Engineering Specific Regulatory T Cells to Treat Allergy

工程化特异性调节 T 细胞来治疗过敏

基本信息

批准号：
9979502
负责人：
David William Scott
金额：
$ 22.87万
依托单位：
HENRY M. JACKSON FDN FOR THE ADV MIL/MED
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-04-06 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9979502
关键词：
Affect Allergens Allergic Allergic Disease American Anaphylaxis Antigen-Presenting Cells Antigens Autoimmunity B-Lymphocytes Cell Proliferation Cell surface Cells Data Drops Dyes Egg Proteins Engineering Enzyme-Linked Immunosorbent Assay Epitopes Fc Receptor Food Hypersensitivity Future Goals Hemophilia A Human Human Engineering Hypersensitivity IgE Immune response Immunize Immunomodulators In Vitro Interleukin-10 Intravenous Label Mendelian disorder Modeling Molecular Conformation Mus Ovalbumin Peptides Pollen Receptors, Antigen, B-Cell Regulatory T-Lymphocyte Role Second Messenger Systems Specificity Symptoms System T-Cell Receptor Temperature Testing Therapeutic Transforming Growth Factor beta Translating Treg therapy Venoms base chimeric antigen receptor clinical translation cytokine desensitization effective therapy in vivo in vivo Model mast cell novel therapeutics ovalbumin-alum pre-clinical prevent response trafficking

项目摘要

Abstract: Novel therapies to prevent and reverse adverse immune responses are needed in allergy, autoimmunity, and monogenic diseases. The focus of our lab is to develop and translate effective therapies to prevent and reverse such adverse immune responses. For example, allergies to food, venom or pollen affect up to one in five Americans but treatments primarily involve provision of systemic symptomatic relief and very few offer direct efforts to prevent or reverse the specific responsiveness. The long-term goal of this project is to develop a therapeutic approach that safely confers long-lasting protection against allergic disease in an antigen-specific manner. Regulatory T-cell (Treg) therapy is potentially promising, but polyclonal Tregs are not specific. Our lab has developed engineered human and mouse regulatory T cells (Tregs), rendered specific by expression of single chain Fv or T-cell receptors (TCR) as chimeric antigen receptors (CAR), both of which have shown efficacy in vitro and in vivo in models of hemophilia and autoimmunity. Recently, we modified this Treg approach to express antigen on Tregs; these cells, which we term BAR (for B-cell Antibody Receptor Tregs), can interact and suppress specific B cells via recognition by the B-cell receptor, an approach that has long-term advantages over non-specific immune modulators or other CAR approaches. Importantly, BAR Tregs can suppress reactivity in a passive anaphylaxis model, a result that suggests direct activity of IgE-sensitized mast cells. We hypothesize that BAR Tregs have potential to treat allergy. In this proposal, we wish to focus on BAR Tregs because they target the relevant specific B cells or IgE-sensitized mast cells. Based on our preliminary data that both human and murine BAR Tregs are functional in a model of allergy to ovalbumin (OVA), our goals are to utilize these BAR Tregs in both active and passive anaphylaxis models to establish their effect on the IgE response and to follow their trafficking and persistence, as well as mechanism of action via targeting of IgE-sensitized mast cells. The results of this study would provide pre-clinical evidence for efficacy leading to clinical translation of adverse immune responses.

抽象的：过敏症需要新的疗法来预防和逆转不良免疫反应，自身免疫性疾病和单基因疾病。我们实验室的重点是开发和翻译预防和逆转此类不良免疫反应的有效疗法。例如，多达五分之一的美国人对食物、毒液或花粉过敏，但主要是治疗涉及提供系统性症状缓解，很少提供直接努力来预防或扭转特定的反应性。该项目的长期目标是开发一个安全地提供针对过敏性疾病的持久保护的治疗方法抗原特异性方式。调节性 T 细胞 (Treg) 疗法具有潜在前景，但多克隆 Tregs 不具有特异性。我们的实验室已开发出工程人类和小鼠调节性 T 细胞 (Treg)，通过单链 Fv 或 T 细胞的表达而具有特异性受体（TCR）和嵌合抗原受体（CAR），两者均已显示出功效血友病和自身免疫模型的体外和体内。最近，我们修改了这个Treg 在 Tregs 上表达抗原的方法；这些细胞，我们称之为 BAR（B 细胞抗体受体 Tregs），可以通过 B 细胞的识别相互作用并抑制特定的 B 细胞受体，一种比非特异性免疫调节剂具有长期优势的方法或其他 CAR 方法。重要的是，BAR Tregs 可以抑制被动反应的反应性过敏反应模型，该结果表明 IgE 致敏肥大细胞的直接活性。我们假设 BAR Tregs 有治疗过敏的潜力。在本提案中，我们希望重点关注 BAR Tregs 是因为它们针对相关的特定 B 细胞或 IgE 致敏的肥大细胞。根据我们的初步数据，人类和小鼠 BAR Tregs 在卵清蛋白 (OVA) 过敏模型，我们的目标是在两种活性中利用这些 BAR Tregs 和被动过敏反应模型以确定其对 IgE 反应的影响并遵循其贩运和持久性，以及通过针对 IgE 敏感肥大的作用机制细胞。这项研究的结果将为临床前的疗效提供证据，从而导致临床不良免疫反应的翻译。