MNA Delivery of Neurokinin 1 Receptor Antagonists to Treat Atopic Dermatitis

MNA 递送神经激肽 1 受体拮抗剂治疗特应性皮炎

• 批准号: 10171787
• 负责人: Louis D Falo
• 金额: $ 47.27万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10171787
• 关键词: Accounting; Acute; Address; Adjuvant; Adult; Affect; Afferent Neurons; Affinity; Agonist; Allergens; Allergic; Anatomy; Anti-Inflammatory Agents; Antibiotics; Antigen-Presenting Cells; Antigens; Atopic Dermatitis; B-Lymphocytes; Binding; Biological; Biomedical Engineering; Cell Maturation; Cell Survival; Cell physiology; Cells; Child; Chronic; Chronic Phase; Clinical Trials; Confusion; Cutaneous; Dendritic Cells; Developed Countries; Developing Countries; Disease; Dose; Effector Cell; Engineering; Environment; Exposure to; FDA approved; Generations; Geometry; Health; Homing; Human; Hypersensitivity; IgE; Immune; Immune Cell Suppression; Immunity; Immunization; Immunologic Memory; Immunology; Immunosuppression; Immunotherapy; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Laboratories; Leukocytes; Maintenance; Mediating; Memory B-Lymphocyte; Methods; Mus; Natural Immunity; Neuroimmune; Neurology; Neuropeptides; Organ Culture Techniques; Painless; Pathogenesis; Pathogenicity; Pathologic; Pharmaceutical Preparations; Phase; Prevalence; Prevention; Prevention strategy; Prevention therapy; Quality of life; Relapse; Reproducibility; Role; Signal Transduction; Site; Skin; Substance P; Substance P Receptor; Supporting Cell; System; T cell response; T-Lymphocyte; Tachykinin; Technology; Testing; Time; adaptive immune response; adaptive immunity; atopy; autocrine; autoreactive T cell; chronic inflammatory skin; cost; crosslink; desensitization; design; dosage; effector T cell; experimental study; immune function; immunoregulation; in vivo; innovation; manufacturing process; mast cell; mouse model; neuroinflammation; novel; prevent; receptor binding; response; skin disorder; skin prick test; small molecule; socioeconomics; symptom treatment; translational approach; translational model; translational study

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.

抽象的 通过此处提出的研究，我们将制定一种“阴性免疫”策略，以实现抗原特异性 预防和免疫疗法的特应性皮炎（AD）的耐受性，这是一种高度常见的慢性炎症 皮肤疾病表现出相当大的社会经济负担。我们打算操纵神经免疫 皮肤中的监管网络，以预防和治疗病理性的先天和适应性免疫回报 考虑AD的急性和慢性阶段。新颖的“阴性免疫抑制”方法是 设计以防止幼稚的T和B细胞启动，并启动放射性过敏原特异性T和B细胞 效应子响应。为此，我们将管理员过敏原/抗原和对抗者 Neurokinin-1受体（NK1R）以防止其炎性激动剂的受体结合，这种相互作用是 对先天和适应性效应子和记忆免疫功能的主动性至关重要。理由 方法是消除/减少皮肤过敏原/Ag遭遇时的注射将保持 静止的抗原呈递细胞（APC）的微环境。这将导致抗 能够以耐受性方式向T细胞呈现抗原的炎症APC。这 策略将首次实现预防和治疗AD的抗原特定策略。 我们假设：“通过有效的共同环境促进抗炎皮肤微环境 过敏原/AG和NK1R拮抗剂的递送将产生抗炎APC以耐受Ag 特定的T细胞并减轻/消除导致AD的预先存在的内存B和T细胞响应”。 使用新颖和启用微针，将采用阴性免疫方法 阵列（MNA）在我们的实验室中开发。这些MNA与 高度可复制的剂量控制并已制定以实现过敏原 / Ag的简单递送 神经免疫调节的小分子至特定的皮肤地层。结合这种创新的免疫调节 我们新颖的MNA输送技术的方法将使我们能够设计皮肤微环境 预防和治疗AD的“体内”。重要的是，我们的实验包括转化研究的重点 在人类皮肤上的专门设计，以使该策略快速转化为临床试验。