Innate response cytokines in inflammatory synovitis: novel targets and strategies

Abstract

Host immune and inflammatory factors contribute to progression of inflammatory synovitis – targeting specific factors such as tumour necrosis factor brings about substantial clinical benefit. We have focused on the effector function of innate immune response cytokines in synovitis including IL-15 and members of the IL-1/IL-1 receptor superfamily, particularly IL-18. Our strategy has been to identify mediators with plausible bioactivity, to establish that they or their target ligands are present in inflammatory synovial tissues and, thereafter, to target them in vivo using appropriate inflammatory rodent models. Thus, IL-15 is a 4a-helix inflammatory cytokine with plausible biologic effects on synovial cell subsets, expressed in synovial tissues in rheumatoid arthritis (RA) and psoriatic arthritis, and when targeted in vivo leads to suppression of collagen-induced arthritis in DBA/1 mice. A recent phase I/II study in patients with RA in which HuMaxIL-15 was administered weekly for 4 weeks suggested that IL-15 blockade was well tolerated and provided preliminary evidence for efficacy, suggesting our approach is valid. We recently gathered a similar evidence base for IL-18, demonstrating widespread IL-18 expression in synovial tissues in RA and psoriatic arthritis effector function in T cells, macrophages, fibroblasts and neutrophils in synovial tissues, and finally providing in vivo evidence that IL-18 has an effector function in vivo by showing that IL-18-deficient mice have reduced the severity of collagen-induced arthritis. A striking feature is the synergy exhibited by IL-18 with IL-12 and IL-15. Studies in which IL-18 is targeted in human inflammatory arthropathies are now awaited. Finally, since IL-15 and IL-18 are both key mediators of dendritic cell (DC) effector function, and are expressed in synovial DCs, we have focused on the means whereby DCs could promote or sustain inflammatory synovitis. To this end, we have shown that collagen-pulsed DCs adoptively transferred into naive DBA/1 recipients initiate a remitting relapsing arthritis, mediated in part via innate response cytokines, including tumour necrosis factor. By facilitating transfer of gene-targeted cell donors, or administration of cytokine inhibitors, this model provides a novel system in which to test the relative role of innate response cytokines during initiation of but also during chronic phases of inflammatory arthritis.