ENGINEERING AN ENDOGENOUS LECTIN TO TREAT AUTOIMMUNE DISEASES

MENDEZ-HUERGO, SANTIAGO P.; DI LELLA, SANTIAGO; CAGNONI, ALEJANDRO; BLIDNER, ADA; MOROSI, LUCIANO G.; HOCKL, PABLO F.; MORALES, ROSA; STUPIRSKI, JUAN C.; CORREALE, JORGE; CARAMELO, JULIO; ESTRIN, DARIO; MARIÑO, KARINA; RABINOVICH, GABRIEL A.

Ciudad de Buenos Aires

Congreso; Reunion Conjunta de Sociedades de Biociencias; 2017

SAIC SAIB SAI SAA SAB SAB SAFE SAFIS SAH SAP

Glycosylation is a highly regulated process capable of modulating thefate and function of T cells. In the present work, we studied how differentialglycosylation can modulate regulatory (Treg) and effector T (Teff) cellfunction and capitalized on this information for the design of a noveltherapeutic strategy for autoimmune diseases. We found that Galectin-1 (Gal1)treatment ameliorates the clinical symptoms of mice bearing experimentalautoimmune encephalomyelitis (EAE) (p<0.05), animal model of multiplesclerosis (MS), by dampening Th1 and Th17 responses while enhancing the Tregcell compartment (p<0.01). Mechanistically, Tregs but not Teff cells, areprotected from Gal1-induced apoptosis (p<0.001) through differentialN-glycan branching and α2,6 sialylation (α2,6SA) of cell surface glycoproteins. In MS patients, we found thatduring the relapse phase of the disease they show low levels of circulatingGal1 (p<0.001), and identified a subpopulation of CD4 T cells ?absent duringthe remitting phase? characterized by low levels of α2,6SA (p<0.001) and susceptibility to Gal1-induced apoptosis(p<0.001). To capitalize on this information for therapeutic purposes, westudied physicochemical properties that hinder translation of thisimmunoregulatory lectin to clinical settings. We found that Gal1-induced apoptosisof T cells is impaired by both acidic (p<0.05) and oxidative conditions(p<0.01), typical hallmarks of inflammatory settings. Thus, we geneticallyengineered Gal1 protein to generate stable mutants capable of circumventing theselimitations. These mutants showed enhanced capacity to induced apoptosis ofactivated T cells (p<0.05), IL-10 secretion by T cells (p<0.001) and IL-27secretion by DCs (p<0.001). Finally, these mutants showed enhancedtherapeutic potential in mouse models of MS (EAE) (p<0.001), arthritis (CIA)(p<0.01) and colitis (TNBS-IBD) (p<0.05). Our findings provide novel therapeuticstrategies for treating a broad range of autoimmune diseases.