Constitutive IL-1RA production by modified immune cells protects against IL-1-mediated inflammatory disorders.
Constitutive IL-1RA production by modified immune cells protects against IL-1-mediated inflammatory disorders.
复制标题
修饰的免疫细胞产生的组成型 IL-1RA 可预防 IL-1 介导的炎症性疾病。
DOI：
10.1126/scitranslmed.ade3856
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发表时间：
2023
影响因子：
17.1
通讯作者：
Hoffman,
中科院分区：
文献类型：
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作者：
Colantuoni,Mariasilvia;JofraHernandez,Raisa;Pettinato,Emanuela;Basso-Ricci,Luca;Magnani,Laura;Andolfi,Grazia;Rigamonti,Chiara;Finardi,Annamaria;Romeo,Valentina;Soldi,Monica;SergiSergi,Lucia;Rocchi,Martina;Scala,Serena;Hoffman,
白细胞介素-1（IL-1）通路的失调导致免疫疾病，其可导致慢性组织和器官炎症。尽管IL-1阻断剂在改善这些症状和改善患者生活质量方面显示出希望，但迫切需要更有效、持久的治疗。我们开发了一种慢病毒（LV）介导的基因转移策略，使用移植的自体造血干/祖细胞（HSPC）作为IL-1受体拮抗剂（IL-1 RA）的来源，用于全身递送到组织和器官。用编码IL-1 RA的LV转导的小鼠和人HSPC的移植确保了稳定的IL-1 RA产生，同时维持了HSPC在体内的克隆形成和分化能力。我们研究了细胞介导的IL-1 RA递送在IL-1依赖性炎症的三种模型中的功效，其中治疗在诱导型痛风模型中阻碍了中性粒细胞募集，在cryopyrin相关周期性综合征的遗传模型中预防了全身性和多组织炎症，并且在多发性硬化症的实验性自身免疫性脑脊髓炎模型中降低了疾病严重程度。我们的研究结果表明，HSPC介导的IL-1 RA递送作为一种潜在的治疗方式，可用于抑制涉及IL-1驱动的炎症的多种免疫相关疾病中的组织和器官炎症。
Dysregulation of the interleukin-1 (IL-1) pathway leads to immune diseases that can result in chronic tissue and organ inflammation. Although IL-1 blockade has shown promise in ameliorating these symptoms and improving patients’ quality of life, there is an urgent need for more effective, long-lasting treatments. We developed a lentivirus (LV)–mediated gene transfer strategy using transplanted autologous hematopoietic stem/progenitor cells (HSPCs) as a source of IL-1 receptor antagonist (IL-1RA) for systemic delivery to tissues and organs. Transplantation of mouse and human HSPCs transduced with an IL-1RA–encoding LV ensured stable IL-1RA production while maintaining the clonogenic and differentiation capacities of HSPCs in vivo. We examined the efficacy of cell-mediated IL-1RA delivery in three models of IL-1–dependent inflammation, for which treatment hindered neutrophil recruitment in an inducible model of gout, prevented systemic and multi-tissue inflammation in a genetic model of cryopyrin-associated periodic syndromes, and reduced disease severity in an experimental autoimmune encephalomyelitis model of multiple sclerosis. Our findings demonstrate HSPC-mediated IL-1RA delivery as a potential therapeutic modality that can be exploited to suppress tissue and organ inflammation in diverse immune-related diseases involving IL-1–driven inflammation.