MNA Delivery of Neurokinin 1 Receptor Antagonists to Treat Atopic Dermatitis

摘要 通过这里提出的研究，我们将发展一种“阴性免疫”的策略，以实现抗原特异性。 特应性皮炎(AD)是一种非常常见的慢性炎症性疾病，对预防和免疫治疗的耐受性 皮肤病造成相当大的社会经济负担。我们打算操纵神经免疫系统 皮肤中用于预防和治疗病理性先天免疫反应和获得性免疫反应的调节网络 说明AD的急性期和慢性期。新的“负面免疫”方法已经被 防止原始T和B细胞的启动，并消除现有的过敏原特异性T和B细胞 效应器反应。为了做到这一点，我们将给过敏原/抗原和 神经激肽-1受体(NK1R)阻止其炎性激动剂与受体结合，这种相互作用是 对启动先天和适应性效应器和记忆免疫功能至关重要。这样做的理由是 方法是消除/减少皮肤过敏原/抗原遇到时的炎症将保持 为抗原提呈细胞(APC)提供静止的微环境。这将导致产生反 炎性APC能够以耐受性的方式将遇到的抗原呈递给T细胞。这 该战略将首次使预防和治疗阿尔茨海默病的抗原特异性战略成为可能。 我们假设：“通过有效的协同作用，促进抗炎皮肤微环境。” 递送变应原/抗原和NK1R拮抗剂将产生抗炎APC以耐受Ag 并减轻/消除引起阿尔茨海默病的预先存在的记忆B细胞和T细胞反应。 将使用新的和使能的微针实施阴性免疫方法 我们实验室开发的阵列(MNAs)。这些MNAs整合和释放生物活性物质，与 高度可复制的剂量控制，并已被配方以实现过敏原/抗原和 神经免疫调节小分子作用于特定的皮肤层。结合这一创新的免疫调节 采用我们新颖的MNA输送技术，将使我们能够设计皮肤微环境 “体内”防治阿尔茨海默病。重要的是，我们的实验包括翻译研究 在人类皮肤上，专门设计使这一策略能够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.