The parasitic helminth product ES‐62 suppresses pathogenesis in collagen‐induced arthritis by targeting the interleukin‐17–producing cellular network at multiple sites

Among many survival strategies, parasitic worms secrete molecules to modulate host immune responses. One such product, ES-62, is protective in the collagen-induced arthritis (CIA) model of rheumatoid arthritis. As IL-17 has been reported to play a pathological role in the development of rheumatoid arthritis, we investigated whether targeting of IL-17 may explain the protection afforded by ES-62 in the CIA model. DBA/1 mice progressively display arthritis following immunization with type-II collagen. The protective effects of ES-62 were assessed by determination of cytokine levels, flow cytometric analysis of relevant cellular populations and in situ analysis of joint inflammation. ES-62 was found to downregulate IL-17 responses in the CIA model. Firstly, it acts to inhibit priming and polarisation of IL-17 responses by targeting a complex IL-17-producing network, involving signalling between dendritic cells and γδ or CD4+ T cells. In addition, ES-62 directly targets Th17 cells by downregulating MyD88 expression to suppress responses mediated by IL-1 and TLR ligands. Moreover, ES-62 modulates migration of γδ T cells and this is reflected by direct suppression of CD44 upregulation and, as evidenced by in situ analysis, dramatically reduced levels of IL-17-producing cells, including lymphocytes, infiltrating the joint. Finally, there is strong suppression of IL-17 production by cells resident in the joint, such as osteoclasts within the bone areas. Such unique multi-site manipulation of the initiation and effector phases of the IL-17 inflammatory network could be exploited in the development of novel therapeutics for rheumatoid arthritis.