VIERNES 24/11/17, a la hora 12.00, en la Sala de Seminarios del IAL.
Disertante: Dr. Gabriel Rabinovich
Título: A ´sweet tale´ of tolerance and immunity: from basic discovery to drug design
Gabriel A. Rabinovich et al Laboratorio de Inmunopatología, Instituto de Biología y Medicina Experimental (IBYME, CONICET) y Facultad de Ciencias Exactas y Naturales, Universidad de Beunos Aires, Argentina. E-mail: email@example.com
In the postgenomic era, the study of the glycome- the whole repertoire of saccharides in cells and tissues- has enabled the association of unique glycan structures with specific physiological and pathological processes. The responsibility for deciphering this biological information is assigned to endogenous glycan-binding proteins or lectins whose expression is regulated at sites of inflammation, infection and tumor growth. Galectins, a family of highly conserved glycan-binding proteins, control immune and vascular signaling programs, by modulating reorganization, clustering and signaling threshold of relevant glycosylated receptors. Our laboratory investigates the molecular interactions between endogenous galectins and glycans leading to the control of immune tolerance and homeostasis. In the past years, we have identified essential roles for galectin-1 (Gal-1), a proto-type member of this family, in tolerogenic circuits operating during tumor growth, microbial invasion and resolution of inflammation associated to autoimmune disorders, neurodegeneration, pregnancy and cardiovascular diseases. Mechanistically, this endogenous lectin acts by selectively dampening Th1 and Th17 responses, instructing the differentiation of tolerogenic dendritic cells, promoting the expansion of regulatory T cells, favoring M2 macrophage polarization and modulating eosinophil trafficking. Moreover, our studies identified a glycosylation-dependent, Gal-1-mediated program that links tumor hypoxia, immunosuppression and vascularization and hinders success of anti-angiogenic and immunotherapeutic modalities. These observations, confirmed in a variety of experimental settings and human patient samples, prompted us to generate and validate a set of anti-Gal-1 mAb aimed at overcoming cancer immunosuppression, preventing aberrant angiogenesis and reinforcing antimicrobial responses. Moreover, using an interdisciplinary approach ranging from computational modeling, protein engineering, and cell biology, we designed and validated stable galectin-tailored variants aimed at potentiating tolerogenic circuits and promoting resolution of autoimmune inflammation. In conclusion, our studies contributed to elucidate novel pathways via which endogenous galectins translate glycan-encoded information into unique signaling programs, findings that bring unifying principles to the diverse fields of immune regulation, oncology and vascular biology. These observations have opened new possibilities for development of therapeutic strategies aimed at potentiating antitumor responses, reinforcing antimicrobial immunity and limiting autoimmune inflammation.