Manipulating Cutaneous Neuroimmunity to Treat Contact Dermatitis

 描述(申请人提供)：通过这里提出的研究，我们将开发一种抗原特异性阴性免疫策略来预防和治疗接触性皮炎。此外，建议的研究将建立一个模型方法，可以扩展到开发预防或治疗广泛的T细胞介导的炎症性皮肤病的治疗方法。我们建议在抗原攻击时操纵皮肤中的神经炎性反应，以防止抗原特异性T细胞反应的发展，包括防止T细胞记忆的发展。此外，我们将扩展这一策略，以减轻/消除作为慢性炎症性皮肤病基础的已建立的记忆T细胞反应。为了实现这一目标，我们将利用我们实验室开发的新型微针阵列(MNA)技术。这些MNAs的配方是为了实现抗原(Ag)和神经免疫调节小分子同时输送到特定的皮肤层。通过将这种创新的免疫调节方法与我们新颖的MNA递送技术相结合，我们将在体内设计皮肤微环境。我们的方法的目的是产生抗原特异性抗炎抗原提呈细胞(APC)，能够以耐受性的方式将抗原提呈给T细胞。这一战略将首次实现针对抗原的特定疗法，用于预防和治疗T细胞介导的皮肤病。我们将评估这一策略在预防抗原特异性效应和记忆T细胞(目标1)以及缓解/消除先前存在的记忆反应(目标2)方面的效果。我们将确定阻止免疫诱导的机制，包括对皮肤APC功能的影响，以及对记忆T细胞的诱导、功能和存活的影响。重要的是，我们的实验包括专注于人类皮肤的翻译研究(目标1和2)，这些研究是专门为使这一策略快速转化为临床试验而设计的。

 DESCRIPTION (provided by applicant): Through studies proposed here, we will develop a strategy for antigen-specific negative immunization to prevent and treat contact dermatitis. Further, the studies proposed will establish a model approach that could be extended for the development of therapies to prevent or treat a broad range of T-cell mediated inflammatory skin diseases. We propose to manipulate neuroinflammatory responses in the skin at the moment of antigen challenge to prevent the development of antigen-specific T-cell responses including prevention of the development of T-cell memory. Further, we will extend this strategy to mitigate/abrogate established memory T-cell responses that underlie chronic inflammatory skin diseases. To accomplish this we will utilize novel microneedle array (MNA) technology developed in our laboratory. These MNAs have been formulated to achieve simultaneous delivery of antigen (Ag) and neuroimmunomodulatory small molecules to a specific skin stratus. By combining this innovative immune-regulatory approach with our novel MNA delivery technology, we will engineer the cutaneous microenvironment "in vivo". The purpose of our approach is to generate Ag specific anti-inflammatory antigen presenting cells (APCs) capable of presenting Ag to T cells in a tolerogenic fashion. This strategy will enable, for the first time an Ag-specific therapy for the prevention and treatment of T-cell mediated skin diseases. We will evaluate the effects of this strategy on the prevention of Ag-specific effector and memory T-cells (Aim 1), and the mitigation/abrogation of preexisting memory responses (Aim 2). We will determine mechanisms that prevent immune induction, including effects on skin APC function, and memory T-cell induction, function, and survival. Importantly, our experiments include translational studies focusing on human skin (Aims 1 and 2) that are specifically designed to enable rapid translation of this strategy to clinical trials.