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

J Li, HC Hsu, PA Yang, Q Wu, H Li… - Arthritis & …, 2012 - Wiley Online Library
J Li, HC Hsu, PA Yang, Q Wu, H Li, LE Edgington, M Bogyo, RP Kimberly, JD Mountz
Arthritis & Rheumatism, 2012Wiley Online Library
Objective 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). Methods 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 …
Objective
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).
Methods
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.
Results
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.
Conclusion
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.
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