In Europe >33 million people suffer from diabetes, a chronic disease associated with long-term pathology representing one of the biggest cost factors for the health care system. The ultimate goal of this proposal is to develop a novel immunomodulatory diabetes therapy by identifying parasitic worm (helminth) regulatory mechanisms which protect against autoimmune diseases. The applicants’ previous work has shown that infection with the filarial helminth Litomosoides sigmodontis prevents Type I diabetes onset in the nonobese diabetic (NOD) mouse model and induces regulatory mechanisms.In the first objective, depletion and transfer experiments will show which L. sigmodontis-induced regulatory mechanisms prevent diabetes onset in NOD mice. Identification of helminth-induced regulatory mechanisms that prevent diabetes onset will enable the establishment of an in vitro screening assay to test worm antigen fractions for their protection.In the second objective the contribution of endosymbiontic Wolbachia bacteria, present in most human filarial helminths and L. sigmodontis, to the helminth-mediated protective effect will be studied to determine whether Wolbachia antigens should be included in the screening process.While it is well accepted that helminth infections prevent the onset of autoimmune diseases, it is not known whether helminth infections ameliorate or prevent the onset of metabolic diseases like Type 2 diabetes (e.g. by reducing the associated pro-inflammatory immune response). Thus, the final objective examines whether L. sigmodontis infection prevents the onset of diet-induced insulin resistance in mice.Identification of helminth-induced regulatory mechanisms that prevent the onset of diabetes, followed by the identification of worm derived products that induce these regulatory immune responses may lead to new treatment regimens for Type I diabetes and prevent the development of Type 2 diabetes without increasing the risk for opportunistic infections.