Use of Substance P antagonists to regulate the skin immune function

利用P物质拮抗剂调节皮肤免疫功能

基本信息

批准号：
8078942
负责人：
Adriana T Larregina
金额：
$ 37.12万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8078942
关键词：
Address Affinity Alcohol or Other Drugs use Antigen-Presenting Cells Antigens Binding C Fiber CD14 gene CD8B1 gene Cell physiology Cells Cellular Immunity Clinical Trials Complex Contact hypersensitivity Cutaneous Cutaneous Administration Cytotoxic T-Lymphocytes Dendritic Cells Dermal Development Dinitrochlorobenzene Disease Exposure to Generations Haptens Health Homing Human Immune Immune System Diseases Immune response Immune system Inflammation Inflammation Mediators Inflammatory Langerhans cell Lymphoid Tissue Mediating Modeling Mus Natural Killer Cells Nervous system structure Neuropeptides Organ Penetration Peripheral Phase Population Pre-Clinical Model Prevention Proteins Recurrence Regulation Research Resolution Role Sensory Signal Transduction Skin Substance P Substance P Receptor T cell response T memory cell T-Lymphocyte TNF gene Testing Translations immune function keratinocyte lymph nodes mast cell migration model design prevent prototype response skin disorder socioeconomics therapy development

项目摘要

DESCRIPTION (provided by applicant): Recurrent inflammatory diseases are common skin disorders with high socioeconomic impact. Contact hypersensitivity (CHS) is the prototype recurrent skin inflammatory disease that relays on the interaction of the immune and nervous systems. CHS requires activation of CD4+ and CD8+ effector T cells recognizing haptens present in skin cells. Activation of effector T cells, in CHS requires immunostimulatory skin dendritic cells DCs (sDCs) including epidermal Langerhans cells (LCs) and dermal DCs (DDCs) that transport haptens to skin draining lymph nodes (sDLNs) and activate naive T cells. Thus, inhibition of immunostimulatory DCs would be ideal for the prevention and treatment of skin immune diseases. However, the development of therapies targeting stimulatory sDCs has been extremely difficult due to the complex regulation of the skin immune system. The generation of immunostimulatory DCs requires a pro- inflammatory microenvironment at the moment of DC-antigen (Ag) /hapten interaction. This inflammatory microenvironment is initiated by pro-inflammatory neuropeptides released after skin exposure to Ag/haptens. Substance-P (SP) is the prototype pro-inflammatory neuropeptide which favors cellular immunity by promoting the activation, proliferation and survival of immune cells. In the skin, SP is mainly secreted by sensory C-fibers that interconnect cells with immune function such as LCs, mast cells (MCs), and keratinocytes. SP exerts its immunostimulatory functions by binding the neurokinin 1 receptor (NK1R).We have described that sDCs express functional NK1R and respond to NK1R agonistic binding by inducing Th1 and CTL effector immune responses to protein Ag. Nevertheless, relevant studies addressing the role of locally secreted SP, on the maturation and T cell immunostimulatory function of sDCs during the initiation and recurrence of skin CHS are lacking. We hypothesize that: "Pro-inflammatory signaling by SP through the NK1R, at the moment of skin Ag/hapten penetration, promotes the activation of immunostimulatory sDCs and their precursors resulting in the initiation, persistence and recurrence of skin immune diseases which can be limited by local administration of NK1R antagonists". To test our hypothesis we propose the following specific aims: Specific Aim 1: To analyze the mechanisms employed by SP to induce immunostimulatory sDCs during the sensitization phase of CHS. Specific Aim 2: To analyze the role and mechanisms employed by SP in T cell responses, stimulated by sDCs during sensitization, elicitation and resolution of CHS. Specific Aim 3: To analyze, the possibility of using local administration of specific NK1R antagonists to suppress CHS by down-regulating the T cell-stimulatory function of sDCs and their precursors. PUBLIC HEALTH RELEVANCE: Recurrent inflammatory skin diseases are common disorders with high socioeconomic impact. Contact hypersensitivity (CHS), is the prototype recurrent skin inflammatory disease that depends on the interaction of the immune and nervous systems. The initiation and recurrence of CHS is triggered by pro-inflammatory neuropeptides released locally in the skin at the moment of antigen exposure. Substance-P (SP), a potent neuropeptide, is responsible for the initiation and recurrence of skin inflammation and for the activation of the population of dendritic cells, the most potent skin resident antigen presenting cells. In this application we propose to inhibit the effects of SP by blocking specifically its functional neurokinin-1 receptor (NK1R) by delivering synthetic non-peptide NK1R antagonists locally in the skin at the moment of Ag exposure. This will be accomplished using both murine, and a unique model of human skin explants that we have developed to facilitate translation to clinical trials. The studies we propose have the potential to overcome recurrent skin inflammatory and immune diseases and they include translational preclinical models designed as a direct prelude to human clinical trials.

