OP0005 LOCAL INHIBITION OF ENDOGENOUS IL-18 THROUGH ADENOVIRAL OVEREXPRESSION OF IL-18BPC RESULTS IN REDUCED INCIDENCE AND SEVERITY OF COLLAGEN-INDUCED ARTHRITIS
R.L. Smeets, F.A.J. Van de Loo, L.A.B. Joosten, O.J. Arntz, M.B. Bennink, W.B. Van den Berg

IL-18 is an important cytokine in the inflammatory process of the rheumatoid arthritis (RA) joint. Previous experiments have shown that treatment with either IL-18 antibodies or IL-18 binding protein (IL-18BP) was efficacious in experimental arthritis.

Methods:The purpose of this study was to determine if a replication deficient adenoviral vector containing the murine IL-18BP isoform c gene (AD5CMV.IL-18BPc) had an effect on endogenous IL-18 in collagen-induced arthritis (CIA).

Results: 1x107 PFU of AD5CMV.IL-18BPc or a control vector Ad5CMV.Luc was injected into the knee joint of DBA/1 mice prior to the onset of CIA. The overexpression of IL-18BPc led to a 66% (p<0.001) reduction in knee joint swelling and a 50% (p<0.01) reduction in distal paw swelling when compared to the vector controls. Additionally, serum levels of IL-6 were reduced in the treated mice (5.0 pg/ml) compared to the control (12.7 pg/ml, p<0.001). Anti-collagen type II antibody levels were not affected.

Conclusions:These data indicate that IL-18 has a pro-inflammatory role in CIA that can be significantly reduced by treatment with adenoviral overexpression of IL-18BPc.

Editorial Comment: These studies support the development of IL-18 inhibitors as a rational therapeutic strategy for RA. It will be important to know whether joint damage is prevented or suppressed by this intervention, and whether treatment is effective after the arthritis is established.

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OP0006 BLOCKING ENDOGENOUS IL-17 DURING ESTABLISHED MURINE COLLAGEN ARTHRITIS PREVENTS BONE DESTRUCTION AND DOWNREGULATES SYNOVIAL RANKL AND IL-1 EXPRESSION
E. Lubberts, B. Oppers, L. Joosten, L. Van den Bersselaar, W. Van den Berg

To study the role of endogenous IL-17 in the destructive process of collagen-induced arthritis (CIA), mice were treated with soluble IL-17 receptor fusion protein (sIL-17R:Fc) after the onset of disease.

Results: While no significant difference in clinical arthritis score was noted, a significant reduction in bone erosion was observed in the radiographic analysis 8 and 14 days after disease onset in the sIl-17R:Fc treated mice when compared to control. T cell responses to murine collagen peptides and IgG1 and IgG2a anti-collagen antibody levels were similar in both groups. However, Il-1 and RANKL levels of mRNA expression were reduced in the synovium of sIL-17R:Fc treated mice compared with expression in the control group 14 days after disease onset.

Conclusions: These data suggest that the T cell factor IL-17 may play an important role in mediating key catabolic cytokines in arthritis and may prove to be a novel therapeutic target in destructive arthritis.

Editorial Comment: Recent data suggest that T cells can provide an important contribution to RANK-RANKL mediated bone destruction in animal models of RA. It is interesting in these studies that bone destruction but not inflammation was suppressed by this T-cell directed intervention. These studies, like the CD40-CD40L studies, renew interest in the T cell as a target for treatment of RA.

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OP0011 RAPID ONSET OF COLLAGEN-INDUCED ARTHRITIS IN FCGAMMA RIIA TRANSGENIC MICE ON A RESISTANT GENETIC BACKGROUND
C.T. Sardjono 1, R. Slocombe 2, M. Powell 1, P. Mottram 1, M.P. Hogarth

FcgRIIa is a low affinity Fc receptor for IgG found only in humans. It plays a major role in immune complex clearance and signal transduction for cell activation.

Methods: In this study, Sardjono et al investigated what role FcgRIIa might have in the development of rheumatoid arthritis (RA). Transgenic mice expressing FcgRIIa, DBA/1 (H-2q), a known CIA susceptible murine strain, and wild type (H-2b) mice were injected with type II collagen and followed for 36 days. Mice were scored based on swelling, redness, and joint function, 0 for a normal joint and up to 12 for severe inflammation and joint dysfunction.

Results: The transgenic FcgRIIa mice developed CIA by day 21 with a mean score of 5.8 + 2.8 while DBA/1 and wild type mice showed no signs of disease. DBA/1 mice developed CIA by day 28 with a mean score of 4.9 + 3.4; wild type mice showed no evidence of disease. However, by day 30-35, both FcgRIIa and DBA/1 mice had similar disease severity showing histological evidence of infiltration of inflammatory cells, pannus formation, some cartilage destruction, and loss of normal bone structure of affected joints.

Conclusions: These data suggest that FcgRIIa transgenic mice may provide an animal model for the study of human RA.

Editorial Comment: It is generally accepted that rheumatoid factor positive (RF⁺) RA patients have more severe and more erosive disease than (RF^-) RA patients. The ability of RF-containing immune complexes to bind to FcgRIIa and activate the FcR-bearing cell to release inflammatory cytokines can explain this. This mechanism is of course not the sole inflammatory pathway in RA. Nonetheless, these results are interesting and support the role of immune complexes (perhaps containing RF, collagen type II and other antigens) in initiating and/or perpetuating synovial and systemic inflammation.

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