Epidemiological data has long shown that the prevalence of parasitic infections inversely correlates with that of allergic diseases such as asthma. This led to the hypothesis that parasites may suppress pathogenic immune responses, and that their products contain immunomodulatory products which could be developed for therapeutic use. In mouse models of asthma, infection with the mouse intestinal parasite Heligmosomoides polygyrus suppresses allergic immune responses and lung pathology. To test if these suppressive effects are mediated by parasite-derived molecules, we collected the excretory/secretory products of H. polygyrus: a mixture of around 400 proteins released by the parasite, termed “HES”. We administered HES directly to the mouse airways and found that it replicated the suppressive effects of infection. In a mouse model of asthma dependent on administration of the clinically-relevant allergenic fungus Alternaria, HES suppressed airway resistance, histological inflammation, airway eosinophilia and type 2 cytokine responses. We found that HES suppressed early (1 h postadministration of allergen) IL-33 release, and that this resulted in suppression of downstream type 2 responses. The IL-33 pathway has been strongly implicated by genome-wide association studies as of crucial importance in asthma, and levels of IL-33 are increased in severely asthmatic lungs. We have now identified 2 potentially therapeutic individual proteins from HES: in purified recombinant forms the first suppresses the release of IL-33 from mouse cells, and the second signals through the TGF-R pathway, suppressing activation and inducing a regulatory phenotype in human and mouse T cells. We are presently investigating the mechanism of action and binding partners of these molecules, and their potential utility in human disease.