描述（由申请人提供）：复发性炎症性疾病是具有较高社会经济影响的常见皮肤病。接触性超敏反应 (CHS) 是一种典型的复发性皮肤炎症性疾病，依赖于免疫系统和神经系统的相互作用。 CHS 需要激活 CD4+ 和 CD8+ 效应 T 细胞来识别皮肤细胞中存在的半抗原。 CHS 中效应 T 细胞的激活需要免疫刺激性皮肤树突状细胞 DC (sDC)，包括表皮朗格汉斯细胞 (LC) 和真皮 DC (DDC)，它们将半抗原转运至皮肤引流淋巴结 (sDLN) 并激活初始 T 细胞。因此，抑制免疫刺激性树突状细胞对于预防和治疗皮肤免疫疾病是理想的。然而，由于皮肤免疫系统的复杂调节，针对刺激性 sDC 的疗法的开发极其困难。免疫刺激性 DC 的产生需要 DC-抗原 (Ag)/半抗原相互作用时的促炎微环境。这种炎症微环境是由皮肤暴露于银/半抗原后释放的促炎神经肽引发的。 Substance-P (SP) 是原型促炎神经肽，通过促进免疫细胞的激活、增殖和存活来促进细胞免疫。在皮肤中，SP 主要由感觉 C 纤维分泌，这些纤维将具有免疫功能的细胞（例如 LC、肥大细胞 (MC) 和角质细胞）互连。 SP 通过结合神经激肽 1 受体 (NK1R) 发挥其免疫刺激功能。我们已经描述了 sDC 表达功能性 NK1R，并通过诱导 Th1 和 CTL 效应子对 Ag 蛋白的免疫反应来响应 NK1R 激动性结合。然而，目前尚缺乏关于局部分泌的 SP 在皮肤 CHS 发生和复发过程中对 sDC 成熟和 T 细胞免疫刺激功能的作用的相关研究。我们假设：“SP 通过 NK1R 发出的促炎信号，在皮肤 Ag/半抗原渗透时，促进免疫刺激性 sDC 及其前体的激活，导致皮肤免疫疾病的发生、持续和复发，这些疾病可以得到限制通过局部施用 NK1R 拮抗剂”。为了检验我们的假设，我们提出以下具体目标：具体目标 1：分析 SP 在 CHS 致敏阶段诱导免疫刺激性 sDC 的机制。具体目标 2：分析 SP 在 CHS 致敏、引发和消退过程中由 sDC 刺激的 T 细胞反应中的作用和机制。具体目标 3：分析局部施用特定 NK1R 拮抗剂通过下调 sDC 及其前体的 T 细胞刺激功能来抑制 CHS 的可能性。公共卫生相关性：复发性炎症性皮肤病是具有重大社会经济影响的常见疾病。接触性超敏反应（CHS）是一种典型的复发性皮肤炎症性疾病，取决于免疫系统和神经系统的相互作用。 CHS 的发生和复发是由抗原暴露时皮肤局部释放的促炎神经肽触发的。 P 物质 (SP) 是一种有效的神经肽，负责皮肤炎症的引发和复发以及树突细胞群（最有效的皮肤驻留抗原呈递细胞）的激活。在此应用中，我们建议在 Ag 暴露时在皮肤局部递送合成非肽 NK1R 拮抗剂，从而特异性阻断 SP 的功能性神经激肽-1 受体 (NK1R)，从而抑制 SP 的作用。这将使用小鼠和我们开发的独特的人类皮肤外植体模型来完成，以促进转化为临床试验。我们提出的研究有可能克服复发性皮肤炎症和免疫疾病，其中包括旨在作为人体临床试验直接前奏的转化临床前模型。