Targeted inhibition of the complement alternative pathway with complement receptor 2 and factor H attenuates collagen antibody-induced arthritis in mice.
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 microg) 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.
Banda
Nirmal K
NK
Division of Rheumatology, University of Colorado Denver, School of Medicine, Aurora, CO 80045, USA.
Levitt
Brandt
B
Glogowska
Magdalena J
MJ
Thurman
Joshua M
JM
Takahashi
Kazue
K
Stahl
Gregory L
GL
Tomlinson
Stephen
S
Arend
William P
WP
Holers
V Michael
VM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy; D002417:Cattle; D024043:Collagen Type II / Q000276:immunology*; D017242:Complement Factor H / Q000008:administration & dosage / Q000502:physiology*; D003169:Complement Inactivator Proteins / Q000008:administration & dosage / Q000502:physiology*; D003170:Complement Pathway, Alternative / Q000276:immunology*; D004338:Drug Combinations; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017464:Receptors, Complement 3d / Q000008:administration & dosage / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000502:physiology*
D000911:Antibodies, Monoclonal; C527099:CR2-Crry fusion protein, mouse; D024043:Collagen Type II; D003169:Complement Inactivator Proteins; D004338:Drug Combinations; D017464:Receptors, Complement 3d; D011993:Recombinant Fusion Proteins; D017242:Complement Factor H