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Cytokines play a key role in the development of rheumatoid arthritis (RA), allowing hypertrophy of the pannus by neovascularisation, articular inflammation and destruction. We recently demonstrated in experimental models the efficacy of vaccination against cytokines, using a heterocomplex of keyhole limpet hemocyanin (KLH) and human tumour necrosis factor (TNF), called TNF kinoid (K). Vascular endothelial growth factor (VEGF) is a potential target in RA, since it plays a major role in angiogenesis and pannus formation.
We aimed at demonstrating an inhibitory effect of a sustained inhibition of VEGF by an anti-VEGF vaccine in collagen-induced arthritis, a model of RA.
Anti-murine VEGF immunisation was performed by injecting intramuscularly VEGF-K formulated in incomplete Freund adjuvant (IFA) in DBA/1 mice. Control groups received KLH or PBS at the same dates. A fourth group received a chemical angiogenesis inhibitor in drinking water from D28 to sacrifice (ammonium tetrathiomolybdate, TM, 0.03 mg/ml). Arthritides were induced by two subcutaneous injections of bovine type II collagen, the first at day 40 in complete Freund adjuvant, the second at day 61 in IFA. Clinical scores of arthritis were evaluated twice per week. Histological scores of the paws were quantified after sacrifice and haematoxylin/eosin staining. Anti-VEGF and anti-KLH antibody (Ab) levels were assessed by ELISA, and the anti-VEGF neutralising capacity of sera by HUVEC bioassay.
VEGF-K and TM groups showed lower arthritic scores as compared to KLH and PBS groups (p<0.005). At histological analysis, inflammation and destruction scores of the paws were lower in VEGF-K group versus KLH (p<0.005) and PBS group (p<0.001). VEGF-K group was the only one to show antiVEGF Ab production as assessed by ELISA at day 60 and sacrifice. The neutralising activity of anti-VEGF Ab was confirmed by HUVEC at sacrifice.
These data show that VEGF-K improves arthritis in a murine RA model.
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