Targeted Inhibition of the Complement Alternative Pathway with Complement Receptor 2 and Factor H Attenuates Collagen Antibody-Induced Arthritis in Mice

被引:60
作者
Banda, Nirmal K. [1 ]
Levitt, Brandt [1 ]
Glogowska, Magdalena J. [1 ]
Thurman, Joshua M. [2 ]
Takahashi, Kazue [3 ]
Stahl, Gregory L. [4 ]
Tomlinson, Stephen [5 ]
Arend, William P. [1 ]
Holers, V. Michael [1 ]
机构
[1] Univ Colorado Denver, Div Rheumatol, Sch Med, Aurora, CO 80045 USA
[2] Univ Colorado Denver, Div Nephrol & Hypertens, Sch Med, Aurora, CO 80045 USA
[3] Massachusetts Gen Hosp Children, Boston, MA 02114 USA
[4] Brigham & Womens Hosp, Boston, MA 02115 USA
[5] Med Univ S Carolina, Dept Microbiol & Immunol, Charleston, SC 29425 USA
基金
美国国家卫生研究院;
关键词
RHEUMATOID-ARTHRITIS; MONOCLONAL-ANTIBODY; ISCHEMIA/REPERFUSION INJURY; JOINT DESTRUCTION; EFFECTOR PHASE; II COLLAGEN; FACTOR-B; ACTIVATION; INFLAMMATION; INDUCTION;
D O I
10.4049/jimmunol.0901826
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
The alternative pathway (AP) of complement is required for the induction of collagen Ab-induced arthritis (CAIA) in mice. The objective of this study was to examine the effect of a recombinant AP inhibitor containing complement receptor 2 and factor H (CR2-fH) on CAIA in mice. CR2 binds to tissue-fixed activation fragments of C3, and the linked fH is a potent local inhibitor of the AP. CAIA was induced in C57BL/6 mice by i.p. injections of 4 mAb to type II collagen (CH) on day 0 and LPS on day 3. PBS or CR2-fH (250 or 500 mu g) were injected i.p. 15 min after the mAb to CH on day 0 and 15 min after LPS on day 3; the mice were sacrificed on day 10. The disease activity score (DAS) was decreased significantly (p < 0.001) in both groups receiving CR2-fH compared with the PBS. Histology scores for inflammation, pannus, bone damage, and cartilage damage decreased in parallel with the DAS. C3 deposition in the synovium and cartilage was significantly reduced (p < 0.0001) in the mice treated with CR2-fH In vitro studies with immune complexes containing type II collagen and mAb to CH showed that CR2-fH specifically inhibited the AP with minimal effect on the classical pathway (CP) and no effect on the lectin pathway (LIP). The relative potency of CR2-fH in vitro was superior to mAbs to factor B and C5. Thus, CR2-fH specifically targets and inhibits the AP of complement in vitro and is effective in CAIA in vivo. The Journal of Immunology, 2009, 183: 5928-5937.
引用
收藏
页码:5928 / 5937
页数:10
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