PMID- 22006294
OWN - NLM
STAT- MEDLINE
DCOM- 20120914
LR  - 20211020
IS  - 1529-0131 (Electronic)
IS  - 0004-3591 (Print)
IS  - 0004-3591 (Linking)
VI  - 64
IP  - 4
DP  - 2012 Apr
TI  - Treatment of arthritis by macrophage depletion and immunomodulation: testing an 
      apoptosis-mediated therapy in a humanized death receptor mouse model.
PG  - 1098-109
LID - 10.1002/art.33423 [doi]
AB  - 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.
CI  - Copyright (c) 2012 by the American College of Rheumatology.
FAU - Li, Jun
AU  - Li J
AD  - University of Alabama at Birmingham, AL, USA.
FAU - Hsu, Hui-Chen
AU  - Hsu HC
FAU - Yang, PingAr
AU  - Yang P
FAU - Wu, Qi
AU  - Wu Q
FAU - Li, Hao
AU  - Li H
FAU - Edgington, Laura E
AU  - Edgington LE
FAU - Bogyo, Matthew
AU  - Bogyo M
FAU - Kimberly, Robert P
AU  - Kimberly RP
FAU - Mountz, John D
AU  - Mountz JD
LA  - eng
GR  - P30 AI027767/AI/NIAID NIH HHS/United States
GR  - R01 AI071110-04/AI/NIAID NIH HHS/United States
GR  - R01 EB005011/EB/NIBIB NIH HHS/United States
GR  - P30 AR048311-08/AR/NIAMS NIH HHS/United States
GR  - I01 BX000600/BX/BLRD VA/United States
GR  - P30 AR048311-09/AR/NIAMS NIH HHS/United States
GR  - P30 AR048311-10/AR/NIAMS NIH HHS/United States
GR  - R01 AI071110-01A2/AI/NIAID NIH HHS/United States
GR  - R01 AI071110/AI/NIAID NIH HHS/United States
GR  - P30 AI027767-24/AI/NIAID NIH HHS/United States
GR  - R01-AI-71110-02S1/AI/NIAID NIH HHS/United States
GR  - P30 AR046031/AR/NIAMS NIH HHS/United States
GR  - T32 CA009302/CA/NCI NIH HHS/United States
GR  - 1-R01-EB-005011-06/EB/NIBIB NIH HHS/United States
GR  - R01-AI-083705-01A2/AI/NIAID NIH HHS/United States
GR  - R01 AI071110-03/AI/NIAID NIH HHS/United States
GR  - P30 AR048311/AR/NIAMS NIH HHS/United States
GR  - R01 AI071110-02S1/AI/NIAID NIH HHS/United States
GR  - P30 AI027767-23/AI/NIAID NIH HHS/United States
GR  - R01 AI083705/AI/NIAID NIH HHS/United States
GR  - P30-AR-046031/AR/NIAMS NIH HHS/United States
GR  - P30-AR-048311/AR/NIAMS NIH HHS/United States
GR  - 1-AI-071110-01A1/AI/NIAID NIH HHS/United States
GR  - R01 AI083705-01A2/AI/NIAID NIH HHS/United States
GR  - P30 AI027767-22S1/AI/NIAID NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20111013
PL  - United States
TA  - Arthritis Rheum
JT  - Arthritis and rheumatism
JID - 0370605
RN  - 0 (Antibodies, Monoclonal)
RN  - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand)
SB  - IM
MH  - Animals
MH  - Antibodies, Monoclonal/*therapeutic use
MH  - Apoptosis/drug effects/*immunology
MH  - Arthritis, Experimental/*drug therapy/immunology/metabolism
MH  - Disease Models, Animal
MH  - Humans
MH  - Joints/drug effects/immunology
MH  - Macrophages/drug effects/*immunology
MH  - Mice
MH  - Receptors, TNF-Related Apoptosis-Inducing Ligand/*metabolism
MH  - Severity of Illness Index
MH  - T-Lymphocytes/drug effects/immunology/metabolism
PMC - PMC3596268
MID - NIHMS331856
COIS- All authors claim to have no financial interests which could create a potential 
      conflict of interest or the appearance of a conflict of interest with regard to 
      the work.
EDAT- 2011/10/19 06:00
MHDA- 2012/09/15 06:00
PMCR- 2013/04/01
CRDT- 2011/10/19 06:00
PHST- 2011/10/19 06:00 [entrez]
PHST- 2011/10/19 06:00 [pubmed]
PHST- 2012/09/15 06:00 [medline]
PHST- 2013/04/01 00:00 [pmc-release]
AID - 10.1002/art.33423 [doi]
PST - ppublish
SO  - Arthritis Rheum. 2012 Apr;64(4):1098-109. doi: 10.1002/art.33423. Epub 2011 Oct 
      13.