Tolerance Mechanisms in Collagen-Induced Arthritis an Animal Model of Rheumatoid Arthritis

Abstract: Collagen-induced arthritis (CIA) is one of the most commonly used animal models for Rheumatoid arthritis (RA). CIA is induced in susceptible mouse strains after immunization with heterologous type II collagen (CII). In mice of the H-2q haplotype rat CII (rCII) is used whereas in mice of the H-2r haplotype bovine CII is utilized. The broad objective of this thesis was to gain an understanding of the tolerance mechanisms operating in CIA. The initial studies were investigating what mechanisms are in place in order to achieve T cell tolerance to the cartilage CII protein. The immunodominant T cell epitope of rCII has been identified to position 256-270 in H-2q mouse strains. Transplantation of skin tissue expressing this epitope onto naïve arthritis susceptible mice induced transient tolerance to the grafted epitope and arthritis protection. Breaking of tolerance correlated with a regained susceptibility to CIA but not rejection of the grafted epitope, showing that these inflammatory responses involve different mechanisms. However, since the heterologous CII sequence can be posttranslationally modified (PTM) where lysines can be glycosylated we also investigated the differential effect of these epitopes on tolerance and pathology of T cells. Vaccination of neonatal H-2q-mice with the glycosylated CII-peptide was superior in protecting mice from subsequent arthritis induction, compared with the hydroxylated or non-modified CII-peptide. A similar observation was also made in the autologous CIA model where transgenic mice expressing the heterologous CII protein in cartilage (MMC mice) were used. These studies were extended to investigate if there are regulatory processes occurring in an autologous model of CIA. Indeed, it was found that MMC mice had a population of CD4+CD25- T cells that were suppressive and these cells required CTLA-4 signaling. Since arthritis is a disease that involves both arms of the immune system (i.e. adaptive and innate) tolerance mechanism that may aid T cells indirectly in controlling arthritis were also investigated. It was observed that macrophages could be alternatively activated to express a fewer B7.1 molecules with an increased IL-10 production when treated with peptides and these macrophages were poor activators of T cells. Finally we observed that the cytokine interferon-? (IFN-?) had a profound effect on joint resident cells. Mice deficient for IFN-? had an exacerbated arthritis associated with activated synovial cells including macrophages, fibroblasts and osteoclasts when compared to IFN-? competent mice. In addition, transferring fibroblasts from mice producing endogenous IFN-? could reverse the IFN-? deficient mice arthritis phenotype.