Recombinant Galectin-1 and Its Genetic Delivery Suppress Collagen-Induced Arthritis via T Cell Apoptosis

Abstract

Galectin-1 (GAL-1), a member of a family of conserved β-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 Aq-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.

Intra-articular lentivirus-mediated delivery of galectin-3 shRNA and galectin-1 gene ameliorates collagen-induced arthritis

“…Our gene therapy results with Lt.Gal1 confirmed and extended earlier findings showing that administration of galectin-1 protein or fibroblasts engineered to secrete galectin-1 on the day of the disease onset abrogated the clinical and histopathological manifestations of CIA in DBA/1 mice. 18 Moreover, lymph node cells from galectin-1-treated mice were more susceptible to antigen-induced T-cell death than the control mice. We explored i.a.…”

“…16,17 A single injection of syngenic DBA/1 fibroblasts engineered to secret galectin-1 at the onset of disease abrogated experimental arthritis in mice. 18 Furthermore, microarray analysis of peripheral mononuclear cells has identified galectin-3 as a blood biomarker in the rat CIA model. 19 Local gene transfer into the rheumatoid joints has been evaluated to bypass the inherited obstacle associated with delivery of therapeutic compounds.…”

Psoriasis in humans is associated with down‐regulation of galectins in dendritic cells

“…Exogenous gal-1 has immunosuppressive and anti-inflammatory effects in experimental models of inflammation and autoimmunity such as inflammatory bowel disease, autoimmune retinal disease, autoimmune diabetes, and collagen-induced arthritis [5][6][7][8]. In addition, gal-1-deficient mice show augmented Th1 and Th17 responses and enhanced susceptibility to autoimmune neuroinflammation [3].…”

Immuno- and genetic therapy in autoimmune diseases

“…Galectin-1 induced antigen-specific T cell apoptosis and also provoked a clear switch to a Th2 cytokine profile production. 3 Using the same delivery system, a novel TNF antagonist 182 and IFN␤ 183 were shown to be of clinical benefit at different stages of disease development.…”

“…Importantly, gene therapy has been shown to be capable of achieving biological effects at least at a thousand-fold lower concentrations than those used for the same gene product as protein. 3 This is an advantage as certain cytokines, which are toxic in bolus protein injections, can be delivered safely and effectively locally by gene therapy.…”