Evaluating type 2 immune responses during gastrointestinal nematode infection using a STAT6 inhibitor

Approximately 20% of the world’s population suffer from allergic airways diseases such as asthma. Present treatments, such as inhaled corticosteroids and β-agonists reduce symptoms; however, they are not curative. In addition, of those who suffer from severe asthma, present treatments do not alleviate symptoms and exacerbations continue to cause morbidity. Specifically, allergic airways disease is primarily mediated by a maladaptive Type 2 inflammatory condition that induces dyspnea, wheezing and intermittent airway obstruction. Therefore, therapeutics that target the underlying immunologic mechanisms of disease are of great clinical interest.Abundant data from both murine models and human studies suggest that a key transcription factor involved in mediating allergen-induced Type 2 immune responses is signal transducer and activator of transcription 6 (STAT6). In allergy, STAT6 is responsible for mediating production of the canonical Type 2 cytokines (IL-4, -13, -5, -9), mucus production, smooth muscle contraction and IgE production.STAT6 inhibitory peptide (STAT6-IP) is a cell-penetrating peptide, capable of inhibiting T helper 2-biased airwary inflammation in ovalbumin/ragweed allergy models and in respiratory synctitial virus infection models. In these models, intranasal STAT6-IP delivery potently reduces allergic inflammatory responses, including eosinophil levels in the bronchoalveolar lavage fluid and mucus production in airway epithelial cells. To date, it is not known whether STAT6-IP modulates protective Type 2 immune responses.The overall goal of this M.Sc. was to investigate the potential of STAT6-IP to modulate protective Type 2 immune responses during helminth infection. Heligmsomoides polygyrus bakeri (Hpb) was used as the model helminth due to the requirement for effective Type 2 immunity in both primary and challenge infection.4In order to define potential modulation of Type 2 responses during helminth infection by STAT6-IP, STAT6-dependent immune responses were first assessed in STAT6-deficient mice. Our results indicate that STAT6 was required to reduce adult worm and egg burden formation of intestinal granulomas, and production of Hpb-adult worm specific IgG.STAT6-IP was first tested in primary Hpb infection, which is characterized by a chronic infection and inefficient Type 2 responses. Our data suggest that neither intranasal nor intraperitoneal delivery of STAT6-IP at the time of initial infection was sufficient to modulate infection outcomes such as antibody responses and granuloma formation. However, three-day intranasal delivery of STAT6-IP resulted in reduced adult worm burden and fewer eggs per gram of intestinal feces. Moreover, upon repeated intraperitoneal delivery of STAT6-IP (nine doses over the course of 13 days), no detectable differences were obtained in most outcomes compared to PBS-treated animals, although adult-worm specific IgG1 was reduced at early times after primary infection. Altogether, our findings suggest that STAT6-IP, given as a short-term immunomodulator in allergic airways disease, is unlikely to alter protective Type 2 immunity in the gastrointestinal tract.We also investigated whether STAT6-IP delivery at the time of primary Hpb infection altered the course of Hpb challenge infection, which is curative, due to the Th2-dependent induction of alternatively activated macrophages, which mediate larval killing within the granuloma. Our data demonstrate that three-dose delivery of ST A T6-IP , via either the intraperitoneal or intranasal route, had no effect on worm expulsion and granuloma formation during challenge infection. However, three-dose intraperitoneal delivery of STAT6-IP-Arg9 reduced adult-worm specific IgG1 responses, suggesting that STAT6-IP may modulate humoural immunity.5Overall, STAT6-IP has the potential to act as a novel therapy for allergic lung diseases without potential side effects to protective Type 2 immune responses in the gastrointestinal tract.

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