Manipulating Cutaneous Neuroimmunity to Treat Contact Dermatitis

操纵皮肤神经免疫治疗接触性皮炎

• 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
• 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

 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（由申请人提供）：通过本文提出的研究，我们将开发抗原特异性阴性免疫策略，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，可以扩展用于开发预防或治疗广泛的T细胞介导的炎症性皮肤病的疗法。我们建议在抗原激发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/消除慢性炎症性皮肤病的基础建立记忆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已被配制成实现抗原（Ag）和神经免疫调节小分子同时递送到特定的皮肤层云。通过将这种创新的免疫调节方法与我们的新型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能够以致耐受性方式将Ag呈递给T细胞的Ag特异性抗炎抗原呈递细胞（APC）。该策略将首次实现用于预防和治疗T细胞介导的皮肤病的Ag特异性疗法。我们将评估这种策略对预防Ag特异性效应和记忆T细胞（目标1）以及减轻/消除预先存在的记忆反应（目标2）的影响。我们将确定防止免疫诱导的机制，包括对皮肤APC功能的影响，以及记忆T细胞的诱导，功能和存活。重要的是，我们的实验包括专注于人类皮肤的转化研究（目标1和2），这些研究专门设计用于将该策略快速转化为临床试验。