Akademik Veri Yönetim Sistemi
HUMAN GENE THERAPY, 2026 (SCI-Expanded, Scopus)
Rheumatoid arthritis is a chronic autoimmune disease characterized by persistent synovial inflammation and progressive joint destruction. Although biological disease-modifying anti-rheumatic drugs (DMARDs) have transformed treatment, their systemic immunosuppression, high cost, and incomplete efficacy in certain joints remain significant challenges. To address these limitations, we developed a localized gene therapy using the human indoleamine 2,3-dioxygenase (hIDO) gene driven by the E-selectin (ELAM-1) promoter, which is responsive to inflammatory cytokines. We assessed ELAM-1 promoter responsiveness to interleukin-1 beta (IL-1 beta) stimulation in vitro mainly using the HeLa cell line, measuring hIDO expression and enzymatic activity by enzyme-linked immunosorbent assay, quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blotting and kynurenine assays. In vivo, we established a robust collagen-induced arthritis (CIA) model in BALB/c mice, which are normally resistant to CIA, and delivered pELAM-1pro/hIDO plasmids intra-articularly via liposomes. Therapeutic efficacy was evaluated by clinical scoring, ankle circumference, histopathology, immunohistochemical quantification of synovial CD4(+) T cells and CD68(+) macrophages, and endpoint immunohistochemical assessment of IDO expression. In vitro, the ELAM-1 promoter allowed rapid, high-level expression of hIDO within 2 h of IL-1 beta stimulation, without IDO-induced suppression of the promoter. In vivo, pELAM-1pro/hIDO treatment significantly reduced ankle swelling and clinical arthritis scores more rapidly than constitutive CMV-driven hIDO, achieving marked histological improvement on day 7. The treated joints exhibited substantial reductions in pathogenic CD4(+) T cells and CD68(+) macrophages, consistent with the IDO immunoregulatory mechanism. This study supports the feasibility of a localized gene therapy approach using an inflammation-responsive promoter and suggests localized immunomodulation at disease sites in a manner consistent with inflammation-associated promoter activity.