Review
ES-62, a filarial nematode-derived immunomodulator with anti-inflammatory potential

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Abstract

Arthropod-transmitted filarial nematodes can survive for in excess of a decade via modulation of the vertebrate host immune system. Although human infection can result in very severe pathology, most infected individuals show remarkably little evidence of this. Analysis of the anti-nematode response indicates that apparently pathology-free individuals have an anti-inflammatory immunological phenotype and it has been suggested that this favours maintenance of host good health. It is considered that parasite-derived molecular secretions contribute to the anti-inflammatory phenotype and we have thus investigated the properties of a filarial nematode glycoprotein secreted in some abundance, ES-62. This molecule shows a plethora of immunomodulatory activities that can be classified as anti-inflammatory. It has been observed in a number of studies that several autoimmune disorders including rheumatoid arthritis (RA) exhibit reduced incidence and severity in geographic regions in which filarial nematodes are transmitted to humans. Furthermore, it has been speculated that these two observations are linked although molecular explanations for such an association have not been forthcoming. Although the aetiology of RA remains unknown a majority of data are consistent with it being mediated via excess pro-inflammatory cytokine production. Given that ES-62 is anti-inflammatory, we hypothesised that it might be able to counter the pathology associated with diseases like RA. Indeed, we found that exposure to ES-62 prevented initiation of collagen-induced arthritis (CIA) in a murine model and also suppressed progression of established disease. Ex vivo analyses demonstrated that these effects correlated with inhibition of TNF-α production and inhibition of collagen-specific TH-1 responses. The nematode product was also able to suppress pro-inflammatory cytokine release in vitro in synovial cells derived from RA patients. ES-62 thus constitutes a pathogen-derived immunomodulator with significant therapeutic potential.

Section snippets

Filarial nematode parasites and modulation of the host immune system

Filarial nematodes are arthropod-transmitted parasites of vertebrates including humans. Of the eight species, which are known to infect humans, three—Wuchereria bancrofti, Brugia malayi and Onchocerca volvulus—represent major causes of morbidity in the Tropics [1]. In excess of 150 million people are infected with one or more of these three worms and such individuals may suffer debilitating health problems. These include elephantiasis, chronic skin lesions and eye damage leading to blindness.

ES-62—biological and structural aspects

ES-62 was discovered in one of our laboratories (WH) as a secreted protein of the rodent filarial nematode Acanthocheilonema viteae in 1989 [5]. The name ES-62 derives from “excretions–secretions” (ES) and from the observation that the parasite-derived molecule had a molecular mass of ∼62,000 when analysed by SDS-PAGE under reducing conditions [5] (although gel filtration analysis [6] and sedimentation equilibrium data [7] both subsequently indicated that the secreted molecule existed as a

Effects on dendritic cells

It is now accepted that the phenotype of an acquired immune response is considered to reflect the early cytokine environment in which naive CD4+ T lymphocytes interact with antigen. It has been suggested for example, that early exposure to IL-4 can push an immune response in a TH-2 direction [19]. As filarial nematode infection is thought of as being associated with a TH-2 phenotype, we investigated whether ES-62 was able to spontaneously induce IL-4 secretion in naive murine spleen cells. IL-4

ES-62—anti-inflammatory potential

The recently defined “Hygiene Hypothesis” proposes that increased incidence of disease associated with aberrant immune responses in the West reflects an absence of appropriate priming of the immune response by infectious agents such as parasitic helminths during childhood [43]. Consistent with this, it is long recognised that several autoimmune disorders exhibit reduced incidence and severity in geographic regions with high helminth load (reviewed in [43]). Rheumatoid arthritis (RA), for

Concluding remarks and future prospects

Discovery of safe, novel immunomodulators, effective in the treatment of chronic inflammatory diseases such as rheumatoid arthritis, is currently a major therapeutic objective. Long-term immune system deviation is most striking in the host–parasite relationship, in which microbes may co-exist over decades with a human host. It is therefore perhaps axiomatic that such a relationship should offer a rich supply of anti-inflammatory immunomodulators of potential therapeutic value.

Filarial nematodes

Acknowledgements

We would like to thank the Edward Jenner Institute for Vaccine Research, the Leverhulme Trust, the Medical Research Council, Tenovus Scotland, the Wellcome Trust, the Biotechnology and Biological Sciences Research Council and the World Health Organisation for supporting our research on filarial nematodes.

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