CONCANAVALIN A-INDUCED T-CELL-MEDIATED HEPATIC-INJURY IN MICE - THE ROLE OF TUMOR-NECROSIS-FACTOR

Concanavalin A activates T lymphocytes in vitro and causes T-cell-depe ndent hepatic injury in mice. T lymphocytes were previously identified as effector cells of concanavalin A-induced liver injury. Here we rep ort that hepatic injury is characterized by apoptotic cell death. On c oncanavalin A challenge, the cytokines tumor necrosis factor-alpha (TN F alpha), interleukin-2, granulocyte macrophage-colony stimulating fac tor, and interferon-gamma were detectable in the circulation of the mi ce. Pretreatment of mice with anti-mouse TNF-alpha antiserum protected them from concanavalin A-induced liver injury. Nude mice failed to re lease TNF-alpha or interleukin-2 after concanavalin A challenge and we re protected from liver injury. Lymph node cell transfer from responde r mice to resistant nude mice resulted in susceptibility of the latter towards concanavalin A, i.e., to induction of cytokine release and he patotoxicity. These experiments suggest that immunocompetent T cells p lay a pivotal role in concanavalin A-stimulated TNF-alpha release in v ivo. After intravenous administration of fluorescein isothiocyanate la beled concanavalin A to mice, the most fluorescence was found within t he liver. In vitro, concanavalin A stimulation of separate cultures of mouse lymph node cells or nonparenchymal liver cells induced the rele ase of minute amounts of TNF, whereas stimulation of cocultures of the se cells resulted in production of substantial amounts of TNF-alpha. T hese findings may explain the hepatotropic effect of concanavalin A. I n conclusion, T-cell-dependent concanavalin A-induced apoptotic liver injury in mice is related to immunological and cytokine-mediated disor ders and possibly to autoreactive hepatic processes.