Targeted inhibition of the complement alternative pathway with complement receptor 2 and factor H attenuates collagen antibody-induced arthritis in mice.
Targeted inhibition of the complement alternative pathway with complement receptor 2 and factor H attenuates collagen antibody-induced arthritis in mice.
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DOI：
10.4049/jimmunol.0901826
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发表时间：
2009-11-01
期刊：
影响因子：
--
通讯作者：
Holers VM
中科院分区：
文献类型：
--
作者：
Banda NK;Levitt B;Glogowska MJ;Thurman JM;Takahashi K;Stahl GL;Tomlinson S;Arend WP;Holers VM
补体替代途径（AP）是在小鼠中诱导胶原抗体诱导性关节炎（CAIA）所必需的。本研究的目的是检测一种含有补体受体2和因子H（CR2 - fH）的重组AP抑制剂对小鼠CAIA的影响。CR2与组织固定的C3活化片段结合，相连的fH是AP的一种强效局部抑制剂。在第0天通过腹腔注射4种抗II型胶原（CII）单克隆抗体以及在第3天注射脂多糖（LPS），在C57BL/6小鼠中诱导CAIA。在第0天抗CII单克隆抗体注射后15分钟以及第3天LPS注射后15分钟，腹腔注射磷酸盐缓冲液（PBS）或CR2 - fH（250或500μg）；在第10天处死小鼠。与PBS组相比，接受CR2 - fH的两组小鼠的疾病活动评分（DAS）均显著降低（p < 0.001）。炎症、血管翳、骨损伤和软骨损伤的组织学评分与DAS平行下降。在接受CR2 - fH治疗的小鼠中，滑膜和软骨中的C3沉积显著减少（p < 0.0001）。对含有II型胶原和抗CII单克隆抗体的免疫复合物进行的体外研究表明，CR2 - fH特异性抑制AP，对经典途径（CP）影响极小，对凝集素途径（LP）无影响。CR2 - fH在体外的相对效力优于抗因子B和C5的单克隆抗体。因此，CR2 - fH在体外特异性靶向并抑制补体的AP，在体内对CAIA有效。
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 (CII) on day 0 and LPS on day 3. PBS or CR2-fH (250 or 500 μg) were injected i.p. 15 min after the mAb to CII 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 CII showed that CR2-fH specifically inhibited the AP with minimal effect on the classical pathway (CP) and no effect on the lectin pathway (LP). 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.
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DOI：
10.4049/jimmunol.181.11.8068
发表时间：
2008-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Huang Y;Qiao F;Atkinson C;Holers VM;Tomlinson S
通讯作者：
Tomlinson S
DOI：
10.1084/jem.20070432
发表时间：
2007-06-11
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Katschke KJ Jr;Helmy KY;Steffek M;Xi H;Yin J;Lee WP;Gribling P;Barck KH;Carano RA;Taylor RE;Rangell L;Diehl L;Hass PE;Wiesmann C;van Lookeren Campagne M
通讯作者：
van Lookeren Campagne M
影响因子：
19.6
作者：
Elliott, MK;Jarmi, T;Gilkeson, GS
通讯作者：
Gilkeson, GS
影响因子：
6
作者：
Nandakumar, KS;Svensson, L;Holmdahl, R
通讯作者：
Holmdahl, R
影响因子：
4.4
作者：
Banda, Nirmal K.;Takahashi, Kazue;Arend, William P.
通讯作者：
Arend, William P.