Recombinant human alpha-interferon is now under intensive investigation as therapy for chronic Type B hepatitis. Recent reports have suggested that prolonged alpha-interferon therapy may induce autoimmune reactions. We have evaluated the problem of autoimmunity related to alpha-interferon therapy by testing for 15 different antibodies in the sera of 31 patients treated with alpha-interferon. No patient had autoantibodies before treatment; 27 (87%) of 31 patients developed at least one autoantibody. Eleven patients had antinuclear antibodies and 21 had smooth muscle antibodies, both of which usually developed during alpha-interferon therapy. In contrast, antibodies to endocrine organs such as thyroid microsomal, thyroglobulin and parietal cell antibodies arose in 12 patients, but usually several months after alpha-interferon treatment. The appearance of these autoantibodies did not correlate with disease activity or response to alpha-interferon. No patient developed autoantibodies specifically associated with autoimmune liver diseases such as liver kidney microsomal antibodies, autoantibodies to soluble liver antigen and the primary biliary cirrhosis specific subtypes of antimitochondrial antibodies. These results suggest that prolonged alpha-interferon therapy can induce autoantibody production and, in susceptible patients, may lead to autoimmune disorders.
The production of interferon (IFN) from cultured peripheral blood mononuclear cells (PBMC) after virus or mitogen stimulation was evaluated in 141 patients positive for antibodies to human immunodeficiency virus type 1 (HIV-1). IFN-alpha production by PBMC of patients at Centers for Disease Control (CDC) stage II (Walter Reed [WR] 1) was comparable to that produced by PBMC of healthy controls. However, cells of patients at early CDC stage III (WR 2) produced significantly lower titers of IFN-alpha (P less than .001), and IFN-alpha was almost absent at CDC stage IV (WR 6) (P less than .001). IFN-gamma production was altered in patients at late CDC stage III (WR 4-5) and CDC IV (WR 6). A strong correlation between the disappearance of antibodies to core proteins and low IFN-alpha level was observed. IFN-alpha levels were significantly diminished in patients positive for HIV antigen. Reduced IFN-alpha production paralleled the HIV-1-related depletion of CD4+ lymphocytes and might serve as an additional parameter in defining the stage of HIV-1 infection.
Sulphoevernan is a sulphated ~-1 --, 3, 1 -, 4 polyglucan (Mr 20000) with a helical structure. This compound effectively inhibits both human immunodeficiency virus type 1 (HIV-1) and type 2 infection of cells in vitro at concentrations around 0-5 ~tg/ml. Moreover, the compound completely inhibits HIV-l-induced syncytium formation at a concentration of 1 ~tg/ml. Competition experiments with 35S-labelled sulphoevernan revealed that the mannose-specific lectin from Narcissus pseudonarcissus prevented binding of sulphoevernan to HIV-1, whereas the antibody OKT4A did not reduce the amount of sulphoevernan bound to MT-2 cells. These data indicate that the non-cytotoxic polymer sulphoevernan binds to the virus rather than to the host cell. In vivo studies, using Rauscher leukaemia virus in NMRI mice, revealed that, at a daily dose of 20 mg/kg, the animals were protected against virus-induced increases in spleen weight. From these in vitro and in vivo data we conclude that sulphoevernan has potential in the treatment of acquired immunodeficiency syndrome.
The present study investigates the potential capacity of the immunostimulant Corynebacterium parvum (C.p.) to induce tumor necrosis factor-alpha (TNF-alpha) in human peripheral blood mononuclear cells (PBMC) and blood monocytes (BMo) in vitro. Both at the mRNA and protein level, stimulation of PBMC and BMo upon C.p. induces TNF-alpha. Compared to the hitherto used TNF-alpha inducers in vitro such as Sendai virus, phytohemagglutinin or lipopolysaccharide the C.p. stimulus displayed a threefold stronger induction of TNF-alpha production (p less than 0.001). Using C.p. as an inducer it was possible to demonstrate that TNF-alpha production is regulated by prostaglandin E2; preincubation of the cells with prostaglandin E2 resulted in a reduced C.p.-mediated TNF-alpha production (p less than 0.001). Coincubation of interferon-gamma (IFN-gamma) together with C.p. led to an enhanced release of TNF-alpha, supporting the assumption that C.p. is a potent TNF-alpha inducer. The additive effect of IFN-gamma and TNF-alpha on the receptor level was demonstrated by addition of IFN-gamma antibodies to the PBMC cultures. Under these conditions TNF-alpha production, stimulated by C.p. and IFN-gamma, was decreased by 30%, compared to the production in assays supplemented with C.p. alone. From these data we conclude that C.p. is a new inducer of TNF-alpha in vitro and a useful tool to study TNF-alpha production of PBMC and BMo from either healthy donors or from patients.
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