Recombinant galectin-1 and its genetic delivery suppress collagen-induced arthritis via T cell apoptosis.
Galectin-1 (GAL-1), a member of a family of conserved beta-galactoside-binding proteins, has been shown to induce in vitro apoptosis of activated T cells and immature thymocytes. We assessed the therapeutic effects and mechanisms of action of delivery of GAL-1 in a collagen-induced arthritis model. A single injection of syngeneic DBA/1 fibroblasts engineered to secrete GAL-1 at the day of disease onset was able to abrogate clinical and histopathological manifestations of arthritis. This effect was reproduced by daily administration of recombinant GAL-1. GAL-1 treatment resulted in reduction in anticollagen immunoglobulin (Ig)G levels. The cytokine profile in draining lymph node cells and the anticollagen IgG isotypes in mice sera at the end of the treatment clearly showed inhibition of the proinflammatory response and skewing towards a type 2-polarized immune reaction. Lymph node cells from mice engaged in the gene therapy protocol increased their susceptibility to antigen-induced apoptosis. Moreover, GAL-1-expressing fibroblasts and recombinant GAL-1 revealed a specific dose-dependent inhibitory effect in vitro in antigen-dependent interleukin 2 production to an A(q)-restricted, collagen type 2-specific T cell hybridoma clone. Thus, a correlation between the apoptotic properties of GAL-1 in vitro and its immunomodulatory properties in vivo supports its therapeutic potential in the treatment of T helper cell type 1-mediated autoimmune disorders.
Rabinovich
G A
GA
Immunology Department, Faculty of Chemical Sciences, National University of Córdoba 5000, Argentina.
Daly
G
G
Dreja
H
H
Tailor
H
H
Riera
C M
CM
Hirabayashi
J
J
Chernajovsky
Y
Y
D000818:Animals; D017951:Antigen Presentation; D017209:Apoptosis / Q000235:genetics* / Q000276:immunology; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology* / Q000517:prevention & control; D003094:Collagen / Q000276:immunology*; D005347:Fibroblasts / Q000378:metabolism / Q000637:transplantation; D037483:Galectin 1; D005786:Gene Expression Regulation; D006388:Hemagglutinins / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics* / Q000627:therapeutic use; D006614:Hindlimb; D006801:Humans; D006825:Hybridomas / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate; D007074:Immunoglobulin G / Q000096:biosynthesis; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use; D007274:Injections, Intraperitoneal; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics / Q000627:therapeutic use*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D018417:Th1 Cells / Q000378:metabolism; D018418:Th2 Cells / Q000378:metabolism; D014162:Transfection
D037483:Galectin 1; D006388:Hemagglutinins; D007074:Immunoglobulin G; D007166:Immunosuppressive Agents; D011994:Recombinant Proteins; D003094:Collagen