ENGINEERING AN ENDOGENOUS LECTIN TO TREAT AUTOIMMUNE DISEASES

SANTIAGO P. MÉNDEZ HUERGO ; ADA BLIDNER ; ROSA MORALES ; JULIO CARAMELO ; GABRIEL A. RABINOVICH ; ALEJANDRO CAGNONI ; PABLO HOCKL ; JORGE CORREALE ; KARINA MARIÑO ; SANTIAGO DI LELLA ; LUCIANO MOROSI ; JUAN C. STUPIRSKI ; DARÍO ESTRÍN

Buenos Aires

Congreso; SAIC 2017; 2017

SAIC

Glycosylation is a highly regulated process capable of modulatingthe fate and function of T cells. In the present work, we studied howdifferential glycosylation can modulate regulatory (Treg) and effector T (Teff)cell function 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 experimental autoimmuneencephalomyelitis (EAE) (p<0.05), animal model of multiple sclerosis (MS),by dampening Th1 and Th17 responses while enhancing the Treg cell compartment(p<0.01). Mechanistically, Tregs but not Teff cells, are protected fromGal1-induced apoptosis (p<0.001) through differential N-glycan branching andα2,6 sialylation (α2,6SA) of cell surfaceglycoproteins. In MS patients, we found that during the relapse phase of thedisease they show low levels of circulating Gal1 (p<0.001), and identified asubpopulation of CD4 T cells ?absent during the remitting phase? characterizedby 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 circumventingthese limitations. These mutants showed enhanced capacity to induced apoptosisof activated 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 enhanced therapeuticpotential 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.