Engineering the Skin Microenvironment to Promote Allergen Tolerance

改造皮肤微环境以促进过敏原耐受性

• 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
• 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

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.

摘要 过敏性接触性皮炎（ACD）是一种破坏性的T细胞介导的皮肤炎症， 由于反复接触过敏原（如镍或毒葛）。ACD是世界上 常见的皮肤病，约占人口的15- 20%，每年的费用为 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 治疗涉及非特异性抗炎药，其暂时抑制皮肤炎症， 炎症，但未能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（T细胞）介导的。研究表明，增强过敏原或 自身抗原特异性的Tcl 4群体可促进耐受性或低反应性， 改善组织破坏性炎症。局部微环境中存在的信息 树突状细胞遇到或呈递过敏原的位置决定了T细胞是否会成为 炎性效应T细胞（Teff）或保护性Teff。 我们提出的研究目标是开发一种抗原特异性策略， 治疗接触性皮炎我们最近证明了TReg的持续本地交付- 诱导（“TRI”）因子和过敏原与可降解的聚合物微粒（MP）或 微针阵列（MNAs）扩增变应原特异性Teff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。在这 我们将通过设计局部皮肤或淋巴结微环境来诱导耐受性， 促进Treg分化。为此，我们将利用我们的多学科团队的联合力量 有经验和能力专门提供Treg诱导因子， 皮肤或皮肤引流淋巴结的微环境， 大小控制释放系统。重要的是，我们的实验包括翻译研究 专注于人类皮肤，旨在将该策略快速转化为临床应用 审判