally important to create approaches that reverse these pathways to prevent unwanted TRM accumulation within inflamed tissues.

免疫系统必须在最有可能遇到病原体的部位（上皮细胞）保护宿主屏障器官与宿主环境之间的界限。令人兴奋的最新数据表明记忆 T 细胞群 (TRM) 长期驻留在外周组织内，并提供第一线宿主防御引起局部感染的病原体。然而，在某些设置中，内存的本地持久性提供强烈反应的 T 细胞是有害的。 TRM 被认为在局部、经常性的治疗中发挥着关键作用。炎症性皮肤病。该提案旨在解决我们对健康和疾病中调节皮肤 TRM 的机制。定义控制 TRM 的机制前体在皮肤内的定位和持久性对于优化疫苗以提供局部治疗非常重要保护以及预防不必要炎症的治疗。引导间隙的机制皮肤 TRM 的迁移、持久性和反应将在对 HSV 的正常免疫反应中定义感染和自身免疫性白癜风。虽然已知局部细胞因子微环境可指导 TRM 形成时，抑制 TRM 分化/持续的因素尚不清楚。该提案将调查假设TRM的形成取决于细胞因子微环境的促进或抑制。最后，虽然 TRM 已在皮肤炎症性疾病部位被发现，但靶向 TRM 是一种未经测试的治疗方法。我们将使用具有临床应用的白癜风小鼠模型来研究新的假设是，自身反应性 TRM 会维持脱色，而自身反应性 TRM 的耗尽会导致色素脱失。预防和/或改善疾病。上调促进 T 细胞持续存在的途径外周组织是当前疫苗设计的关键焦点；制定方法可能同样重要逆转这些途径，防止发炎组织内不必要的 TRM 积累。