Keratinocyte regulation of skin immunity

角质形成细胞对皮肤免疫的调节

• 批准号: 7926442
• 负责人: ANTHONY A GASPARI
• 金额: --
• 依托单位: BALTIMORE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7926442
• 关键词: Address; Affect; Allergic; Allergic Contact Dermatitis; Allergic Disease; Animal Model; Antigen Presentation; Antigen-Presenting Cells; Asthma; Biological Assay; Biological Models; Bone Marrow; Cell Communication; Cell Count; Cell Proliferation; Cells; Cellular Immunity; Clinic; Clonal Anergy; Clone Cells; Conflict (Psychology); Contact Dermatitis; Cutaneous; Data; Dermal; Dermatitis; Dermatology; Disease; Environment; Enzyme-Linked Immunosorbent Assay; Epithelial; Fibroblasts; Flow Cytometry; Gene Targeting; General Population; Genes; Glycolipids; Health; Healthcare; Human; Immune System Diseases; Immunity; Immunocompetent; In Vitro; Incubated; Inflammatory; Inflammatory Response; Knockout Mice; Mediating; Middle East; Modeling; Molecular; Mus; Natural Immunity; Nature; Organ; Patients; Phase; Play; Population; Procedures; Regulation; Role; Signal Transduction; Skin; Surface; System; T cell anergy; T cell response; T-Lymphocyte; Testing; Tissues; Veterans; Visit; alpha-galactosylceramide; experience; in vivo; in vivo Model; keratinocyte; killer T cell; monocyte; mouse model; novel; novel strategies; peripheral tolerance; reconstitution; skin disorder; tissue culture

DESCRIPTION (provided by applicant): Hypothesis: The purpose of this study is to define how KC control T-cell mediated immunity in the skin. We will utilize both human and mouse models of the common skin condition, allergic contact dermatitis (ACD). We selected this skin condition because it is a common skin disease in Veterans. We hypothesize that Keratinocytes (KC) are tolerigenic Antigen presenting cells for Natural killer (NK)T-cells. KC-NKT-cell interactions via CD1d plays an important role in maintaining peripheral tolerance by inducing NKT clonal anergy. We will test our central hypothesis CD1d on KC may tolerize epidermotropic NKT, potentially dampening contact dermatitis. We will study KC-NKT-cell interactions, and how they affect cell mediated immunity in the skin, using mouse models as well as direct studies of human KC and NKT-cells. Specific Objectives: There are three specific objectives: 1) To study the effects of KC- NKT-cell interactions in vitro and whether this tolerizes NKT-cells. 2) To define the role of anergic iNKT-cells in the afferent and efferent phases of murine ACD. 3) To determine the effects of the loss of CD1d by epidermal KC on ACD (loss of tolerance). Relevance to the VA: Contact dermatitis a very common inflammatory skin diseases in the industrialized world. It is a major health concern for patients and has a major impact on the economy. Contact dermatitis is a significant problem for veterans as well, representing a common cause for visits to Dermatology clinics in veterans. Subject Populations: KC and NKT-cells will be obtained from healthy controls for in vitro studies. An animal model system will be used to ACD in mice engrafted with skin from CD1d gene knockout mice. This in vivo model will allow us to confirm the role of KC derived CD1d, and will extend our in vitro studies on the role of CD1d in controlling innate immunity in vivo. Procedures: Tissue culture of KC, NKT-cells, monocytes, cell proliferation assays, flow cytometry, ELISA, qPCR, in vivo studies with gene targeted mice will be utilized to address the questions that are the central focus of this proposal: How KC CD1d controls NKT-cell responses, and this controls the course of ACD. Significance of findings to the VA: Dermatitis a common skin disease in Veterans as it is in the general population. Veterans returning from the Middle East Conflicts will experience health problems, including diseases of the immune system that will affect the skin, such as contact dermatitis. The proposed studies are of a fundamental nature that will further the understanding of the interface between innate immunity (NKT-cells), and tissues that interface with the environment (in this proposal epithelial surfaces in the skin), and are relevant to allergic diseases in other organs such as asthma. The proposed immunological study will utilize ACD as a model to dissect out patho-mechanisms of this disease. These studies will be of great utility in understanding this common skin disease, and will be applied to allergic health problems in Veterans returning from the Middle East Conflicts. PUBLIC HEALTH RELEVANCE: Potential Impact on Veteran's Healthcare: Dermatitis a common skin disease in Veterans as it is in the general population. Veterans returning from the Middle East Conflicts will experience health problems, including diseases of the immune system that will affect the skin, such as contact dermatitis. The proposed studies are of a fundamental nature that will further the understanding of the interface between innate immunity (NKT-cells), and tissues that interface with the environment (in this proposal epithelial surfaces in the skin), and are relevant to allergic diseases in other organs such as asthma. The proposed immunological study will utilize ACD as a model to dissect out patho- mechanisms of this disease. These studies will be of great utility in understanding this common skin disease, and will be applied to allergic health problems in Veterans returning from the Middle East Conflicts.

