Centre for Biodiscovery and Molecular Development of Therapeutics, Australian Institute of Tropical Health and Medicine, James Cook University, and the Prince Charles Hospital, QLD, Australia
Coeliac disease (CeD) is a gluten-sensitive autoimmune enteropathy. A gluten-free diet is effective treatment, but compliance is demanding. Because human immunity is in part defined by co-evolution with helminths that must induce tolerance in the host to survive, we have investigated the therapeutic potential of both live infection with the human hookworm Necator americanus (Na) to improve gluten tolerance in people with CeD, and hookworm derived products to suppress autoimmune inflammation. This presentation focuses on the clinical application of live hookworm infection. In people with CeD once infected with Na, gluten stimulation promoted mucosal IFN-γ responsiveness, but IL-23 and IL-17A responses were suppressed, and IL-5 and TGF-β responsiveness developed. On the basis that this platform might promote gluten tolerance, we trialled an escalating gluten challenge in healthy participants with CeD. Two of twelve participants were withdrawn immediately after micro-challenge because of adverse responses to gluten. Thereafter, 10 completed a modest and sustained 12 week challenge designed to mimic twice weekly inadvertent exposures to gluten, after which mean quality of life and coeliac symptom index (CSI) scores remained unchanged. Histological indices did not deteriorate. Frequencies of intestinal intraepithelial T cells expressing IFN-γ were reduced and mucosal Foxp3+ regulatory T cells increased. After a 12 week washout, 8 of 8 subjects completed a 2 week moderate gluten challenge equivalent to a small bowl of pasta daily during which CSI values and tissue transglutaminase titres progressively declined. Testing the faecal and duodenal microbiome before and after hookworm plus low dose gluten challenge established increased diversity and richness of the microbiota, outcomes that are more consistent with a healthy and regulated intestinal milieu. Based on these remarkable results, we have initiated a randomised multi-stage clinical trial designed to restore gluten tolerance through micro-challenge in the context of Na infection, then progressively increase gluten consumption to a level consistent with a liberal diet. The trial protocol will be described.