Use of Substance P antagonists to regulate the skin immune function

描述（由申请人提供）：复发性炎症性疾病是常见的皮肤疾病，具有很高的社会经济影响。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需要激活识别皮肤细胞中存在的半抗原的CD4+和CD8+效应T细胞。在CHS中，效应T细胞的激活需要免疫刺激皮肤树突状细胞DCs (sdc)，包括表皮朗格汉斯细胞（LCs）和真皮树突状细胞DCs (ddc)，它们将半抗原转运到皮肤引流淋巴结（sDLNs）并激活幼稚T细胞。因此，抑制免疫刺激dc将是预防和治疗皮肤免疫性疾病的理想方法。然而，由于皮肤免疫系统的复杂调节，针对刺激性sdc的治疗方法的开发一直非常困难。免疫刺激dc的产生需要dc抗原(Ag) /半抗原相互作用时的促炎性微环境。这种炎症微环境是由皮肤暴露于Ag/半抗原后释放的促炎神经肽引发的。物质- p （SP）是一种原型的促炎神经肽，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主要由连接具有免疫功能的细胞（如lc、肥大细胞（MCs）和角质形成细胞）的感觉c纤维分泌。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效应对蛋白Ag的免疫反应来响应NK1R的激动性结合。然而，缺乏有关局部分泌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：“在皮肤Ag/半抗原渗透的时刻，SP通过NK1R发出的促炎信号，促进了免疫刺激性sdc及其前体的激活，导致皮肤免疫性疾病的开始、持续和复发，这可以通过局部使用NK1R拮抗剂来限制”。为了验证我们的假设，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。特异性目的2：分析SP在T细胞反应中的作用和机制，这些反应是由sdc在致敏、诱导和解决CHS过程中刺激的。特异性目的3：分析局部使用特异性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高度社会经济影响的常见疾病。接触性超敏反应（CHS）是依赖于免疫系统和神经系统相互作用的复发性皮肤炎症性疾病的原型。CHS的开始和复发是由抗原暴露时皮肤局部释放的促炎神经肽引发的。p物质（SP）是一种有效的神经肽，负责皮肤炎症的开始和复发，以及树突状细胞群的激活，树突状细胞是最有效的皮肤常驻抗原递呈细胞。在这个应用中，我们提出通过在银暴露的时刻在皮肤局部递送合成的非肽NK1R拮抗剂，通过特异性阻断其功能性神经动素-1受体（NK1R）来抑制SP的作用。这将使用小鼠和我们开发的一种独特的人类皮肤移植模型来完成，以促进转化为临床试验。我们提出的研究具有克服复发性皮肤炎症和免疫疾病的潜力，它们包括作为人体临床试验直接前奏的转化临床前模型。

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.