Therapeutic vaccination by two DerG LEAPS conjugates incorporating different PG (aggrecan) epitopes protect by different immune mechanisms in the PG G1 domain induced mouse model of rheumatoid arthritis

Abstract

Abstract Background Development of a therapeutic vaccine for rheumatoid arthritis (RA) requires modulating antigen specific inflammatory T cell responses that drive disease. RA can be initiated and driven by responses to multiple antigens but peptide vaccines usually contain few epitopes. The challenge is to elicit the appropriate responses by these vaccines. Method We used the proteoglycan (PG, aggrecan) G1 domain-induced arthritis model of RA. Mice were immunized with either one or two different DerG LEAPS vaccines containing PG epitopes (PG70 or PG275Cit) in Seppic ISA51vg adjuvant subcutaneously after signs of arthritis were noted. Mice were examined trice weekly for arthritis progression. At study end serum antibodies to the vaccine epitopes and splenic T-cell responses to PG G1 domain were determined. Results Immunization with DerGPG70 or DerGPG275Cit conjugate, alone or in combination, stopped the progression of disease. DerGPG275Cit was effective in protection but did not induce significant serum antibodies whereas DerGPG70 (alone or with DerGPG275Cit) induced both protection and antibodies. Spleen cells from DerGPG70-immunized mice had an anti-inflammatory response to PG G1 in vitro. Conclusions Immunization with DerG LEAPS conjugates of different epitopes of PG alone or together were effective at modulating the inflammatory response and stopping disease progression. As observed previously, the DerGPG70 conjugate modulated disease through up-regulation of Th2, and down-regulation of Th1 and Th17 responses. Results suggest mechanistically different immune responses to the two vaccines. Combination of them provided not only broader epitope coverage, but also a greater therapeutic effect than either vaccine alone.