No abstract

Administration of dextran sulfate sodium (DSS) solutions to rats induced colitis which resembled mucosal lesions of human ulcerative colitis. Recent reports have shown that some cytokines are related to the pathogenesis of ulcerative colitis. In the present report, we describe the production of two cytokines in colitis mucosa in this DSS model. Using a cytotoxicity assay and a radioimmunoassay, we observed significant increases in levels of tumor necrosis factor-α (TNF-α) in the colitis mucosa and detected interleukin-1α in the mucosa of 3 of 5 DSS rats and an increase in TNF-α had a tendency to be inhibited by treatment with FK 506. Immunohistochemical investigation of DSS mucosa showed that the number of activated T cells increased at the earlier phase of inflammation. Luminol-dependent chemiluminescence values and myeloperoxidase activities were increased in the late phase of colitis and were suppressed by the FK 506 treatment. These findings may support the role of TNF-α and T-cell activation in the pathogenesis of DSS colitis.

SUMMARYWe investigated the therapeutic effect and immunological action mechanism of IgG in experimental colitis induced by 3% dextran sulfate sodium in rats. Intravenous injection of homologous (rat) IgG (400 mg/kg per day) caused a significant suppression of occult blood discharge and ulcerative lesions in the colon, while no suppressive effect was observed in the case of heterologous (human) IgG. The positive effect of rat IgG on the lesions was also clearly shown by the histological examinations. Generation of proinflammatory cytokines, i.e. tumour necrosis factor-alpha (TNF-a) and IL-1a, in the lesions was found to be inhibited by administration of rat IgG. Little or no suppressive action was exerted by human IgG. Careful examination of recruited T cells and macrophages, both of which are thought to play important roles in the development of ulcerative colitis, indicated that rat IgG, but not its human counterpart, decreased the number of immunocompetent cells in colonic mucosa. Meanwhile, in an in vitro study, both forms of IgG were shown to suppress production of TNF-a and IL-1a from lamina propria mononuclear cells isolated from rat colon. These findings suggest that, mainly by suppressing recruitment of immunocompetent cells into the lesions, homologous IgG may reduce the occurrence of colitis.

The authors have previously reported that homologous immunoglobulin (Ig)G reduces the occurrence of dextran sulfate sodium (DSS)‐induced colitis, mainly by suppressing recruitment of immunocompetent cells into colitis lesions. However, the mechanisms of cell recruitment and of its suppression by IgG remain unclear. In addressing these questions, this study focused on the activation of T cells in the presence of macrophages. The authors found that [3H]‐thymidine uptake of T cells from DSS‐induced colitis mice, but not from normal mice, was significantly enhanced when cultured with DSS‐pulsed macrophages. From the profile of cytokine production, it was suggested that T helper 1 (Th1)‐type cells become predominant during stimulation. Addition of homologous IgG significantly suppressed T cell proliferation in a dose‐dependent manner, while no suppressive effect was observed with heterologous IgG. Mouse IgG F(ab′)2, but not Fc, fragments partially mimicked the suppressive effect of whole IgG. These findings provide evidence that Th1‐type cells may play an important role in the development of DSS‐induced colitis and that homologous IgG exerts its protective action at least in part through the F(ab′)2 portion.

A method for the heat treatment of human IgG solution at 60 °C for 10 h was established. Human immunodeficiency, mumps, vaccinia and 4 other viruses were added to the IgG solution in 33% sorbitol and heated at 60 °C. Those viruses were inactivated within 1 h. Heat-treated intravenous IgG (IVIG-H) was prepared by heat treatment and polyethylene glycol (PEG) fractionation. Conventional nonheated intravenous IgG (IVIG-C) was prepared from the same source paste by the fractionation method. No physicochemical or biological difference was observed between the heated and control IVIG preparations.