Anticytokine treatment of established type II collagen–induced arthritis in DBA/1 mice: A comparative study using anti‐TNFα, anti–IL‐1α/β, and IL‐1Ra

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Abstract
Objective. To examine the role of tumor necrosis factor α (TNFα), interleukin‐1α (IL‐1α), and IL‐1β in collagen‐induced arthritis (CIA), immediately after onset and during the phase of established arthritis. Methods. Male DBA/1 mice with collagen‐induced arthritis were treated with antibodies against murine TNFα and IL‐1α/β at different time points of the disease. IL‐1 receptor antagonist (IL‐1Ra) was administered using Alzet osmotic minipumps. The effect of anticytokine treatment was monitored by visual scoring. Histology and cytokine reverse transcription polymerase chain reaction (RT‐PCR) analyses were performed at the end of the treatment period. Results. Anti‐TNFα treatment showed efficacy shortly after onset of the disease, but had little effect on fully established CIA. Histologic analysis after early treatment revealed that anti‐TNFα significantly reduced joint pathology, as determined by infiltration of inflammatory cells and cartilage damage. Anti–IL‐1α/β treatment ameliorated both early and full‐blown CIA. This clear suppression of established arthritis was confirmed by administration of high doses of IL‐1Ra. Dose‐response experiments showed that a continuous supply of 1 mg/day was needed for optimal suppression. Histologic analysis showed markedly reduced cartilage destruction both in the knee and the ankle joints. Autoradiography demonstrated full recovery of chondrocyte synthetic function of articular cartilage. In addition, we found that the IL‐1β isoform plays a dominant role in established CIA. Profound suppression of CIA was observed with anti–IL‐1β, although elimination of both IL‐1α and IL‐1β still gave better protection. Analysis of messenger RNA with RT‐PCR revealed that IL‐1β was highly upregulated in synovium and cartilage at late stages of CIA, whereas anti–IL‐1β treatment markedly reduced IL‐1β message in the synovium. Conclusion. The present study identified different TNFα/IL‐1 dependencies in various stages of CIA and revealed that blocking of TNFα does not necessarily eliminate IL‐1. Continuous, high doses of IL‐1Ra are needed to block CIA.

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