Use of Substance P antagonists to regulate the skin immune function

描述(申请人提供)：复发性炎症性疾病是一种常见的皮肤病，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，效应性T细胞的激活需要免疫刺激的皮肤树突状细胞(SDCs)，包括表皮朗格汉斯细胞(LCS)和真皮DC(DDCS)，它们将半抗原运送到皮肤引流淋巴结(SDLN)并激活初始T细胞。因此，抑制免疫刺激的树突状细胞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SDCs的治疗方法的开发一直是极其困难的。在DC-抗原/半抗原相互作用的瞬间，免疫刺激DC的产生需要一个促炎的微环境。这种炎性微环境是由皮肤暴露于抗原/半抗原后释放的促炎神经肽启动的。P物质(SP)是一种典型的促炎性神经肽，通过促进免疫细胞的活化、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C纤维连接具有免疫功能的细胞，如LCS、肥大细胞(MCs)和角质形成细胞。SP通过与神经激肽1受体(NK1R)结合发挥免疫刺激作用，我们已经描述了SDCs表达功能性NK1R，并通过诱导Th1和CTL效应器对蛋白Ag的免疫反应来应答NK1R的激动性结合。然而，关于局部分泌的SP-1在皮肤CHS的发生和复发过程中对SDCs的成熟和T细胞免疫刺激功能的作用的相关研究还很少。我们推测：“在皮肤抗原/半抗原穿透的瞬间，SP通过NK1R的促炎信号，促进免疫刺激的SDCs及其前体的激活，导致皮肤免疫性疾病的启动、持续和复发，这可以通过局部应用NK1R拮抗剂来限制”。为了验证我们的假设，我们提出了以下具体目标：具体目标1：分析在慢性阻塞性肺病致敏阶段SP诱导免疫刺激性SDCs的机制。具体目的2：分析在慢性阻塞性肺疾病的致敏、激发和消退过程中，SP在SDCs刺激的T细胞反应中的作用和机制。具体目的3：分析局部应用特异性NK1R拮抗剂通过下调SDCs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一种常见疾病，具有很高的社会经济影响。接触性超敏反应(CHS)是一种依赖免疫系统和神经系统相互作用的典型复发性皮肤炎症性疾病。CHS的启动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，与皮肤炎症的发生和复发以及树突状细胞(DC)的激活有关，树突状细胞是最有效的皮肤常驻抗原提呈细胞。在这一应用中，我们建议通过特异性地阻断其功能性神经激肽-1受体(NK1R)来抑制SP的作用，方法是在暴露于Ag的瞬间在皮肤局部传递合成的非肽NK1R拮抗剂。这将通过使用小鼠和一种独特的人类皮肤移植模型来实现，我们已经开发了这种模型，以便于转化为临床试验。我们提出的研究有可能克服反复发作的皮肤炎性和免疫性疾病，其中包括作为人类临床试验的直接前奏而设计的翻译临床前模型。

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.