Mechanisms of effects of complement inhibition in murine collagen-induced arthritis.
OBJECTIVE
To determine the mechanisms of amelioration of collagen-induced arthritis (CIA) in DBA/1J mice by inhibition of complement activation.


METHODS
Mice received 2 intradermal injections of bovine type II collagen (CII), on days 0 and 21. From day 21 (immediately after the second injection of CII) through day 35, mice received intraperitoneal injections of either phosphate buffered saline (PBS), a monoclonal mouse antibody to murine C5 (anti-C5 antibody), or the C3 convertase inhibitor Crry-Ig.


RESULTS
On days 30 and 32, the clinical disease activity score was lower in mice treated with anti-C5 antibody than in those treated with Crry-Ig. Histopathologic evidence of joint damage was 75% lower in the mice treated with anti-C5 antibody than in those treated with either PBS or Crry-Ig. Spleen cells from mice receiving either form of complement inhibition exhibited decreased CII-stimulated proliferation, whereas increased proliferative responses were exhibited by lymph node cells from mice treated with Crry-Ig. Treatment with anti-C5 antibody decreased production of IgG1 anticollagen antibody, while production of IgG2a antibody was inhibited by both complement inhibitory treatments. CII-stimulated spleen cells from anti-C5-treated mice produced lower levels of tumor necrosis factor alpha (TNFalpha) and interleukin-10 (IL-10) compared with those from mice treated with Crry-Ig. Lower steady-state messenger RNA (mRNA) levels for TNFalpha, interferon-gamma (IFNgamma), IL-18, and IL-6 were observed in the joints of anti-C5-treated mice, and for IFNgamma and IL-6 in mice receiving Crry-Ig, all in comparison with PBS-treated mice. However, mRNA levels for IL-1beta and TNFalpha were lower in the joints after treatment with anti-C5 compared with Crry-Ig.


CONCLUSIONS
These results indicate that inhibition of complement in CIA leads to decreased production of IgG2a antibody and suppressed CII-induced spleen cell proliferation. The greater inhibitory effects on CIA of anti-C5 antibody in comparison with Crry-Ig may be attributable primarily to decreased levels of IL-1beta and TNFalpha mRNA in the joints.
Banda
Nirmal K
NK
University of Colorado Health Sciences Center, Denver, CO 80262, USA.
Kraus
Damian
D
Vondracek
Andrea
A
Huynh
Long H
LH
Bendele
Alison
A
Holers
V Michael
VM
Arend
William P
WP
D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000276:immunology*; D001323:Autoantibodies / Q000276:immunology; D003094:Collagen; D003167:Complement Activation / Q000276:immunology*; D050577:Complement C3-C5 Convertases / Q000037:antagonists & inhibitors*; D003182:Complement C5 / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D007375:Interleukin-1 / Q000032:analysis; D016753:Interleukin-10 / Q000096:biosynthesis; D015850:Interleukin-6 / Q000096:biosynthesis; D016209:Interleukin-8 / Q000096:biosynthesis; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D001323:Autoantibodies; D003182:Complement C5; D007375:Interleukin-1; D015850:Interleukin-6; D016209:Interleukin-8; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007371:Interferon-gamma; D003094:Collagen; D050577:Complement C3-C5 Convertases