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

• 批准号: 7872833
• 负责人: Adriana T Larregina
• 金额: $ 37.5万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 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/7872833
• 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; 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; Peptides; 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; Testing; Translations; immune function; keratinocyte; lymph nodes; mast cell; migration; model design; prevent; prototype; public health relevance; response; skin disorder; socioeconomics; therapy development

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高社会经济影响的常见皮肤疾病。接触性超敏反应（CHS）是原型的复发性皮肤炎症性疾病，它与免疫系统和神经系统的相互作用相关。 CHS需要激活CD4+和CD8+效应T细胞，以识别皮肤细胞中存在的触觉。 CHS中效应T细胞的激活需要免疫刺激性皮肤树突状细胞DCS（SDC），包括表皮Langerhans细胞（LCS）和皮肤DCS（DDCS）（DDCS），这些DCS（DDCS）将触发运输到皮肤排水淋巴结（SDLNS）和活化的幼稚T细胞。因此，抑制免疫刺激性DC将是预防和治疗皮肤免疫疾病的理想选择。但是，由于皮肤免疫系统的复杂调节，靶向刺激性SDC的疗法的发展非常困难。免疫刺激性DC的产生需要在DC抗原（Ag） /Hapten相互作用时进行炎症性微环境。这种炎症性微环境是由皮肤暴露于Ag/Hapens后释放的促炎性神经肽引发的。物质-P（SP）是促炎性神经肽的原型，它通过促进免疫细胞的激活，增殖和存活来利用细胞免疫。在皮肤中，SP主要由具有免疫功能（例如LCS，MAST细胞（MCS）和角质形成细胞）的感官C纤维分泌。 SP通过结合神经蛋白1受体（NK1R）来发挥其免疫刺激功能。我们描述了SDCS表达功能性NK1R，并通过诱导TH1和CTL效应子对蛋白质Ag的诱导TH1和CTL效应的免疫反应来响应NK1R激动剂结合。然而，缺乏针对局部分泌SP的作用，SDC在皮肤CH的启动和复发过程中SDC的成熟和T细胞免疫刺激功能的相关研究。我们假设：“ SP通过NK1R进行促炎的信号传导，在皮肤Ag/Hapten渗透率时，促进了免疫刺激SDC及其前体的激活，导致皮肤免疫疾病的起始，持久性和免疫疾病的复发，这些疾病可以受到NK1R抗体的位置限制的皮肤免疫疾病。为了检验我们的假设，我们提出了以下特定目的：具体目的1：分析SP在CHS敏化阶段诱导免疫刺激SDC的机制。具体目的2：分析SP在T细胞反应中采用的作用和机制，这在CHS的致敏，启发和分辨率过程中刺激了SDC。特定目的3：为了分析，使用特定NK1R拮抗剂的局部给药来抑制CHS，通过下调SDC及其前体的T细胞刺激功能来抑制CH。公共卫生相关性：复发性炎症性皮肤疾病是具有高社会经济影响的常见疾病。接触超敏反应（CHS）是原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的起始和复发是由抗原暴露时在皮肤中局部释放的促炎性神经肽引起的。物质-P（SP）是一种有效的神经肽，负责皮肤炎症的起始和复发以及树突状细胞的激活，这是最有效的皮肤耐药抗原呈递细胞。在此应用中，我们建议通过在Ag暴露时在皮肤中本地局部的合成非肽NK1R拮抗剂递送合成的非肽NK1R拮抗剂，从而抑制SP的效果。这将是使用鼠类和人类皮肤外植体的独特模型来实现的，我们已经开发出来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性和免疫疾病，其中包括被设计为人类临床试验的直接偏好的翻译临床前模型。