Genetic Factors and Nasal Tolerance in Rat Models for Rheumatoid Arthritis

Abstract: We used three animal models of rats for rheumatoid arthritis (RA) in this study. Firstly, We found that CXI induced arthritis (CXIIA) is associated with the RT1 f haplotype and follows a chronic disease course affecting peripheral joints with both progression and relapses. The main difference of pathological changes in CXIIA rats against rats with CIIIA was a larger number of infiltrating lymphocytes which tended to form follicle-like aggregates. Surprisingly, males were more susceptible to CXIIA than females whereas the opposite has been observed in other rat arthritis models, including CIIIA. We also found that nasal and tracheolaryngeal cartilage is affected in LEW.1A and DA rats to varying degree in CIIIA but not in any strain in the pristane induced model. Next, we investigated the role of genetic factors in arthritis development after pristane injection. In newly made MHC congenic strains with DA background, we found that rats with the RT1 f haplotype developed much more severe and chronic diseases as compared with DA rats. Antibodies against T cell receptor (R73) and CD4 T cells but not CD8 T cells could suppress the arthritis. When DA.1F rats were injected with anti-MHC class II molecule antibodies, the anti-RT1B antibody but not anti-RT-1D suppressed the arthritis severity. Since RT1 D molecule is identical between the RT1a and f haplotypes, this indicates that the disease is associated with MHC class II genes. Furthermore we found that in the chronic phase of PIA, only DA.1F rats had a DTH response to CXI, demonstrating that chronicity of the disease is linked with a T cell response specific to cartilage-restricted antigens. In a linkage study of the new cross between E3 and LEW.1F strains, the results confirmed the previously identified locus Pia4 on chromosome 12. On chromosome 1, linked to the albino locus, we identified a novel QTL, Pia9 in the LEW.1F cross. This locus was associated with arthritis severity in the early phase of disease. A locus on chromosome 16, denoted Pia11, was also associated with arthritis severity in the early phase of the disease. By using a congenic LEW.1F strain, which carries E3 allele at the Pia9 locus, we confirmed that the E3 alleles significantly suppress arthritis severity during the early phase of the disease. Rats with Pia9 alleles from LEW.1F and Pia11 alleles from E3, were shown to suffer from even more severe arthritis in the early stage of the disease. On the other hand, the Pia9 and the suggestive locus on chromosome 14 affected only males during the chronic phase of the disease. Finally, we have assessed the efficiency of nasally administrated cartilage-specific collagens to vaccinate against development of arthritis, and to ameliorate already established chronic arthritis. Cartilage specific CIX CII and CXI were used for intranasal vaccination. We found all cartilage specific collagens administrated nasally but not collagen type I can suppress PIA and also have ameliorative effects on established PIA. Concerning CIIIA and CXIIA, only cognate collagens have effects indicating an antigen-specific suppression. These findings demonstrate that there are different mechanisms involved in tolerance induction in different rat models for RA.