Capitalizing on Galectin1-glycan interactions for the design of novel therapeutic strategies in Inflammatory Bowel Diseases

MARIÑO, KARINA VALERIA; RABINOVICH, GABRIEL A.

San Francisco

Simposio; Kenneth Rainin Foundation Innovations Symposium 2017: Emerging IBD strategies; 2017

Background: Interactions between glycans and endogenous lectins are crucial in the development and resolution of many chronic inflammatory diseases. Galectin-1 (Gal1), a carbohydrate-binding protein, can exert protective immunomodulatory activity in models of inflammatory diseases including acute TNBS-induced colitis. However, the role of Gal1 and its carbohydrate ligands in the development and resolution of intestinal inflammation is still not well understood. The therapeutic potential of this anti-inflammatory lectin is hampered by its sensitivity to the inflammatory environment, as acidic and oxidative conditions negatively affect its activity.Hypothesis: Could exogenous Gal1 or its tailored-designed recombinant Gal-1 variants (resistant to acidosis and oxidation), act as immunosuppressive agents to dampen intestinal inflammation?Methods: We evaluated colitis development both in wild-type (WT) animals and in mice devoid of Gal1 or glycosyltransferases essential for generating or hindering Gal1-specific ligands. We tested Gal1 therapeutic potential in DSS-induced colitis and T-cell transfer chronic model of colitis, and assessed the therapeutic effects of Gal1 variants specifically designed to overcome inflammatory microenvironments during intestinal inflammation. We evaluated Gal1 and its variants in vitro and in vivo by analyzing changes in immune responses (T-cell proliferation, cytokine production, frequency of regulatory T cells), and disease progression by body weight and histopathological scores.Results: Gal1-deficient iTregs did not suppress inflammation in an adoptive transfer model. DSS-induced inflammation did not respond to Gal1 treatment. Tailored-designed Gal1 variants showed uncoupled immunomodulatory activities. Decoupling of biological functions in Gal1 variants results in improved therapeutic application of Gal1 in the TNBS experimental model of colitis. Conclusions: An altered glycosylation impairs resolution of intestinal inflammation, causing differential Gal1 binding to CD4+/CD8+ T cells and affecting their survival, highlighting the importance of Galectin-1-glycan interactions in colitis resolution. Gal1-deficient mice have shown more severe colitis and were incapable of recovering the weight loss caused by the TNBS treatment, validating the key role of Gal1 in maintaining mucosal homeostasis. It could be hypothesized that Gal1 KO mice failed to switch from a Th1 to a Th17 response, as seen in WT animals.Impact on our knowledge of IBD: The therapeutic potential of Gal1 was confirmed in the TNBS-model, but DSS-induced inflammation did not respond to Gal1 administration; mechanisms in the initiation and perpetuation of disease pathogenesis may dictate Gal1 therapy. Decoupling of biological functions in Gal1 variants could result in specific therapeutic applications of these tailor-designed lectins at different stages of disease.