Engineering the Skin Microenvironment to Promote Allergen Tolerance

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， 因反复接触过敏原(如镍或有毒常春藤)所致。ACD是世界上最大的 常见的皮肤病，困扰着大约15%-20%的人口，每年的成本是 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 治疗包括非特异性抗炎药，暂时抑制皮肤 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 通常使用高度特异的机制来抑制过度炎症，其中许多 是由调节性T细胞(Tregs)介导的。研究表明，增强过敏原或 自身抗原特异的Tregs群体可以促进耐受性或低反应性，以及 改善组织破坏性炎症。当地微环境中存在的信息 树突状细胞遇到或存在变应原的位置决定了T细胞是否会 炎性效应T细胞(T细胞)或保护性T细胞。 我们提出的研究的目标是开发一种抗原特异性策略来预防 治疗接触性皮炎。我们最近证明了Treg的持续局部递送- 用可降解的聚合物微粒(MPS)或 微针阵列(MNAs)扩展变应原特异性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性。在这 建议，我们将通过工程局部皮肤或淋巴结微环境来诱导耐受 促进Treg分化。为此，我们将利用我们多学科团队的联合 专门将Treg诱导因素交付给已定义的 使用微针阵列和微针技术研究皮肤或皮肤引流淋巴结的微环境 规模的控制释放系统。重要的是，我们的实验包括翻译研究 专注于人类皮肤，旨在使这一策略快速转化为临床 审判。

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.