Manipulating Cutaneous Neuroimmunity to Treat Contact Dermatitis

操纵皮肤神经免疫治疗接触性皮炎

基本信息

批准号：
9302683
负责人：
Louis D Falo
金额：
$ 42.1万
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：
2015
资助国家：
美国
起止时间：
2015-07-07 至 2020-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9302683
关键词：
Academy Allergic Contact Dermatitis American Anatomy Anti-Inflammatory Agents Anti-inflammatory Antigen Presentation Antigen-Presenting Cells Antigens Autoimmune Diseases Autoimmune Process Biomedical Engineering C Fiber CD8B1 gene Cell physiology Cells Cellular Immunity Chronic Clinical Trials Contact Dermatitis Cutaneous Data Defense Mechanisms Dermatologic Dermatologist Dermatology Dermis Development Devices Disease Drug Delivery Systems Engineering Environment Epidermis Event Exposure to Generations Goals Haptens Health Homing Human Immune Immune System Diseases Immunity Immunization Immunology Immunosuppression Incidence Inflammation Inflammation Mediators Inflammatory Investigation Joints Laboratories Langerhans cell Leukocytes Link Maintenance Mediating Mediator of activation protein Memory Modeling Modernization Mus Nervous system structure Neuroimmune Neurology Neuropeptides PPBP gene Painless Pathogenicity Pathologic Penetration Phase Prevalence Prevention Prevention therapy Process Proteins Publications Publishing Receptor Activation Recruitment Activity Regulation Relapse Role Sensory Signal Transduction Skin Societies Substance P Substance P Receptor Suggestion System T cell response T memory cell T-Cell Development T-Lymphocyte Technology Testing Therapeutic Therapeutic Effect Time Translations Vaccination Work adaptive immune response age difference antigen challenge base chronic inflammatory skin cost desensitization design dosage experimental study gender difference in vivo innovation neuroinflammation novel novel strategies prevent progenitor public health relevance relating to nervous system response sensory mechanism skin disorder small molecule socioeconomics therapy development translational approach translational study

项目摘要

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.

描述（由适用提供）：通过此处提出的研究，我们将制定一种抗原特异性阴性免疫抑制的策略，以预防和治疗接触性皮炎。此外，提出的研究将建立一种模型方法，该方法可以扩展，以开发疗法，以预防或治疗广泛的T细胞介导的炎症性皮肤病。我们建议在抗原挑战时操纵皮肤中的神经炎症反应，以防止抗原特异性T细胞反应的发展，包括预防T细胞记忆的发展。此外，我们将扩展这种策略，以减轻/消除慢性炎症性皮肤疾病的基础的已建立记忆T细胞反应。为了实现这一目标，我们将利用实验室中开发的新型微针阵列（MNA）技术。这些MNA已被制定为实现抗原（Ag）和神经免疫调节的小分子的简单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的新型MNA输送技术相结合，我们将设计皮肤微环境“体内”。我们方法的目的是生成AG特异性抗炎抗原呈递细胞（APC），能够以耐受性方式向T细胞呈现Ag。该策略将首次实现AG特异性治疗，用于预防和治疗T细胞介导的皮肤疾病。我们将评估该策略对预防特异性效应子和记忆T细胞的影响（AIM 1），以及先前存在的记忆响应的缓解/杂志（AIM 2）。我们将确定防止免疫学诱导的机制，包括对皮肤APC功能的影响以及记忆T细胞诱导，功能和生存。重要的是，我们的实验包括针对人皮肤的转化研究（目标1和2），这些研究专门设计为将此策略快速转化为临床试验。