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： 变态反应需要新的疗法来预防和逆转不良免疫反应， 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。例如, 对食物、毒液或花粉的过敏影响多达五分之一的美国人，但治疗主要是 包括提供系统性症状缓解，很少有直接努力预防或 反转特定的反应。这个项目的长期目标是开发一种 安全地提供对变态反应性疾病的长期保护的治疗方法 抗原特异性方式。调节性T细胞(Treg)疗法有潜在的前景，但 多克隆树不是特异性的。我们的实验室已经开发出了工程化的人和老鼠 调节性T细胞(Tregs)，通过表达单链Fv或T细胞而呈现特异性 受体(TCR)作为嵌合抗原受体(CAR)，这两种受体都在 血友病和自身免疫模型的体外和体内实验。最近，我们修改了这个Treg 在树突状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，这是一种比非特异性免疫调节剂或 其他车辆接近。重要的是，杆状支架可以抑制被动的反应性。 过敏反应模型，这一结果表明IgE致敏的肥大细胞直接活动。我们 假设BAR Tregs具有治疗过敏的潜力。在这项提案中，我们希望将重点放在 在BAR树突状细胞上，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，人类和小鼠的杆状突起在 卵清蛋白(OVA)过敏模型，我们的目标是在两种活动中利用这些Bar Tregs 和被动过敏反应模型，以确定它们对IgE反应的影响并遵循它们的 靶向IgE致敏肥大的转运和持久性及其作用机制 细胞。这项研究的结果将为临床疗效提供临床前证据。 不良免疫反应的翻译。