Abstract | OBJECTIVE: METHODS: Ubiquitous Cre (Ubc.Cre) human/mouse-chimeric DR5-transgenic mice were crossed with viable SHP-1-defective motheaten (mev/mev) mice. TRA-8 was administered weekly for up to 4 weeks. The clinical scores, histopathologic severity, and macrophage and CD4 T cell phenotypes were evaluated. The role of TRA-8 in depleting inflammatory macrophages and CD4 T cells was also evaluated, using synovial fluid obtained from patients with rheumatoid arthritis (RA). RESULTS: The levels of inflammatory macrophages ( interleukin-23-positive [IL-23+] IRF-5+) and CD4 T cells (IL-17+ GM-CSF+) were elevated in mev/mev mice. In DR5-transgenic mev/mev mice, DR5 expression was up-regulated in these 2 cell populations. TRA-8 treatment depleted these cell populations and resulted in a significant reduction in inflammation and in the titers of autoantibodies. In synovial cells from patients with RA, the expression of IRF5 and DR5 was negatively correlated with the expression of PTPN6. TRA-8, but not TRAIL, suppressed RA inflammatory macrophages and Th17 cells under conditions in which the expression of SHP-1 is low. CONCLUSION: In contrast to TRAIL, which lacks the capability to counteract the survival signal in the absence of SHP-1, TRA-8 eliminated both IRF-5+ IL-23+ M1 macrophages and pathogenic GM-CSF+ IL-17+ CD4 T cells in a SHP-1-independent manner. The results of the current study suggest that TRA-8 can deplete inflammatory cell populations that result from a hyperactive GM-CSF/IRF-5 axis.
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Authors | Jun Li, PingAr Yang, Qi Wu, Hao Li, Yanna Ding, Hui-Chen Hsu, David M Spalding, John D Mountz |
Journal | Arthritis and rheumatism
(Arthritis Rheum)
Vol. 65
Issue 10
Pg. 2594-605
(Oct 2013)
ISSN: 1529-0131 [Electronic] United States |
PMID | 23818173
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
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Copyright | Published 2013. This article is a U.S. Government work and is in the public domain in the USA. |
Chemical References |
- Antibodies, Monoclonal
- IRF5 protein, human
- Interferon Regulatory Factors
- Interleukin-23
- Receptors, TNF-Related Apoptosis-Inducing Ligand
- TRA-8 monoclonal antibody
- PTPN6 protein, human
- Protein Tyrosine Phosphatase, Non-Receptor Type 6
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Topics |
- Adult
- Aged
- Animals
- Antibodies, Monoclonal
(pharmacology)
- Arthritis, Rheumatoid
(metabolism, pathology)
- Disease Models, Animal
- Female
- Humans
- Interferon Regulatory Factors
(metabolism)
- Interleukin-23
(metabolism)
- Macrophages
(metabolism, pathology)
- Male
- Mice
- Mice, Transgenic
- Middle Aged
- Protein Tyrosine Phosphatase, Non-Receptor Type 6
(deficiency, metabolism)
- Receptors, TNF-Related Apoptosis-Inducing Ligand
(antagonists & inhibitors, drug effects, metabolism)
- Synovial Membrane
(metabolism, pathology)
- Th1 Cells
(metabolism, pathology)
- Th17 Cells
(metabolism, pathology)
- Up-Regulation
(drug effects)
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