C4b-binding protein (C4BP) inhibits development of experimental arthritis in mice.
OBJECTIVE
To assess the human complement inhibitor C4b-binding protein (C4BP) for treatment of arthritis.


METHODS
We have used two mouse models of rheumatoid arthritis (RA) to assess the therapeutic effect of C4BP on different phases of arthritis, the collagen antibody-induced arthritis (CAIA), an acute antibody-induced disease and the collagen-induced arthritis (CIA), which carries the full complexity of arthritis.


RESULTS
Purified human C4BP injected intraperitoneally alleviated CAIA significantly in a manner similar to cobra venom factor that depletes complement due to massive activation. Furthermore, C4BP was injected before and after the disease development into CIA mice. In the former case, the disease onset was delayed and in the latter, the severity of the disease was reduced in animals treated with C4BP. However, C4BP did not affect the anti-CII antibody synthesis. C4BP present in mouse sera decreased activity of the classical but not the alternative pathway of the complement system when these were assessed in a fluid phase. However, C4BP was efficiently inhibiting the alternative pathway when present on the activating surface. Taken together, the disease ameliorating effect of C4BP appears to be related to inhibition of both pathways of complement.


CONCLUSIONS
Although human C4BP was cleared relatively fast from the circulation and was only moderately affecting complement activity, its effect on the disease severity was substantial, suggesting that minor alterations in complement activity can have significant therapeutic value in RA.
Blom
A M
AM
Department of Laboratory Medicine, Division of Medical Protein Chemistry, Lund University, University Hospital Malmö Entrance 46, The Wallenberg Laboratory floor 4, S-205 02 Malmö, Sweden. Anna.Blom@med.lu.se
Nandakumar
K S
KS
Holmdahl
R
R
D000818:Animals; D000911:Antibodies, Monoclonal; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000517:prevention & control; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology / Q000517:prevention & control; D003094:Collagen / Q000276:immunology; D015935:Complement C4b / Q000276:immunology; D050716:Complement C4b-Binding Protein / Q000627:therapeutic use*; D003170:Complement Pathway, Alternative / Q000187:drug effects; D003171:Complement Pathway, Classical / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008817:Mice, Mutant Strains
D000911:Antibodies, Monoclonal; D050716:Complement C4b-Binding Protein; D015935:Complement C4b; D003094:Collagen