Galectin
-1, an endogenous lectin with immunomodulatory activities, induces selective, Fas-independent apoptosis of activated T cells. The aim of the present study was to evaluate the effect galectin-1 exerts on concanavalin A (Con A)-induced hepatitis, a T-cell-dependent model of liver injury. Con A administration resulted in liver injury, as shown by the increased transaminase plasma levels and liver DNA fragmentation, and caused spleen T-cell activation, which was associated with a strong increment in liver infiltrating T helper cells. Moreover, Con A injection leads to a marked increase in plasma tumor necrosis factor ␣ (TNF-␣) and interferon gamma (IFN-␥) levels. Galectin-1 pretreatment dose-dependently prevented both liver injury and T-helper cell liver infiltration induced by Con A. In vivo and in vitro experiments indicated that the protective effects of galectin-1 depend on the selective elimination of Con A-activated T cells. In addition, galectin-1 almost completely prevented the Con A-induced increase in plasma TNF-␣ and IFN-␥, an effect that was, at least in part, independent on the elimination of activated T helper cells, because galectin-1 prevented lipopolysaccharide (LPS)induced release of TNF-␣ and IFN-␥ also from macrophages in vitro, without affecting their viability. The present study suggests that galectin-1 is potentially useful in the treatment of T-cell-mediated human liver disorders. (HEPATOL-OGY 2000;31:399-406.)
T-cell-mediated liver damage is a key event in the pathogenesis of many chronic human liver diseases, such as liver transplant rejection, primary biliary cirrhosis, and sclerosing cholangitis. Moreover, it has been recently shown that also during the process of hepatitis B virus-and hepatitis C virus-related chronic hepatitis, the cellular immune response raised against viral antigens is responsible for the progression of liver injury. This concept has been confirmed by the demonstration that injection of a T clone specific for hepatitis B surface antigen in hepatitis B surface antigen-transgenic mice causes massive hepatocyte apoptosis resulting in liver failure. Therefore, even if the target antigen is unknown, elimination of activated T cells might block the progression of damage in several types of chronic liver diseases.
Recently, a new hepatitis model has been developed, in which concanavalin A (Con A) injection into mice leads to a dose-dependent liver injury. That T cell activation is a crucial factor in this hepatitis model is shown by the resistance of severe combined immunodeficiency disorder mice, which lack immunocompetent T and B lymphocytes, to Con Ainduced liver injury. 4,5 Furthermore, pretreatment with antiinterferon gamma (anti-IFN-␥) or anti-tumor necrosis factor ␣ (TNF-␣) monoclonal antibodies (mAbs) or IFN-␥ gene ablation confers protection against Con A-induced liver injury, indicating that Th 1 -dependent cytokines are also involved. Galectin-1 (galaptin), a 14.5-kd homodimer, is a member of a family of -galactoside binding proteins that share growth regulatory and immunomodulatory activities. Galectin-1 is constitutively expressed by smooth cardiac and skeletal muscles, thymus, kidney, placenta, laminin and fibronectin, and the hematopoietic cell surface membrane proteins CD43 and CD45 have been identified as galectin-1 receptors. Recent studies showed that human thymic epithelial cells constitutively produce galectin-1, which causes apoptosis of the negatively selected CD4 lo CD8 lo subset of thymocytes. Moreover, although galectin-1 is ineffective on resting T cells, it causes a Fas-independent apoptosis of activated mature T lymphocytes, suggesting that it is also involved in immune response regulation. Administered in vivo, galectin-1 has been shown to be effective in several animal models of T-cell-mediated diseases, including collageninduced arthritis in mice, 18 autoimmune encephalomyelitis in rats, and autoimmune myasthenia gravis in rabbits. In these studies, galectin-1 reduced the number of antigenreactive T cells, indicating that its protective effect was caused by a direct deletion of activated T cells. All together, these data suggest that galectin-1 might be potentially useful in the treatment of T-cell-mediated diseases.
The aims of this study were to investigate the effect of galectin-1 on liver injury induced by Con A administration in mice and to clarify the mechanisms involved.