IL-17/Th17 targeting: On the road to prevent chronic destructive arthritis?

Abstract

Interleukin-17A (IL-17A) contributes to the pathogenesis of arthritis. Data from experimental arthritis indicate IL-17 receptor signaling as a critical pathway in turning an acute synovitis into a chronic destructive arthritis. The identification of six IL-17 family members (IL-17A-F) may extend the role of this novel cytokine family in the pathogenesis of chronic destructive joint inflammation. Whether the successful anti-IL-17A cytokine therapy in murine arthritis can be effectively translated to human arthritis need to be tested in clinical trials in humans. Interestingly, IL-17A and IL-17F are secreted by the novel T helper subset named Th17. This novel pathogenic T cell population induces autoimmune inflammation in mice and is far more efficient at inducing Th1-mediated autoimmune inflammation in mice than classical Th1 cells (IFN-c). In addition to IL-17A and IL-17F, Th17 cells are characterized by expression of IL-6, TNF, GM-CSF, IL-21, IL-22 and IL-26. Th17 cells have been established as a separate lineage of T helper cells in mice distinct from conventional Th1 and Th2 cells. Whether this also applies to human Th17 and whether RA is a Th1 or a Th17 mediated disease is still not clear. This review summarizes the findings about the role of IL-17 in arthritis and discusses the impact of the discovery of the novel Th17 cells for arthritis. Further studies are needed to unravel the role of Th17 cells and the interplay of IL-17 and other Th17 cytokines in the pathogenesis of arthritis and whether regulating Th17 cell activity will have additional value compared to neutralizing IL-17A activity alone. This might help to reach the ultimate goal not only to treat RA patients but to prevent the development of this crippling disease.

Therapeutic effect of tolerogenic dendritic cells in established collagen‐induced arthritis is associated with a reduction in Th17 responses

“…Recent evidence suggests that Th17 cells are key players in the pathogenesis of CIA (4). In mice deficient for the Th17 cell-associated molecules interleukin-17 (IL-17), IL-17 receptor, or IL-23p19, arthritis is markedly suppressed compared with that in their wild-type counterparts (5)(6)(7), and neutralizing antibodies to IL-17 have a therapeutic effect in CIA (8).…”

Anti IL‐17A therapy inhibits bone loss in TNF‐α‐mediated murine arthritis by modulation of the T‐cell balance

“…In IL-1-driven arthritis models such as collagen-induced arthritis, blockade of IL-17 is highly effective in inhibiting inflammation and structural damage to cartilage and bone [30][31][32][33][34][35]. Moreover, IL-17, like IL-1 can elicit cartilage degradation alone or in combination with other cytokines [36,37].…”

A CD46 transgenic mouse model for studying the histopathology of arthritis caused by subcutaneous infection with Streptococcus dysgalactiae subspecies equisimilis

“…RANKL is the primary mediator of osteoclast differentiation, activation and survival (Yasuda et al, 1998b). IL-17A, in contrast, acts upstream from IL-6 and synergizes with TNF-a to promote inflammation and bone turnover in rheumatoid arthritis (Hot & Miossec, 2011;Lubberts, 2008Lubberts, , 2010. IL-17A suppresses the expression of bone resorption-related proteinases and osteoclast differentiation (osteoclast precursors into osteoclasts) (Kitami et al, 2010).…”