Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by increased levels of inflammation that primarily manifests in the joints. Macrophages act as key drivers for the progression of RA, contributing to the perpetuation of chronic inflammation and dysregulation of pro-inflammatory cytokines such as interleukin 1 (IL-1). The goal of this study was to develop a macrophage-based cell therapy for biologic drug delivery in an autoregulated manner. For proof-of-concept, we developed “smart” macrophages to mitigate the effects of IL-1 by delivering its inhibitor, IL-1 receptor antagonist (IL-1Ra). Bone marrow-derived macrophages were lentivirally transduced with a synthetic gene circuit that uses an NF-κB inducible promoter upstream of either the Il1rn or firefly luciferase transgenes. Two types of joint like cells were utilized to examine therapeutic protection in vitro, miPSCs derived cartilage and isolated primary mouse synovial fibroblasts while the K/BxN mouse model of RA was utilized to examine in vivo therapeutic protection. These engineered macrophages were able to repeatably produce therapeutic levels of IL-1Ra that could successfully mitigate inflammatory activation in co-culture with both tissue-engineered cartilage constructs and synovial fibroblasts. Following injection in vivo, macrophages homed to sites of inflammation and mitigated disease severity in the K/BxN mouse model of RA. These findings demonstrate the successful development of engineered macrophages that possess the ability for controlled, autoregulated production of IL-1 based on inflammatory signaling such as via the NF-κB pathway to mitigate the effects of this cytokine for applications in RA or other inflammatory diseases. This system provides proof of concept for applications in other immune cell types as self-regulating delivery systems for therapeutic applications in a range of diseases.

中文翻译：

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用于靶向抗炎药递送的工程化自我调节巨噬细胞


类风湿性关节炎 （RA） 是一种系统性自身免疫性疾病，其特征是炎症水平升高，主要表现在关节中。巨噬细胞是 RA 进展的关键驱动因素，导致慢性炎症的持续存在和促炎细胞因子（如白细胞介素 1 （IL-1））失调。本研究的目标是开发一种基于巨噬细胞的细胞疗法，用于以自动调节方式进行生物药物递送。为了进行概念验证，我们开发了“智能”巨噬细胞，通过递送其抑制剂 IL-1 受体拮抗剂 （IL-1Ra） 来减轻 IL-1 的影响。骨髓来源的巨噬细胞用合成基因回路慢病毒转导，该回路使用 Il1rn 或萤火虫荧光素酶转基因上游的 NF-κB 诱导启动子。使用两种类型的关节样细胞来检查体外的治疗保护作用，miPSCs 衍生的软骨和分离的原代小鼠滑膜成纤维细胞，而 RA 的 K/BxN 小鼠模型用于检查体内治疗保护。这些工程巨噬细胞能够重复产生治疗水平的 IL-1Ra，在与组织工程软骨构建体和滑膜成纤维细胞共培养时可以成功减轻炎症激活。体内注射后，巨噬细胞归居于炎症部位并减轻了 RA 的 K/BxN 小鼠模型中的疾病严重程度。这些发现证明了工程巨噬细胞的成功开发，这些巨噬细胞具有基于炎症信号传导（例如通过 NF-κB 通路）受控、自动调节 IL-1 产生的能力，以减轻该细胞因子在 RA 或其他炎症性疾病中应用的影响。 该系统为其他免疫细胞类型的应用提供了概念验证，作为一系列疾病治疗应用的自我调节递送系统。