ES-62 is a secreted parasitic worm-derived immunomodulator that exhibits therapeutic potential in allergy by downregulating aberrant MyD88 signalling to normalise the inflammatory phenotype and mast cell responses. IL-33 plays an important role driving responses promoting type-2 allergic inflammation, particularly with respect asthma, via MyD88-integrated crosstalk amongst receptor (ST2), TLR4 FcεRI. We have now investigated whether targets this pathogenic network subverting ST2-signalling,...

Abstract Although exogeneous “danger” signals such as LPS can activate APC to produce a Th1 response, the nature of events initiating Th2 response is controversial. We now show that pathogen-derived products have capacity induce bone marrow-derived dendritic cell cultures acquire phenotype promotes differentiation naive CD4+ T cells toward either or phenotype. Thus, LPS-matured (DC1) promote (increased generation IFN-γ and reduced production IL-4) by Ag-stimulated from DO.11.10 transgenic...

Abstract Filarial nematodes, parasites of vertebrates, including humans, secrete immunomodulatory molecules into the host environment. We have previously demonstrated that one such molecule, phosphorylcholine-containing glycoprotein ES-62, acts to bias immune response toward an anti-inflammatory/Th2 phenotype is conducive both worm survival and health. For example, although ES-62 initially induces macrophages produce low levels IL-12 TNF-α, exposure parasite product ultimately renders cells...

Understanding modulation of the host immune system by pathogens offers rich therapeutic potential. Parasitic filarial nematodes are often tolerated in human hosts for decades with little evidence pathology and this appears to reflect parasite-induced suppression proinflammatory responses. Consistent this, we have previously described a nematode-derived, secreted phosphorylcholine-containing glycoprotein, ES-62, immunomodulatory activities that broadly anti-inflammatory nature. We sought...

SUMMARY Praziquantel is a broad-spectrum anthelmintic active against schistosome species which are major parasites of man. Two effects on Schistosoma mansoni have been demonstrated; (i) spastic paralysis the parasite musculature, possibly arising as consequence an influx Ca 2+ into worm (Pax, Bennett & Fetterer, 1978; Coles, 1979) and (ii) vacuolation degeneration tegument (Becker, Mehlhorn, Andrews, Thomas Eckert, 1980). These events may contribute to elimination schistosomes in vivo ,...

Among many survival strategies, parasitic worms secrete molecules that modulate host immune responses. One such product, ES-62, is protective against collagen-induced arthritis (CIA), a model of rheumatoid (RA). Since interleukin-17 (IL-17) has been reported to play pathogenic role in the development RA, this study was undertaken investigate whether targeting IL-17 may explain protection CIA afforded by ES-62.DBA/1 mice progressively display following immunization with type II collagen. The...

In spite of increasing evidence that parasitic worms may protect humans from developing allergic and autoimmune diseases the continuing identification defined helminth-derived immunomodulatory molecules, to date no new anti-inflammatory drugs have been developed these organisms. We approached this matter in a novel manner by synthesizing library drug-like small molecules based upon phosphorylcholine, active moiety Acanthocheilonema viteae product, ES-62, which as an immunogenic protein is...

Rheumatoid arthritis (RA) remains a debilitating autoimmune condition as many patients are refractory to existing conventional and biologic therapies, hence successful development of novel treatments critical requirement. Towards this, we now describe synthetic drug-like small molecule analogue, SMA-12b, an immunomodulatory parasitic worm product, ES-62, which acts both prophylactically therapeutically against collagen-induced (CIA) in mice. Mechanistic analysis revealed that SMA-12b...

Summary Bioactive interleukin (IL)‐12 is a 70 000‐molecular weight (MW) heterodimeric cytokine comprising p40 and p35 chains. However, can also form homodimers that antagonize bioactive IL‐12 or heterodimerize with p19 to IL‐23, which exhibits overlapping yet distinct functions of IL‐12. We now define signalling mechanisms regulate lipopolysaccharide (LPS)‐mediated induction in macrophages may therefore provide therapeutic targets for precise specific fine‐tuning responses. Thus, whilst...

Abstract Parasite survival and host health may depend on the ability of parasite to modulate immune response by release immunomodulatory molecules. Excretory-secretory (ES)-62, one such well-defined molecule, is a major secreted protein rodent filarial nematode Acanthocheilonema viteae, has homologues in human nematodes. Previously we have shown that ES-62 exclusively associated with Th2 Ab mice. Here provide rationale for this polarized showing molecule suppresses IFN-γ/LPS-induced...

E-S 62, a major excretory-secretory product of the rodent filarial parasite, Acanthocheilonema viteae, inhibits polyclonal activation (DNA synthesis) mouse B cells by mitogenic anti-Ig antibodies. This effect appears to be due at least in part phosphorylcholine (PC) moiety molecule, because it can mimicked PC-BSA or PC-chloride. Activation LPS is not influenced presence 62/PC, suggesting that they may target some aspect signaling via Ag receptor. 62/PC failed inhibit surface Ig-mediated...

Objective: In countries where parasitic infections are endemic, autoimmune disease is relatively rare, leading to the hypothesis that parasite-derived immunomodulators may protect against its development. Consistent with this, we have previously demonstrated ES-62, a 62 kDa phosphorylcholine (PC)-containing glycoprotein secreted by filarial nematodes, can exert anti-inflammatory action in murine collagen-induced arthritis (CIA) model and human rheumatoid arthritis-derived synovial tissue...

SUMMARY Modulation of macrophage/dendritic cell (DC) cytokine production by the filarial nematode phosphorylcholine (PC)‐containing product, ES‐62, is mediated Toll‐like receptor (TLR) 4 and signal transduction depends on TLR adaptor MyD88. Intriguingly, comparison TLR4 knock‐out (ko) mice with mutant C3H/HeJ indicates that ES‐62 responses are not dependent Pro712 residue TLR4, which crucial for response to bacterial lipopolysaccharide (LPS). Because other immunomodulatory effects have been...

We previously demonstrated inhibition of ovalbumin-induced allergic airway hyper-responsiveness in the mouse using ES-62, a phosphorylcholine-containing glycoprotein secreted by filarial nematode, Acanthocheilonema viteae. This correlated with ES-62-induced mast cell desensitisation, although degree to which this reflected direct targeting cells remained unclear as suppression Th2 phenotype inflammatory response, measured eosinophilia and IL-4 levels lungs, was also observed. now show that...

The parasitic worm-derived immunomodulator ES-62 protects against disease in the mouse collagen-induced arthritis (CIA) model of rheumatoid (RA) by suppressing pathogenic interleukin-17 (IL-17) responses. Th17-associated cytokine IL-22 also appears to have a role autoimmune arthritis, particularly promoting proinflammatory responses synovial fibroblasts and osteoclastogenesis. present study was undertaken investigate whether protection joint damage afforded reflects suppression IL-22.The...

Objective The hygiene hypothesis suggests that parasitic helminths (worms) protect against the development of autoimmune disease via a serendipitous side effect worm‐derived immunomodulators concomitantly promote parasite survival and limit host pathology. aim this study was to investigate whether ES‐62, phosphorylcholine‐containing glycoprotein secreted by filarial nematode Acanthocheilonema viteae , protects kidney damage in an MRL/ lpr mouse model systemic lupus erythematosus (SLE)....