Treatment of arthritis by macrophage depletion and immunomodulation: testing an apoptosis-mediated therapy in a humanized death receptor mouse model

Jun Li, Hui-Chen Hsu, PingAr Yang, Qi Wu, Hao Li, Laura E Edgington, Matthew Bogyo, Robert P Kimberly, John D Mountz

Research output: Contribution to journalArticleResearchpeer-review

35 Citations (Scopus)

Abstract

To determine the therapeutic efficacy and immunomodulatory effect of an anti-human death receptor 5 (DR5) antibody, TRA-8, in eliminating macrophage subsets in a mouse model of type II collagen-induced arthritis (CIA). A human/mouse-chimeric DR5-transgenic mouse, under the regulation of a mouse 3-kb promoter and a loxP-flanked STOP cassette, was generated and crossed with an ubiquitous Cre (Ubc.Cre) mouse and a lysozyme M-Cre (LysM.Cre)-transgenic mouse to achieve inducible or macrophage-specific expression. Chicken type II collagen was used to induce CIA in mice, which were then treated with an anti-human DR5 antibody, TRA-8. Clinical scores, histopathologic severity, macrophage apoptosis and depletion, and T cell subset development were evaluated.
In human/mouse DR5-transgenic Ubc.Cre mice with CIA, transgenic DR5 was most highly expressed on CD11b+ macrophages, with lower expression on CD4+ T cells. In human/mouse DR5-transgenic LysM.Cre mice, transgenic DR5 was restrictively expressed on macrophages. Both in vivo near-infrared imaging of caspase activity and TUNEL staining demonstrated that TRA-8 rapidly induced apoptosis of macrophages in inflamed synovium. Depletion of pathogenic macrophages by TRA-8 led to significantly reduced clinical scores for arthritis; decreased macrophage infiltration, synovial hyperplasia, osteoclast formation, joint destruction, cathepsin activity, and inflammatory cytokine expression in joints; reduced numbers of Th17 cells; and an increased number of Treg cells in draining lymph nodes.
The anti-human DR5 antibody TRA-8 was efficacious in reducing the severity of arthritis via targeted depletion of macrophages and immunomodulation. Our data provide preclinical evidence that TRA-8 is a potential novel biologic agent for rheumatoid arthritis therapy.
Original languageEnglish
Pages (from-to)1098-1109
Number of pages12
JournalArthritis & Rheumatism
Volume64
Issue number4
DOIs
Publication statusPublished - Apr 2012
Externally publishedYes

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