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：
10613869
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10613869
关键词：
Acute Address Adopted Adrenal Cortex Hormones Allergens Allergic Contact Dermatitis Anti-Inflammatory Agents Antigen Presentation 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 Engineered skin Engineering Evaluation Exposure to FOXP3 gene Goals Haptens Health Human Hypersensitivity Immune System Diseases Immune system Immunology Inflammation Inflammatory Inflammatory Response Interleukin-2 Lymphoid Tissue Maps Mediating Modeling Mus Needles Nickel Phenotype Polymers Population Process Proteins Regulatory T-Lymphocyte Reporter Rhus radicans Sirolimus Skin Skin Tissue Specificity System T cell differentiation T-Cell Activation T-Lymphocyte Technology Therapeutic Time Tissues Translations Ultraviolet Rays analog chemical allergen clinical candidate clinical translation controlled release cost design dihydroxy-vitamin D3 draining lymph node effector T cell efficacy evaluation experience experimental study fabrication in vivo lymph node microenvironment migration mouse model multidisciplinary novel particle 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）是对皮肤的破坏性T细胞介导的注射，与过敏原的反复接触（例如镍或毒Ivy）导致。 ACD是最多的常见的皮肤疾病，大约占人口的15％至20％仅在美国，就超过了20亿美元。除了在可能的情况下避免已知的过敏原外治疗涉及瞬时抑制皮肤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定的机制来抑制过多的炎症，其中许多机制由调节T细胞（Treg）介导。研究表明，增强过敏原或 Treg的自身抗原特异性人群可以促进宽容或不足的人，并且改善组织破坏性感染。当地微环境中存在的信息树突状细胞遇到或存在过敏原决定T细胞是否会变为炎症效应T细胞（TEFF）或受保护的Treg。我们建议的研究的目的是制定一种特定的抗原策略以防止并治疗接触性皮炎。我们最近证明，持续的treg-持续交付具有可降解的聚合微粒（MPS）或微针阵列（MNA）扩展了过敏原特异性Treg并抑制TEFF分化在皮肤过敏原暴露期间，从而促进过敏原特异性耐受性。在这个提案，我们将通过工程局部皮肤或淋巴结微环境来诱导耐受性促进特雷格分化。为此，我们将利用我们的多学科团队的总和经验和能力，专门为定义的Treg诱导因素提供使用微针阵列和微型 - 大小的受控释放系统。重要的是，我们的实验包括翻译研究专注于旨在将这种策略快速转化为临床的人类皮肤试验。