MNA Delivery of Neurokinin 1 Receptor Antagonists to Treat Atopic Dermatitis

摘要 通过本文提出的研究，我们将制定一种“阴性免疫”策略，以实现抗原特异性 特应性皮炎（AD）是一种高度常见的慢性炎症性皮炎， 皮肤病是一个相当大的社会经济负担。我们打算操纵神经免疫系统 皮肤中的调节网络以预防和治疗病理性先天性和适应性免疫应答 占AD的急性和慢性阶段。新的“阴性免疫”方法已经被 经工程化以防止初始T和B细胞的引发并根除现有的过敏原特异性T和B细胞 效应子反应为了实现这一点，我们将给予过敏原/抗原与拮抗剂， 神经激肽-1受体（NK 1 R），以防止其炎症激动剂与受体结合，这种相互作用 对于先天性和适应性效应器和记忆免疫功能的启动至关重要。这样做的理由 方法是在皮肤过敏原/Ag接触时消除/减少炎症将保持 为抗原呈递细胞（APC）提供一个静止的微环境。这将导致反- 能够以致耐受性方式将所遇到的抗原呈递给T细胞的炎性APC。这 该策略将首次实现用于预防和治疗AD的抗原特异性策略。 我们假设：“通过有效的协同作用促进抗炎皮肤微环境， 变应原/Ag和NK 1 R拮抗剂的递送将产生抗炎APC以耐受Ag 特异性T细胞并减轻/消除引起AD的预先存在的记忆B和T细胞应答”。 将使用新型的微针进行阴性免疫接种 阵列（MNAs）在我们的实验室开发。这些MNA整合并释放生物活性剂， 并已配制成实现变应原/ Ag同时递送， 神经免疫调节小分子对特定的皮肤层云。结合这种创新的免疫调节 方法与我们的新的MNA交付技术，将使我们能够工程皮肤微环境 用于预防和治疗AD的“体内”。重要的是，我们的实验包括翻译研究， 专门设计用于将该策略快速转化为临床试验。

ABSTRACT Through studies proposed here, we will develop a strategy of “negative immunization” to achieve antigen-specific tolerance for the prevention and immunotherapy of atopic dermatitis (AD), a highly common chronic inflammatory skin disease that presents a considerable socioeconomic burden. We intend to manipulate neuroimmune regulatory networks in the skin to prevent and treat pathologic innate and adaptive immune responses accounting for the acute and chronic phases of AD. The novel “negative immunization” approach has been engineered to prevent the priming of naïve T and B cells and to eradicate existing allergen specific T- and B- cell effector responses. To accomplish this, we will administrate allergen/antigen together with antagonists of the neurokinin-1 receptor (NK1R) to prevent receptor binding by its inflammatory agonists, an interaction that is critical for the initiation of innate and adaptive effector and memory immune functions. The rationale for this approach is that eliminating/decreasing inflammation at the time of skin allergen/Ag encounter will maintain a quiescent a microenvironment for antigen presenting cells (APCs). This will result in the generation of anti- inflammatory APCs capable of presenting the encountered antigen to T cells in a tolerogenic fashion. This strategy will enable, for the first time, an antigen specific strategy for the prevention and treatment of AD.  We hypothesize that: “Promoting an anti-inflammatory cutaneous microenvironment by efficient co- delivery of allergen/Ag and NK1R antagonists will generate anti-inflammatory APCs to tolerize Ag specific T cells and mitigate/abrogate pre-existing memory B and T-cell responses that cause AD”. The negative immunization approach will be administered, utilizing novel and enabling microneedle arrays (MNAs) developed in our laboratories. These MNAs integrate and release biologically active agents, with highly replicable dosage control and have been formulated to achieve simultaneous delivery of allergen / Ag and neuroimmunomodulatory small molecules to a specific skin stratus. Combining this innovative immunoregulatory approach with our novel MNA delivery technology, will enable us to engineer the cutaneous microenvironment “in vivo” for the prevention and therapy of AD. Importantly, our experiments include translational studies focusing on human skin that are specifically designed to enable rapid translation of this strategy to clinical trials.