Author(s): Harnett W, Harnett MM, Leung BP, Gracie JA, McInnes IB
Filarial nematodes achieve long-term infection via modulation of the host immune system. Although human infection can result in severe pathology, the majority of infected individuals exhibit little evidence of this. Analysis of the immune response during infection indicates that the apparently healthy majority have an anti-inflammatory phenotype and it has been speculated that this may contribute to maintenance of host health. Recent data suggest that parasite-derived molecular secretions contribute to the anti-inflammatory phenotype and we have thus characterised a major filarial nematode secreted glycoprotein, ES-62. This molecule has been found to possess broad immunomodulatory activities that are in general, anti-inflammatory. It has long been recognised that several autoimmune disorders including rheumatoid arthritis (RA) exhibit reduced incidence and severity in geographic regions in which filarial nematodes are endemic. Furthermore, it has been speculated that these two observations are causally linked. However, molecular explanations for such an association have not been forthcoming. Although the aetiology of RA is unknown most data suggest that it is mediated via a pro-inflammatory immune response associated with excess cytokine production. Given that ES-62 is anti-inflammatory, we hypothesised that it might possess activity against diseases like RA. Indeed we found that subcutaneous injection of ES-62 prevented initiation of collagen-induced arthritis (CIA) and also suppressed progression of established disease. Ex vivo analyses demonstrated that these effects were due to inhibition of TNF-alpha production and reversal of collagen specific TH-1 responses. The nematode product was also found to inhibit pro-inflammatory cytokine release in vitro in synovial cells derived from RA patients. ES-62 thus represents a parasite-derived immunomodulator with significant therapeutic potential.