描述（由申请人提供）： 假设：本研究的目的是确定 KC 如何控制皮肤中 T 细胞介导的免疫。我们将利用常见皮肤病过敏性接触性皮炎 (ACD) 的人类和小鼠模型。我们选择这种皮肤病是因为它是退伍军人中常见的皮肤病。我们假设角质形成细胞 (KC) 是自然杀伤 (NK)T 细胞的致耐受性抗原呈递细胞。 KC-NKT 细胞通过 CD1d 相互作用，通过诱导 NKT 克隆无能，在维持外周耐受性方面发挥着重要作用。我们将测试 KC 上的 CD1d 可能耐受亲表皮性 NKT 的中心假设，从而可能抑制接触性皮炎。我们将使用小鼠模型以及对人类 KC 和 NKT 细胞的直接研究来研究 KC-NKT 细胞相互作用，以及它们如何影响皮肤中细胞介导的免疫。具体目标：共有三个具体目标： 1) 研究体外 KC-NKT 细胞相互作用的影响以及这是否使 NKT 细胞耐受。 2) 定义无能 iNKT 细胞在小鼠 ACD 传入和传出阶段中的作用。 3) 确定表皮KC导致CD1d丢失对ACD（耐受性丧失）的影响。与 VA 的相关性：接触性皮炎是工业化世界中非常常见的炎症性皮肤病。它是患者的主要健康问题，并对经济产生重大影响。接触性皮炎对于退伍军人来说也是一个重大问题，是退伍军人去皮肤科诊所就诊的常见原因。受试者人群：KC 和 NKT 细胞将从健康对照中获得，用于体外研究。动物模型系统将用于在植入 CD1d 基因敲除小鼠皮肤的小鼠中进行 ACD。该体内模型将使我们能够确认 KC 衍生的 CD1d 的作用，并将扩展我们对 CD1d 在体内控制先天免疫中的作用的体外研究。程序：KC、NKT 细胞、单核细胞的组织培养、细胞增殖测定、流式细胞术、ELISA、qPCR、基因靶向小鼠的体内研究将用于解决本提案的核心问题：如何 KC CD1d控制 NKT 细胞反应，从而控制 ACD 的进程。研究结果对退伍军人管理局的意义：皮炎是退伍军人和普通人群中常见的皮肤病。从中东冲突返回的退伍军人将遇到健康问题，包括影响皮肤的免疫系统疾病，例如接触性皮炎。拟议的研究具有基础性，将进一步了解先天免疫（NKT 细胞）和与环境接触的组织（在本提案中为皮肤上皮表面）之间的界面，并且与过敏性疾病相关。其他器官，例如哮喘。拟议的免疫学研究将利用 ACD 作为模型来剖析这种疾病的病理机制。这些研究对于了解这种常见的皮肤病将非常有用，并将应用于从中东冲突返回的退伍军人的过敏性健康问题。 公共卫生相关性： 对退伍军人医疗保健的潜在影响：皮炎是退伍军人和普通人群中常见的皮肤病。从中东冲突返回的退伍军人将遇到健康问题，包括影响皮肤的免疫系统疾病，例如接触性皮炎。拟议的研究具有基础性，将进一步了解先天免疫（NKT 细胞）和与环境接触的组织（在本提案中为皮肤上皮表面）之间的界面，并且与过敏性疾病相关。其他器官，例如哮喘。拟议的免疫学研究将利用 ACD 作为模型来剖析该疾病的病理机制。这些研究对于了解这种常见的皮肤病将非常有用，并将应用于从中东冲突返回的退伍军人的过敏性健康问题。