Molly Klimak, Amanda Cimino, Kristin L Lenz, Luke E Springer, Kelsey H Collins, Natalia S Harasymowicz, Nathan Xu, Christine T N Pham, Farshid Guilak
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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.</p><p><strong>Results: </strong>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. 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引用次数: 0
摘要
背景:类风湿性关节炎(RA)是一种全身性自身免疫性疾病,其特点是炎症程度加剧,主要表现在关节部位。巨噬细胞是导致类风湿性关节炎恶化的关键因素,会导致慢性炎症的持续存在以及白细胞介素 1(IL-1)等促炎细胞因子的失调。本研究的目标是开发一种基于巨噬细胞的细胞疗法,以自动调节的方式进行生物给药:为了验证概念,我们开发了 "智能 "巨噬细胞,通过递送 IL-1 抑制剂 IL-1 受体拮抗剂(IL-1Ra)来减轻 IL-1 的影响。我们用合成基因回路慢病毒转导骨髓来源的巨噬细胞,该基因回路使用了Il1rn或萤火虫荧光素酶转基因上游的NF-κB诱导启动子。利用两种类型的关节样细胞(miPSCs 衍生软骨和分离的小鼠滑膜原代成纤维细胞)来检测体外治疗保护,同时利用 K/BxN RA 小鼠模型来检测体内治疗保护:结果:这些工程巨噬细胞能重复产生治疗水平的IL-1Ra,在与组织工程软骨构建物和滑膜成纤维细胞共培养时,能成功缓解炎症激活。在体内注射后,巨噬细胞会聚集到炎症部位,减轻K/BxN小鼠RA模型的疾病严重程度:这些研究结果表明,我们成功地开发出了工程巨噬细胞,这种巨噬细胞能够根据炎症信号(如通过 NF-κB 通路)控制 IL-1 的自动调节产生,从而减轻这种细胞因子对 RA 或其他炎症性疾病的影响。该系统为在其他免疫细胞类型中应用自我调节递送系统提供了概念验证,可用于一系列疾病的治疗。
Engineered self-regulating macrophages for targeted anti-inflammatory drug delivery.
Background: 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.
Methods: 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.
Results: 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.
Conclusion: 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.
期刊介绍:
Established in 1999, Arthritis Research and Therapy is an international, open access, peer-reviewed journal, publishing original articles in the area of musculoskeletal research and therapy as well as, reviews, commentaries and reports. A major focus of the journal is on the immunologic processes leading to inflammation, damage and repair as they relate to autoimmune rheumatic and musculoskeletal conditions, and which inform the translation of this knowledge into advances in clinical care. Original basic, translational and clinical research is considered for publication along with results of early and late phase therapeutic trials, especially as they pertain to the underpinning science that informs clinical observations in interventional studies.