Engineered self-regulating macrophages for targeted anti-inflammatory drug delivery.

Autor: Klimak M; Department of Orthopaedic Surgery, Washington University in St. Louis, St. Louis, MO, 63110, USA.; Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, 63105, USA.; Shriners Hospitals for Children - St. Louis, St. Louis, MO, 63110, USA.; Center of Regenerative Medicine, Washington University in St. Louis, Campus Box 8233, Couch Biomedical Research Bldg., Room 3121, St. Louis, MO, 63110, USA., Cimino A; Department of Orthopaedic Surgery, Washington University in St. Louis, St. Louis, MO, 63110, USA.; Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, 63105, USA.; Shriners Hospitals for Children - St. Louis, St. Louis, MO, 63110, USA.; Center of Regenerative Medicine, Washington University in St. Louis, Campus Box 8233, Couch Biomedical Research Bldg., Room 3121, St. Louis, MO, 63110, USA., Lenz KL; Department of Orthopaedic Surgery, Washington University in St. Louis, St. Louis, MO, 63110, USA.; Shriners Hospitals for Children - St. Louis, St. Louis, MO, 63110, USA.; Center of Regenerative Medicine, Washington University in St. Louis, Campus Box 8233, Couch Biomedical Research Bldg., Room 3121, St. Louis, MO, 63110, USA., Springer LE; Center of Regenerative Medicine, Washington University in St. Louis, Campus Box 8233, Couch Biomedical Research Bldg., Room 3121, St. Louis, MO, 63110, USA.; Division of Rheumatology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA., Collins KH; Department of Orthopaedic Surgery, Washington University in St. Louis, St. Louis, MO, 63110, USA.; Shriners Hospitals for Children - St. Louis, St. Louis, MO, 63110, USA.; Center of Regenerative Medicine, Washington University in St. Louis, Campus Box 8233, Couch Biomedical Research Bldg., Room 3121, St. Louis, MO, 63110, USA.; Department of Orthopaedic Surgery, University of California, San Francisco, San Francisco, CA, 94143, USA., Harasymowicz NS; Department of Orthopaedic Surgery, Washington University in St. Louis, St. Louis, MO, 63110, USA.; Shriners Hospitals for Children - St. Louis, St. Louis, MO, 63110, USA.; Center of Regenerative Medicine, Washington University in St. Louis, Campus Box 8233, Couch Biomedical Research Bldg., Room 3121, St. Louis, MO, 63110, USA.; Department of Orthopaedic Surgery, University of Utah, Salt Lake City, UT, 84108, USA., Xu N; Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, 63105, USA., Pham CTN; Center of Regenerative Medicine, Washington University in St. Louis, Campus Box 8233, Couch Biomedical Research Bldg., Room 3121, St. Louis, MO, 63110, USA.; Division of Rheumatology, Department of Medicine, Washington University in St. Louis, St. Louis, MO, 63110, USA., Guilak F; Department of Orthopaedic Surgery, Washington University in St. Louis, St. Louis, MO, 63110, USA. guilak@wustl.edu.; Department of Biomedical Engineering, Washington University in St. Louis, St. Louis, MO, 63105, USA. guilak@wustl.edu.; Shriners Hospitals for Children - St. Louis, St. Louis, MO, 63110, USA. guilak@wustl.edu.; Center of Regenerative Medicine, Washington University in St. Louis, Campus Box 8233, Couch Biomedical Research Bldg., Room 3121, St. Louis, MO, 63110, USA. guilak@wustl.edu.
Jazyk: angličtina
Zdroj: Arthritis research & therapy [Arthritis Res Ther] 2024 Nov 06; Vol. 26 (1), pp. 190. Date of Electronic Publication: 2024 Nov 06.
DOI: 10.1186/s13075-024-03425-3
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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