Hepatocyte growth factor prevents lupus nephritis in a murine lupus model of chronic graft-versus-host disease

Pathogenic T cells that recognize self-antigens and drive B cell hyperactivity play a central role in the pathogenesis of both human and murine lupus [1-3]. Chronic graft-versus-host disease (GVHD), which is induced in (C57BL/6 × DBA/2) F1 (BDF1) mice by injection of DBA/2 spleen cells, is associated with the activation of donor CD4+ T cells that recognize host major histocompatibility complex (MHC) antigens and drive host B cell hyperactivity [4,5]. Mice of this parent-into-F1 chronic GVHD model show increased T helper (Th) 2 immune responses, and exhibit autoimmune disorders that resemble human systemic lupus erythematosus, primary biliary chirrhosis, and Sjogren's syndrome, which are characterized by lymphocyte infiltration into organs such as the kidneys, liver and salivary glands [6].In contrast, the parent-into-F1 acute GVHD model, which is induced in BDF1 mice by the injection of C57BL/6 (B6) spleen cells, is associated with the activation of donor CD8+ cytotoxic T lymphocytes (CTLs) that recognize host MHC antigens and cause death by affecting host immune and hematopoietic systems [7-9]. As acute GVHD can be inhibited by the addition of neutralizing anti-IL-2 monoclonal antibodies (mAbs) and is not induced by perforin-deficient donor T cells [10,11], acute GVHD is associated with increased Th1-mediated immune responses and with perforin expression on donor T cells.One of the principal distinctions between the acute and chronic GVHD models appears to be the nine-fold reduction in CTL precursor numbers with anti-host specificity (which eliminate autoreactive host B cells) generated during GVHD induced by DBA/2 mouse spleen cells rather than by B6 mouse spleen cells [12]. Previous experiments have demonstrated that cytokines such as IL-12 and IL-18 induce donor anti-host CTLs in chronic GVHD mice and can ameliorate chronic GVHD, or even stimulate the development of acute GVHD [13,14].Recently, we demonstrated that repeated transfection of skeletal muscle with t