| Autor: |
Fu-Yao Jiang, Yan-Zhu Zhang, Yuan-Hong Tai, Chien-Yu Chou, Yu-Ching Hsieh, Ya-Chi Chang, Hsiao-Chen Huang, Zhi-Qin Li, Yuan-Chin Hsieh, I-Ju Chen, Bo-Cheng Huang, Yu-Cheng Su, Wen-Wei Lin, Hsin-Chieh Lin, Jui-I Chao, Shyng-Shiou F. Yuan, Yun-Ming Wang, Tian-Lu Cheng, Shey-Cherng Tzou |
| Jazyk: |
angličtina |
| Rok vydání: |
2023 |
| Předmět: |
|
| Zdroj: |
Inflammation and Regeneration, Vol 43, Iss 1, Pp 1-16 (2023) |
| Druh dokumentu: |
article |
| ISSN: |
1880-8190 |
| DOI: |
10.1186/s41232-023-00264-8 |
| Popis: |
Abstract Background CTLA4Ig is a dimeric fusion protein of the extracellular domain of cytotoxic T-lymphocyte protein 4 (CTLA4) and an Fc (Ig) fragment of human IgG1 that is approved for treating rheumatoid arthritis. However, CTLA4Ig may induce adverse effects. Developing a lesion-selective variant of CTLA4Ig may improve safety while maintaining the efficacy of the treatment. Methods We linked albumin to the N-terminus of CTLA4Ig (termed Alb-CTLA4Ig) via a substrate sequence of matrix metalloproteinase (MMP). The binding activities and the biological activities of Alb-CTLA4Ig before and after MMP digestion were analyzed by a cell-based ELISA and an in vitro Jurkat T cell activation assay. The efficacy and safety of Alb-CTLA4Ig in treating joint inflammation were tested in mouse collagen-induced arthritis. Results Alb-CTLA4Ig is stable and inactive under physiological conditions but can be fully activated by MMPs. The binding activity of nondigested Alb-CTLA4Ig was at least 10,000-fold weaker than that of MMP-digested Alb-CTLA4Ig. Nondigested Alb-CTLA4Ig was unable to inhibit Jurkat T cell activation, whereas MMP-digested Alb-CTLA4Ig was as potent as conventional CTLA4Ig in inhibiting the T cells. Alb-CTLA4Ig was converted to CTLA4Ig in the inflamed joints to treat mouse collagen-induced arthritis, showing similar efficacy to that of conventional CTLA4Ig. In contrast to conventional CTLA4Ig, Alb-CTLA4Ig did not inhibit the antimicrobial responses in the spleens of the treated mice. Conclusions Our study indicates that Alb-CTLA4Ig can be activated by MMPs to suppress tissue inflammation in situ. Thus, Alb-CTLA4Ig is a safe and effective treatment for collagen-induced arthritis in mice. |
| Databáze: |
Directory of Open Access Journals |
| Externí odkaz: |
|
Full text from SpringerLink