Engineering Specific Regulatory T Cells to Treat Allergy

工程化特异性调节 T 细胞来治疗过敏

• 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
• 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

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.

摘要： 在变态反应中需要预防和逆转不良免疫应答的新疗法， 自身免疫和单基因疾病。我们实验室的重点是开发和翻译 预防和逆转这种不良免疫反应的有效疗法。比如说， 对食物、毒液或花粉过敏的美国人多达五分之一， 涉及提供系统性症状缓解，很少提供直接努力预防或 具体的反应。该项目的长期目标是开发一个 治疗方法，安全地赋予长期持久的保护，防止过敏性疾病， 抗原特异性方式。调节性T细胞（Treg）疗法是有潜力的，但 多克隆TclA不是特异性的。我们的实验室已经开发出了工程化的人类和老鼠 调节性T细胞（TcR），通过表达单链Fv或T细胞 受体（TCR）作为嵌合抗原受体（CAR），两者都显示出在免疫应答中的功效。 在血友病和自身免疫模型中的体外和体内。最近，我们修改了Treg 一种在T细胞上表达抗原的方法;这些细胞，我们称之为BAR（B细胞抗体 受体T细胞）可以通过B细胞识别而与特定的B细胞相互作用并抑制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， 其他车的方法。重要的是，BAR T可以抑制被动免疫系统中的反应性。 过敏模型，结果表明IgE致敏的肥大细胞的直接活性。我们 假设BAR T具有治疗变态反应潜力。在这一建议中，我们希望重点 对BAR调节性T细胞有作用，因为它们靶向相关的特定B细胞或IgE致敏的肥大细胞。 基于我们的初步数据，人和鼠的BAR T细胞在一个细胞中都有功能， 在对卵清蛋白（OVA）过敏的模型中，我们的目标是利用这些BAR T蛋白在两种活性 和被动过敏反应模型，以确定其对IgE反应的影响，并跟踪其 贩运和持久性，以及通过靶向IgE致敏的肥大细胞的作用机制 细胞本研究的结果将提供临床前证据，证明其有效性， 翻译不良免疫反应。