| dc.description.abstract | Murine collagen-induced arthritis (CIA) is the most common model for studying human rheumatoid arthritis (RA). Autologous or heterologous type II collagen (CII) emulsified in Freund´s complete adjuvant induces arthritis in susceptible mice, which is histopathologically similar to RA. Although the precise pathogenesis is unknown induction of arthritis require both B and T cell responses to CII. The susceptibility of mice to CIA has, among other things, been linked to the major histocompatibility complex class II molecules. Mouse strains expressing the class II molecule I-Aq (e.g., DBA/1 and B10.Q) or I-Ar (e.g., B10.RIII) have been shown to be the most susceptible strains. The overall aim of this thesis was to modulate the CII specific immune response and thereby the susceptibility to CIA, i.e., (i) prevent CIA in high susceptible DBA/1 mice and (ii) provoke CIA in low susceptible, I-Ad expressing, Balb/C mice.(i) Feeding a protein antigen suppresses a subsequent peripheral challenge to the same antigen by regulatory mechanisms that involve non-antigen specific factors, e.g., immunosuppressive cytokines. This is known as bystander suppression. DBA/1 mice were fed OVA-containing chow and then coimmunized with a mixture of bovine CII (BCII) and OVA. The mice displayed suppressed anti-BCII specific antibody responses, decreased secretion of both T helper 1 and 2 related cytokines by splenocytes after BCII rechallenge in vitro, and they had a delayed onset and reduced progression of arthritis. (ii) I present evidence that CIA resistant Balb/c mice develop full-blown arthritis if a foreign, but not a self-protein, is added to the CFA/BCII inoculum. Increased levels of circulating IL-6 and IgG autoantibodies to BCII, but no apparent BCII specific T cell responses in vitro, are associated with the establishment of the arthritis. Intrinsic CD25+ regulatory cells possibly cause the absence of anti-BCII specific T cell responses in vitro, as CD25-depleted splenocytes prepared from arthritic coimmunized Balb/C mice had increased secretion of IL-2 after restimulation with BCII.In summary, this thesis encourage further studies to evaluate the possibility of ameliorating arthritis by bystander suppressive mechanisms, and provide a novel model that may offer new insight of the etiopathogenesis of human RA. | en |
