Engineering the Skin Microenvironment to Promote Allergen Tolerance

改造皮肤微环境以促进过敏原耐受性

基本信息

批准号：
9753923
负责人：
Louis D Falo
金额：
$ 60.81万
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：
2018
资助国家：
美国
起止时间：
2018-08-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9753923
关键词：
Acute Address Adopted Adrenal Cortex Hormones Allergens Allergic Contact Dermatitis Anti-Inflammatory Agents Antigens Autoantigens Automobile Driving Biocompatible Materials Biomedical Engineering CD14 gene Cholecalciferol Chronic Clinical Trials Contact Dermatitis Cutaneous Data Dendritic Cells Dermal Dermatologic Dermatology Dinitrochlorobenzene Dose Drug Delivery Systems Egg Proteins Engineering Eragrostis Evaluation Exposure to FOXP3 gene Goals Haptens Health Human Hypersensitivity Immune Immune System Diseases Immune system Immunology Inflammation Inflammatory Inflammatory Response Interleukin-2 Lymphoid Tissue Mediating Modeling Mus Nickel Phenotype Population Process Proteins Regulatory T-Lymphocyte Reporter Rhus radicans Sirolimus Skin Skin Tissue Specificity System T-Lymphocyte Technology Therapeutic Time Tissues Translations Ultraviolet Rays analog base biodegradable polymer chemical allergen clinical candidate clinical translation controlled release cost design effector T cell experience experimental study in vivo lymph nodes migration mouse model multidisciplinary novel prevent prophylactic research clinical testing response skin disorder translational approach translational study urushiol

项目摘要

ABSTRACT Allergic contact dermatitis (ACD) is a destructive T-cell-mediated inflammation of the skin, resulting from repeated contact with allergens (e.g. nickel or poison ivy). ACD is one of the most common skin diseases, afflicting roughly 15-20 percent of the population, with annual costs in excess of $2 billion in the U.S. alone. Aside from avoiding known allergens when possible, current treatments involve non-specific anti-inflammatories that transiently suppress cutaneous inflammation, but fail to address the underlying immune dysfunction. In contrast, our bodies ordinarily employ highly specific mechanisms to suppress excessive inflammation, many of which are mediated by regulatory T cells (Tregs). Studies have shown that enhancing allergen or autoantigen-specific populations of Tregs can promote tolerance, or hyporesponsiveness, and ameliorate tissue-destructive inflammation. Information present in the local microenvironments where dendritic cells encounter or present allergen dictates whether T cells will become inflammatory effector T cells (Teff) or protective Tregs. The goal of the studies we propose is to develop an antigen specific strategy to prevent and treat contact dermatitis. We recently demonstrated that sustained local delivery of TReg- Inducing (“TRI”) factors and allergens with degradable, polymeric microparticles (MPs) or microneedle arrays (MNAs) expands allergen-specific Tregs and inhibits Teff differentiation during cutaneous allergen exposure, thereby promoting allergen-specific tolerance. In this proposal, we will induce tolerance by engineering local skin or lymph node microenvironments to promote Treg differentiation. To that end, we will leverage our multidisciplinary team’s combined experience and capabilities to specifically deliver Treg-inducing factors to defined microenvironments of the skin or skin draining lymph nodes using microneedle arrays and micro- sized controlled release systems. Importantly, our experiments include translational studies focusing on human skin that are designed to enable rapid translation of this strategy to clinical trials.

抽象的过敏性接触性皮炎 (ACD) 是一种破坏性 T 细胞介导的皮肤炎症，因反复接触过敏原（例如镍或毒藤）而引起的过敏是最常见的过敏原之一。常见皮肤病，约占人口的 15-20%，每年造成的费用为仅在美国就超过 20 亿美元，除了尽可能避免已知的过敏原外，目前治疗涉及暂时抑制皮肤炎症的非特异性抗炎药炎症，但无法解决潜在的免疫功能障碍，相反，我们的身体。通常采用高度特异性的机制来抑制过度炎症，其中许多是由调节性 T 细胞 (Treg) 介导的。研究表明，增强过敏原或自身抗原特异性的 Tregs 群体可以促进耐受性或低反应性，并且改善局部微环境中存在的组织破坏性炎症。树突状细胞遇到或呈现过敏原的地方决定了 T 细胞是否会变得炎症效应 T 细胞 (Teff) 或保护性 Tregs。我们提出的研究目标是开发一种抗原特异性策略来预防我们最近证明了 TReg- 的持续局部递送。诱导（“TRI”）因素和过敏原与可降解的聚合物微粒（MP）或微针阵列 (MNA) 扩展过敏原特异性 Tregs 并抑制 Teff 分化在皮肤过敏原暴露期间，以这种方式促进过敏原特异性耐受。建议，我们将通过改造局部皮肤或淋巴结微环境来诱导耐受性为此，我们将利用我们的多学科团队的综合力量。经验和能力，专门将 Treg 诱导因子传递给特定的使用微针阵列和微针阵列来研究皮肤或皮肤引流淋巴结的微环境重要的是，我们的实验包括转化研究。专注于人类皮肤，旨在将该策略快速转化为临床试验。