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.

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， 由于反复接触过敏原（例如镍或毒藤）而导致。 ACD 是最 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，但未能解决潜在的免疫功能障碍。相比之下，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 由调节性 T 细胞 (Treg) 介导。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 并治疗接触性皮炎。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，从而促进过敏原特异性耐受。在这个 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 促进Treg分化。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 尺寸的控制释放系统。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。