TARGETED DELETION OF GALECTIN-1 GENE RESULTS IN ENHANCED SUSCEPTIBILITY TO AUTOIMMUNE NEUROINFLAMMATION

G. BIANCO; J. ILARREGUI; M. TOSCANO; L. CAMPAGNA; D. CROCI; J. CORREALE; G. RABINOVICH

RIO DE JANEIRO

Congreso; 13TH INTERNATIONAL CONGRESS OF IMMUNOLOGY; 2007

ICI 2007

Targeted deletion of galectin-1 gene results in enhanced susceptibility to autoimmune neuroinflammation   Germán A. Bianco1 , Juan M. Ilarregui1, Marta A. Toscano1, Leonardo Campagna1, Diego Croci1, Jorge Correale2 & Gabriel A. Rabinovich1   1Division of Inmunogenetics, Hospital de Clínicas "José de San Martín", School of Medicine, University of Buenos Aires, Av. Córdoba 2351. 3rd Floor, C1120 Buenos Aires, Argentina 2Department of Neurology Raul Carrera, Institute for Neurological Research, FLENI, Montañeses 2325, (1428) Buenos Aires, Argentina   Recently we provided evidence of a novel mechanism, based on differential glycosylation of T helper cell subsets, by which galectin-1 (Gal-1) selectively regulates the survival of Th1 cells. In an attempt to elucidate the pathophysiological relevance of our findings, we investigated here the impact of gal-1 gene disruption in the development and progression of Experimental Autoimmune Encephalomyelitis (EAE), a murine model of human multiple sclerosis, and the ability of this protein to regulate the survival of T-cell effectors in vivo. For this purpose, we immunized gal-1-/- and wild-type 129/Sv mice (EAE-resistant strain) using the encephalitogenic peptide MOG35-55. Although the overall incidence of EAE was similar in the two groups, disease severity was significantly enhanced in gal-1-/- mice compared with wild-type littermates (p<0.01). Consistently, areas of inflammation and demyelination were more pronounced in spinal cord sections from gal-1-/- vs wild-type mice. Splenocytes from gal-1-/- mice exhibited more vigorous MOG35-55-specific proliferation and IFN-g production compared to wild-type counterparts (p<0.05). Th1 polarization in gal-1-/- mice was accompanied by an increase in non-sialylated core-1-O-glycans and lower frequency of apoptotic CD4+ T cells. Finally, Gal-1 treatment of C57BL/6 mice (EAE susceptible strain) during the induction of EAE resulted in reduced clinical and pathological severity, diminished MOG35-55-specific IFN-g production and higher fraction of apoptotic CD4+ splenocytes (p<0.01 vs vehicle-treated mice). Thus, deletion of the gal-1 gene results in exacerbated demyelinating disease and profound skewing toward peptide-specific TH1 response, suggesting that galectin-1 is critical for limiting the frequency of pathogenic T-cell responses in vivo.