Therapeutic application of parasitic products and modulation of the human immune system

Helminths are exquisitely adapted to evading and modulating the mammalian immune response; and interestingly similar evasion mechanisms can be shared among distantly related species (click to see Table 4).

This begs the obvious question of whether this ability can ever be exploited for therapeutic purposes. The growing body of epidemiological and experimental data detailed above strongly suggests that a reduction in helminth infection is linked to rising rates of autoimmunity and atopy. This offers the real possibility that helminths applied in a controllable clinical setting, could relieve inflammatory disease yet minimize the adverse effects of the parasite. Indeed, several models of autoimmune disease have validated the potential of such an approach. Although still a very young field, limited clinical trials have already been carried out assessing the effects of the porcine whipworm, Trichuris suis, on IBD (Inflammatory Bowel Disease) (65).

Initial pilot studies using oral ingestion of live T. suis ova at regular intervals hinted at a beneficial effect on IBD without any overt side-effects (62). Larger trials, including one double-blinded and placebo controlled, revealed effective relief of Crohn's disease in nearly 80% of patients but much more modest effects in the case of Ulcerative Colitis (62,66). It should be noted that the patients enrolled in these studies were refractory to standard interventions, so any beneficial effect should be welcomed, but larger trials with improved clinical scoring would be desirable (67). A similar trial, this time using the human hookworm Necator americanus, is also being carried out in Crohn's patients (68). The caveat of a live parasite approach is only too evident; even if the chosen parasite is unable to productively infect the host patient, as is the case with T. suis, there may still be some adverse side-effects, particularly when patients are challenged in conjunction with immunosuppressants, or in otherwise immunosuppressed individuals.

In particular, parasite-mediated immunomodulation may compromise the anti-tumour responsiveness of the patient (69–71). Far more desirable then would be to mimic the beneficial effects of helminth infection by using non-infective products derived from them. Aside from the safety issues, the use of helminth products or their synthetic analogues may also allow a finer level of immunomodulatory control or even potency. Emerging proteomics data and the steady progress in the S. mansoni sequencing project will also surely illuminate the search for novel and efficacious immunomodulatory helminth-derived products (72,73).

One prediction of the Hygiene Hypothesis is that the rising rate of inflammatory disorders is due specifically to a paucity of infection during infancy, which in turn tunes the immune response in subsequent adulthood to a less pathogenic modality. This being the case, therapeutic dosing of a helminth (or products thereof) to relieve fulminant inflammatory disease in an adult may be relatively ineffective. The patient's immune repertoire, both adaptive and innate, has already been shaped by the absence of parasite antigens, and is subject to only relatively minor perturbations.

This may explain the incomplete effects of the T. suis infections described above. A prolonged treatment regimen, infection with an attenuated host-specific helminth, or exposure during the supposed critical period of infancy may all potentially improve the efficacy of such an approach. In some not too distant futurity, there may come a day when we all take ‘helminth supplements’ along with our Omega 3 fatty acids, vitamins, and whatever else goes to make up a modern balanced diet.

Acknowlegements

We thank fellow members of the Cooke and Dunne groups for helpful discussions. We acknowledge the International Diabetes Federation, Brussels, for allowing us to adapt figures and data. Particular thanks go to Chris Bland for assistance with the histology. Our work is funded by the Wellcome Trust and Diabetes UK.