From the worm to the pill, the parasitic worm product ES-62 raises new horizons in the treatment of rheumatoid arthritis

Abstract

Evidence from human studies suggests that parasitic worm infection can protect humans against rheumatoid arthritis (RA) and this idea is strengthened by data generated in model systems. Although therapeutic use of parasitic worms is currently being explored, there are obvious benefits in pursuing drug development through identification and isolation of the 'active ingredients'. ES-62 is a secreted glycoprotein of the filarial nematode Acanthocheilonema viteae, which we have found to protect against the development of collagen-induced arthritis (CIA) in mice. ES-62 activity is dependent on the inflammatory phenotype of the local environment and protection arises via inhibition of Th17- and γδT cell-dependent IL-17 production. At the same time, NK and NK T cell IL-17 production is left intact, and such selectivity suggests that ES-62 might make a particularly attractive therapeutic for RA. However, as a potentially immunogenic protein, ES-62 is unsuitable for development as a drug. Nevertheless, ES-62 activity is dependent on covalently attached phosphorylcholine (PC) residues and we have therefore produced a library of PC-based drug-like ES-62 small-molecule analogues (SMAs) as an alternative therapeutic strategy. Screening this library, we have found an ES-62 SMA that mirrors ES-62 in protecting against CIA and by the same IL-17-dependent mechanism of action.

The helminth product, ES-62 modulates dendritic cell responses by inducing the selective autophagolysosomal degradation of TLR-transducers, as exemplified by PKCδ

“…2b), relative to those receiving control LPS-matured DC (pre-treated with medium alone). Thus, although ES-62 and LPS both signal via TLR4 on DCs78, exposure of DCs to ES-62 alone does not stimulate the classical effector mechanisms (pro-inflammatory cytokine production and priming of Th1/Th17 proliferation and differentiation) of canonical TLR ligands, either in vitro or in vivo : these data therefore confirm and extend our evidence obtained to date (reviewed in refs 9 and 11) that ES-62 and LPS exploit differential TLR4 effector pathways.…”

“…We have previously shown that the α, δ and ε isoforms of PKC regulate TLR4 signalling in mast cells and that ES-62 subverts such TLR4 signalling by downregulating expression of MyD88 and PKC-α and PKC-δ11722: consistent with a similar mode of action in DCs, ES-62 acts homeostatically to limit expression of MyD88 which is upregulated in DCs under inflammatory conditions9. We therefore next investigated whether the α, δ and ε isoforms of PKC played key roles in LPS/TLR4-mediated cytokine responses in bmDCs and whether their differential signalling by ES-62 and LPS could provide a rationale for the observed distinct functional outcomes.…”

“…ES-62 is a PC-containing immunomodulatory glycoprotein that exhibits protective effects in models of allergic and autoimmune disease911 by homeostatically resetting the effector: regulatory B cell balance and consequently modulating the IL-23/IL-17/IL-22 inflammatory axis2345630, dysregulation of which has been implicated in the pathogenesis of chronic inflammatory disorders31. Although the precise cellular networks modulated by the worm product appear to differ depending on the inflammatory context, ES-62 likely affords protection by acting to subvert TLR signalling via partial downregulation of MyD88 expression in effector cells of both innate and adaptive immunity346917.…”

“…Such protection is associated with homeostatic resetting of the IL-23/IL-17/IL-22 inflammatory axis, which appears to become dysregulated in these inflammatory disorders: a key effector driving development of this type of inflammation is the dendritic cell (DC), which ES-62 targets by subverting TLR4 signalling789 to suppress aberrant DC-priming of Th17 cells and IL-17-producing γδ T cells24.…”

“…The precise mechanism(s) underpinning differential LPS- and ES-62-mediated TLR4 signalling in DCs has yet to be fully resolved: however, our recent data indicating that ES-62, but not LPS, can drive the autophagolysosomal-mediated downregulation of MyD88 in DCs under hyper-inflammatory conditions9 suggests that ES-62 may generally act by harnessing homeostatic autophagy-dependent mechanisms to limit aberrant inflammation by degrading key TLR4 signal effectors. In support of this, whilst autophagy is a critical and complex cellular homeostatic mechanism with key roles in TLR-associated immunity, notably in killing of intracellular pathogens, antigen presentation and T cell polarisation, it also controls inflammation, acting to antagonise inflammasome signalling and to limit and resolve inflammation18.…”