Induced tolerogenic dendritic cell therapy of allergic diseases

过敏性疾病的诱导耐受性树突状细胞疗法

• 批准号: 8318489
• 负责人: ULRICH H VON ANDRIAN
• 金额: $ 52.41万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-05 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318489
• 关键词: Address; Adverse event; Aftercare; Allergens; Allergic; Allergic Disease; Anaphylaxis; Animals; Antigens; Apoptosis; Asthma; Autoantigens; Autoimmune Diseases; Autologous; Back; Biocompatible Materials; Biological Assay; Bronchoalveolar Lavage; Caseins; Cell physiology; Cells; Cellular biology; Chronic; Clinical; Clinical Trials; Coculture Techniques; Collaborations; Complement Factor B; Complex; Data; Dendritic Cell Therapy; Dendritic Cells; Disease; Economic Burden; Eragrostis; Experimental Autoimmune Encephalomyelitis; Exposure to; Extrinsic asthma; Faculty; Food Hypersensitivity; Goals; Haplotypes; Harvest; Human; Hypersensitivity; Immune response; Immunosuppression; Immunotherapy; In Vitro; Incidence; Individual; Inflammatory; Inflammatory Response; Infusion procedures; Instruction; Knowledge; Leukocytes; Light; Lung Inflammation; Mediating; Medical; Milk; Milk Hypersensitivity; Modeling; Molecular; Mus; Outcome; Ovalbumin; Patients; Peptides; Peripheral Blood Mononuclear Cell; Phenotype; Physiologic pulse; Process; Property; Proteins; Pyroglyphidae; Regulatory T-Lymphocyte; Research Infrastructure; Respiratory physiology; Risk; Scheme; Severities; Signal Transduction; Sirolimus; Site; Societies; Sorting - Cell Movement; Source; Specificity; Symptoms; T memory cell; T-Lymphocyte; T-Lymphocyte Subsets; Technology; Testing; Therapeutic; Therapeutic Effect; Transforming Growth Factors; Translating; Translations; Work; antigen challenge; antigen processing; base; cell mediated immune response; clinical practice; conventional therapy; cytokine; desensitization; feeding; immunogenic; in vitro Assay; in vivo; insight; interest; mRNA Expression; monocyte; mouse model; novel; novel therapeutics; peripheral blood; pre-clinical; programs; research study; response; transcription factor

T cells mediate immune responses against self and non-self antigens (Ags), including innocuous environmental Ags, which are sometimes erroneously interpreted as 'dangerous'. Misguided responses by Th2 polarized effector T cells (Teff) against certain environmental Ags, called allergens, promote the formation of humoral and cellular inflammatory responses that precipitate clinical symptoms, which become manifest as various forms of allergy or asthma. Current clinical practice employs therapeutic strategies to tolerize allergic patients against specific allergens, indicating that pre-existing pathological Th2 responses can be 're-educated' resulting, at least in some cases, in permanent cures. However, current immunotherapy schemes typically require many months of continuous treatment, are unsuccessful in a sizable fraction of patients and carry the risk of adverse events, particularly anaphylaxis. Project 3 proposes to explore the use of induced tolerogenic dendritic cells (itDC) as an alternative strategy to rapidly achieve allergen-specific immunological tolerance in individuals suffering from allergic asthma or food allergy. The rationale for this project is based on the fact that T cell function is controlled by dendritic cells (DC), which acquire and process Ags and, depending upon their maturation and differentiation status, instruct Agspecific T cells either to mount an effector response or to develop tolerance. A body of preliminary data indicates that short-term exposure of murine as well as human DC to rapamycin and transforming growth factor B (TGFB) coverts the cells into itDC. Preliminary in vitro and in vivo experiments suggest that Ag-pulsed itDC exert tolerogenic effects on Ag-specific conventional T cells a) by converting them into Foxp3+ regulatory T cells (Treg) and b) by deleting Teff at sites of Ag challenge. In light of these findings, the hypothesis will be tested that itDC may be useful to treat T cell-dependent allergic diseases. To achieve this goal, Aim 1 will establish whether and to what extent itDC exert therapeutic effects in mouse models of Agdriven allergic asthma and food allergy. Aim 2 will generate critical clues regarding the clinical translatability of findings in murine models to human food allergy and allergic asthma by systematically exploring the capacity of patient-derived DC to induce tolerogenic responses in autologous T cell subsets. These experiments will be performed in close synergy with Projects 1 and 2 and rely on technology, materials and support from each Core of this Program. If our hypothesis can be proven correct, our objective will be to translate the itDC technology into a clinical platform for cellular therapy of food allergy and asthma.

T 细胞介导针对自身和非自身抗原 (Ag) 的免疫反应，包括无害的环境抗原，这些抗原有时被错误地解释为“危险”。 Th2 极化效应 T 细胞 (Teff) 针对某些环境抗原（称为过敏原）的误导性反应，促进体液和细胞炎症反应的形成，从而引发临床症状，进而导致临床症状。 表现为各种形式的过敏或哮喘。目前的临床实践采用治疗策略来使过敏患者耐受特定的过敏原，这表明预先存在的病理性Th2反应可以被“重新教育”，从而至少在某些情况下实现永久治愈。然而，目前的免疫治疗方案通常需要数月的连续治疗，在相当一部分患者中不成功，并且存在不良事件的风险，特别是过敏反应。项目 3 提议探索使用诱导耐受树突状细胞 (itDC) 作为替代策略，以在患有过敏性哮喘或食物过敏的个体中快速实现过敏原特异性免疫耐受。 该项目的基本原理是基于以下事实：T 细胞功能由树突状细胞 (DC) 控制，树突状细胞获取并处理 Ag，并根据其成熟和分化状态，指示 Ag 特异性 T 细胞产生效应反应或产生耐受性。初步数据主体 表明小鼠和人类 DC 短期暴露于雷帕霉素和转化生长因子 B (TGFB) 会将细胞转化为 itDC。初步的体外和体内实验表明，Ag 脉冲的 itDC 通过将 Ag 特异性常规 T 细胞转化为 Foxp3+ 对 Ag 特异性常规 T 细胞发挥耐受作用 调节性 T 细胞 (Treg) 和 b) 通过删除 Ag 攻击位点的 Teff。根据这些发现，将检验 itDC 可能有助于治疗 T 细胞依赖性过敏性疾病的假设。为了实现这一目标，目标 1 将确定 itDC 是否以及在多大程度上在 Agdriven 小鼠模型中发挥治疗作用 过敏性哮喘和食物过敏。目标 2 将通过系统地探索源自患者的 DC 在自体 T 细胞亚群中诱导耐受性反应的能力，为人类食物过敏和过敏性哮喘的小鼠模型研究结果的临床可转化性提供关键线索。这些实验将与项目1和2紧密配合进行，并依赖于技术、材料和 来自该计划每个核心的支持。如果我们的假设被证明是正确的，我们的目标将是将 itDC 技术转化为食物过敏和哮喘细胞治疗的临床平台。