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Abstract

Analysis of cytokine mRNA and protein in rheumatoid arthritis tissue revealed that many proinflammatory cytokines such as TNFα, IL-1, IL-6, GM-CSF, and chemokines such as IL-8 are abundant in all patients regardless of therapy. This is compensated to some degree by the increased production of anti-inflammatory cytokines such as IL-10 and TGFβ and cytokine inhibitors such as IL-1ra and soluble TNF-R. However, this upregulation in homeostatic regulatory mechanisms is not sufficient as these are unable to neutralize all the TNFα and IL-1 produced.

In rheumatoid joint cell cultures that spontaneously produce IL-1, TNFα was the major dominant regulator of IL-1. Subsequently, other proinflammatory cytokines were also inhibited if TNFα was neutralized, leading to the new concept that the proinflammatory cytokines were linked in a network with TNFα at its apex. This led to the hypothesis that TNFα was of major importance in rheumatoid arthritis and was a therapeutic target. This hypothesis has been successfully tested in animal models, of, for example, collagen-induced arthritis, and these studies have provided the rationale for clinical trials of anti-TNFα therapy in patients with long-standing rheumatoid arthritis. Several clinical trials using a chimeric anti-TNFα antibody have shown marked clinical benefit, verifying the hypothesis that TNFα is of major importance in rheumatoid arthritis. Retreatment studies have also shown benefit in repeated relapses, indicating that the disease remains TNFα dependent. Overall these studies demonstrate that analysis of cytokine expression and regulation may yield effective therapeutic targets in inflammatory disease.

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/content/journals/10.1146/annurev.immunol.14.1.397
1996-04-01
2024-05-26
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  • Article Type: Review Article
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