Collagen-induced arthritis is a well-validated, but strain-dependent mouse model of rheumatoid arthritis, with H-2(q) and H-2(r) strains showing the greatest degree of susceptibility. This protocol describes the induction of arthritis in the C57BL/6 strain (H-2(b)), which forms the genetic background of the majority of genetically modified strains. This protocol involves purification of type II collagen from chicken sternums, immunization of mice, clinical assessment of arthritis and analysis of T- and B-cell responses to type II collagen. Key aspects of the protocol are the need to use chicken collagen for immunization and the importance of avoiding aggressive behavior in males. The incidence of arthritis varies from 50 to 80% and is milder than the classical collagen-induced arthritis model. This procedure takes approximately 3 months to complete.
Objective. Indoleamine 2,3 dioxygenase (IDO) is a catabolic enzyme that initiates the kynurenine pathway of tryptophan degradation and has immunomodulatory properties. The aim of this study was to investigate the regulation of collagen-induced arthritis by tryptophan catabolism mediated by IDO.
Objective. The CD200 receptor (CD200R) is an inhibitory receptor expressed by myeloid cells that is postulated to play an important role in regulation of the immune system. The purpose of this study was to evaluate the efficacy of a soluble ligand of CD200R in established collagen-induced arthritis (CIA) in mice and to analyze changes in cytokine expression following therapy in order to understand its primary mechanism of action.Methods. Arthritis was induced in DBA/1 mice, and CD200-Fc fusion protein, an isotype control monoclonal antibody, or TNFR-Fc fusion protein was administered over a period of 10 days (total of 4 doses). Cytokine expression in the joint was assessed by flow cytometry, enzyme-linked immunosorbent assay, and quantitative real-time polymerase chain reaction.Results. CD200-Fc significantly reduced the severity of established arthritis at the clinical and histologic levels. The therapeutic effect of CD200-Fc at 1 mg/kg was comparable with that of TNFR-Fc at 4 mg/kg. CD200R was found to be expressed in arthritic synovia and in lymph nodes, yet no changes in T cell cytokine levels (interferon-␥, interleukin-5 [IL-5], IL-10, IL-17) were detected after CD200-Fc therapy. There was no evidence of an expansion of forkhead box P3-positive regulatory T cells or a change in serum anticollagen IgG1 and IgG2a levels. However, administration of CD200-Fc markedly decreased the expression of messenger RNA for tumor necrosis factor ␣, IL-1, IL-10, and matrix metalloproteinase 13 in the joint to the same extent as administration of TNFR-Fc.Conclusion. CD200-Fc is an effective therapeutic agent in established CIA that targets proinflammatory cytokine expression in the joint without any obvious systemic immunosuppressive effects. Our findings indicate that CD200-Fc has considerable potential as a novel therapeutic agent in rheumatoid arthritis in humans.
Objective. The p53 tumor-suppressor protein is expressed in rheumatoid arthritis synovium, and loss of p53 function through somatic mutation can occur in longstanding disease. Previous studies demonstrated that p53 is protective in murine collagen-induced arthritis (CIA). To determine if adaptive immune responses or synovial effector functions are responsible for this effect, passive models of arthritis were studied in p53 wild-type and knockout mice.Methods. Models of passive CIA, passive K/BxN serum transfer arthritis, and active CIA were induced in DBA/1 p53 ؊/؊ or p53 ؉ mice. Hind paws were evaluated for histologic evidence of inflammation and joint destruction. Synovial interleukin-6 and matrix metalloproteinases 3 and 13 gene expression was analyzed by real-time quantitative polymerase chain reaction. To evaluate T cell function in p53 ؊/؊ mice, draining lymph node (LN) cells from mice immunized with type II collagen (CII) were evaluated in vitro.Results. Increased disease severity in p53 ؊/؊ mice was confirmed in the standard CIA model. However, clinical arthritis, joint destruction, and synovial gene expression in the passive CIA and K/BxN serum transfer arthritis models were similar in p53 ؊/؊ and p53 ؉ mice. To determine if the p53 effect was related to T cell function, LN cells from CII-immunized mice were isolated and stimulated with antigen in vitro. CIIstimulated T cell proliferation and interferon-␥ production were significantly higher in p53 ؊/؊ mice. An independent assessment of Th1 function using the cutaneous delayed-type hypersensitivity model confirmed that p53 ؊/؊ mice have enhanced T cell responses in vivo.Conclusion. Adaptive immune responses, rather than antibody-mediated responses, in p53 ؊/؊ mice account for increased disease severity in the active CIA model.
The results obtained suggest that the chemical structure of PG present in the bacterial CW is decisive in determining arthritogenicity/non-arthritogenicity. Therefore, from two bacterial strains belonging to normal human intestinal flora and 100% identical by 16S rDNA analysis, one proved to be arthritogenic and the other non-arthritogenic.
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