Targeted depletion of macrophages using an anti-human DR5 antibody prevented arthritis in a novel human/mouse chimeric DR5 Tg mouse (135.29)
| Autor: | Jun Li, Ping-Ar Yang, Qi Wu, Hui-Chen Hsu, John Mountz |
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| Rok vydání: | 2010 |
| Předmět: | |
| Zdroj: | The Journal of Immunology. 184:135.29-135.29 |
| ISSN: | 1550-6606 0022-1767 |
| DOI: | 10.4049/jimmunol.184.supp.135.29 |
| Popis: | The severity of rheumatoid arthritis (RA) correlates with the activation and abundance of macrophages in the inflamed tissues and circulation. The purpose of this study is to generate a humanized mouse (hu/mo) DR5 transgenic (Tg) mouse in which the hu/mo DR5 is targeted to the monocytes/macrophages and promote apoptosis by an anti-human DR5 antibody, TRA-8. The DR5 Tg consists of a human extracellular domain, a mouse transmembrane and intracellular domain under the regulation of the 3kb mo DR5 promoter. A Floxed STOP was inserted between the promoter and hu/mo DR5. Targeted expression of the DR5 Tg in monocytes/macrophages was generated by crossing the DR5 Tg with the lysozyme-Cre (LysMCre) mice. Arthritis was induced by intradermal injection of chicken type II collagen (CII) in CFA/IFA on day 0 and boost on day 21. There was a high percentage of CD11b+ macrophage in the spleen of CII immunized non-Tg mice (10.7%) compared to naïve mice (2.5%). TRA-8 (0.2 mg) was administrated I.V. every 3 days for 3 doses starting at day 14 after boost. After TRA-8 treatment, there was a significant decrease (55.6%) of CD11bhighGr-1+ macrophages. TRA-8 treatment also suppressed the development of arthritis in LysMCre+ hu/mo DR5+ Tg mice. This study demonstrated that selectively reducing the numbers of activated macrophage by using an anti-human DR5 antibody is a novel therapeutic strategy applicable to human RA, which might lead to prevention of joint inflammation and arthritis. |
| Databáze: | OpenAIRE |
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