The observed differential temporal cytokine and chemokine mRNA expression patterns suggest that specific cytokines and chemokines have defined roles at various times during the course of autoimmune arthritis. Since most of these cytokines and chemokines are found in human rheumatoid arthritis (RA) synovium and synovial fluids, these findings may have relevance to RA.

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Viral IL-10 (vIL-10) and soluble TNF receptor (sTNFR) are anti-inflammatory proteins that can suppress collagen-induced arthritis (CIA). These and related proteins have shown efficacy in the treatment of human rheumatoid arthritis; however, neither alone is able to completely suppress disease. Furthermore, they have short half-lives, necessitating frequent administration. To determine the ability of these proteins to act synergistically following gene transfer, arthritis was induced in DBA/1 male mice by immunization with type II collagen on days 0 and 21. Mice were injected i.v. either before disease onset (day 20) or after disease onset (day 28) with 1010 particles of adenovirus encoding vIL-10, a soluble TNF receptor-IgG1 fusion protein (sTNFR-Ig), a combination of both vectors, or a control vector lacking a transgene. Significant synergism was observed with the combination of vIL-10 and sTNFR-Ig, with a substantial reduction in both the incidence and severity of disease as well as inhibition of progression of established disease. sTNFR-Ig alone had no effect on CIA. vIL-10 alone inhibited disease when given before disease onset, but had minimal effect on established disease. Both proteins inhibited spleen cell proliferation and IFN-γ secretion in response to stimulation with type II collagen, but only vIL-10 reduced the synovial mRNA levels of the proinflammatory cytokines IL-1β, TNF-α, and IL-6. These findings demonstrate that vIL-10 and sTNFR-Ig act synergistically in suppressing CIA and suggest that gene transfer offers a potential therapeutic modality for the treatment of arthritis.

Objective. To determine the effect of overexpres-sion or deletion of interleukin-1 receptor antagonist (IL-1Ra) in collagen-induced arthritis (CIA). Methods. Mice overexpressing the IL-1Ra gene under the control of its endogenous promoter, mice lacking IL-lRa, and normal littermate controls were immunized with bovine type 11 collagen (CII) and compared in terms of features of CIA. Results. Mice overexpressing IL-1Ra had a significant reduction in the incidence and severity of CIA. After CII immunization, IL-1Ra messenger RNA was overexpressed in the spleens, but not in the paws, of transgenic mice. Minimal differences were observed in the humoral or cellular immune responses to CII. Mice lacking IL-1Ra had a significantly earlier onset of ClA, with increased severity. Conclusion. Endogenous expression of IL-1Ra is a critical determinant of susceptibility to CIA. These findings suggest potential therapeutic interventions for autoimmune arthritis. Cytokines play a central role in the pathophysi-ology of autoimmune arthritides such as rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA). The proinflammatory cytokine interleukin-1 (IL-1) ap

Objective. To determine the effect of overexpression or deletion of interleukin-1 receptor antagonist (IL-1Ra) in collagen-induced arthritis (CIA).Methods. Mice overexpressing the IL-1Ra gene under the control of its endogenous promoter, mice lacking IL-lRa, and normal littermate controls were immunized with bovine type 11 collagen (CII) and compared in terms of features of CIA.Results. Mice overexpressing IL-1Ra had a significant reduction in the incidence and severity of CIA. After CII immunization, IL-1Ra messenger RNA was overexpressed in the spleens, but not in the paws, of transgenic mice. Minimal differences were observed in the humoral or cellular immune responses to CII. Mice lacking IL-1Ra had a significantly earlier onset of ClA, with increased severity.Conclusion. Endogenous expression of IL-1Ra is a critical determinant of susceptibility to CIA. These findings suggest potential therapeutic interventions for autoimmune arthritis.Cytokines play a central role in the pathophysiology of autoimmune arthritides such as rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA). The proinflammatory cytokine interleukin-1 (IL-1) ap-