A macaque model of rheumatoid arthritis by immunization with citrullinated peptides: lessons for the human disease

Background Recent evolution in the understanding of rheumatoid arthritis (RA) mechanisms is the role of antibodies directed against citrullinated (cit) proteins (ACPAs). The shared epitope (SE) on the MHC class II is the main genetic risk factor of RA and favors presence of ACPAs. Mouse models dependent on cit peptides immunization require transgenic expression of the SE and are controversial. Non-human primates are ideal to study the interaction between ACPA and RA since 8% carry, similarly to humans, the SE called the H6 haplotype.Objectives The goal of this study was to develop a new animal model of RA based on immunization of genetically predisposed macaques against cit peptides to generate an ACPA-mediated model of arthritis.Methods Six macaques were intra dermally (ID) immunized with 4 peptides: vimentin (59–71) and (66–78), α fibrinogen (79–91) and aggrecan (89–103). H6 animals were immunized with either cit (n=2) or arginine (arg) (n=2) containing peptides. Two non H6 animals were immunized with cit peptides. These peptides are known to induce a T cell response in RA patients carrying the SE. T-cell response was assessed with Interferon γ ELISPOT and B-cell response by ELISA. An intra articular (IA) boost was done 30 weeks after initial immunization with either incomplete Freud's adjuvant (IFA) alone, IFA and cit peptides and IFA plus non relevant peptides.Results In the macaques, the T-cell response was specific to cit or arg peptides (depending on the peptides used for immunization). Surprisingly, the presence of the H6 epitope did not influence the response. Conversely the antibodies generated in response to the peptides were cross-reactive between the cit and arg peptides. Since no clinical response was observed, an IA boost was performed with the same 4 cit peptides and IFA adjuvant. This led to a prolonged neutrophil-rich mono-arthritis preferentially in H6 animals (Figure). Conversely, animals boosted with IFA alone only or with IFA plus myelin oligodendrocyte glycoprotein (MOG) peptides and previously immunized with MOG peptides presented with a transient mono-arthritis. Histological analysis revealed a local mononuclear infiltrate in one of the two animals that had prolonged knee monoarthritis. There was no clinical polyarthritis but 2 animals displayed synovial proliferation in 1 MCP and 1 MTP, respectively.