학술논문
Death Receptor 5–Targeted Depletion of Interleukin-23–Producing Macrophages, Th17, and Th1/17 Associated With Defective Tyrosine Phosphatase in Mice and Patients With Rheumatoid Arthritis
Document Type
Academic Journal
Author
Source
Arthritis & Rheumatism. Oct 01, 2013 65(10):2594-2605
Subject
Language
English
ISSN
0004-3591
Abstract
OBJECTIVE: METHODS: Ubiquitous Cre (Ubc.Cre) human/mouse-chimeric DR5–transgenic mice were crossed with viable SHP-1–defective motheaten (me/me) 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 me/me mice. In DR5-transgenic me/me 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