ammonium-trichloro(dioxoethylene-o-o--)tellurate and Lupus-Erythematosus--Systemic

Topics: Adjuvants, Immunologic; Androgens; Animals; Antibodies, Anti-Idiotypic; Antiphospholipid Syndrome; Aspirin; Bone Marrow Transplantation; Bromocriptine; Cyclosporine; Disease Models, Animal; Estrogens; Ethylenes; Heparin; Hydroxyquinolines; Immunoglobulins, Intravenous; Immunosuppression Therapy; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lymphocyte Transfusion; Mice; T-Lymphocytes, Regulatory

It has recently been found that in systemic lupus erythematosus (SLE), a multisystem inflammatory disorder characterized by autoantibody production and decreased cellular immune response, increased spontaneous production of IL-10 occurs. The immunomodulator AS101 (ammonium trichloro(dioxoethylene-0,0')tellurate) was previously shown to significantly decrease IL-10 levels in cancer patients and in murine models. This study shows that AS101 inhibits the development of SLE-related autoimmune pathological manifestations. AS101 decreased the spontaneous IL-10 production by mononuclear cells from SLE patients in vitro. In vivo, systemic injection of AS101 to SCID mice transplanted with mononuclear cells from SLE patients significantly decreased serum human IL-10 levels. There was also a decrease in all serum human Ig isotypes, in anti-dsDNA, and in anti-Sm Igs. In the New Zealand Black/New Zealand White/F1 model, AS101 significantly increased serum TNF-alpha and IFN-gamma while decreasing IL-10 levels; these changes were accompanied by a rapid decrease in anti-dsDNA and anti-ssDNA Igs. More importantly, continuous treatment of New Zealand Black/New Zealand White/F1 mice with AS101 for 6 mo led to the development of proteinuria in 30% of the treated mice compared with 100% in PBS-treated mice (p < 0.001). AS101 treatment reduced the level of immmune complex deposition in the glomeruli, prevented glomerular hypercellularity and mesangial expansion and led to a much smaller mean glomerular volume in treated mice (185 +/- 6 vs 428 +/- 47.103 microm3; p < 0.01). We suggest that treatment with a nontoxic immunomodulator such as AS101, previously used in phase II trials on cancer patients, may be an effective therapeutic approach for controlling SLE.

Topics: Adjuvants, Immunologic; Adult; Animals; Cells, Cultured; Ethylenes; Female; Humans; Interleukin-10; Leukocytes, Mononuclear; Lupus Erythematosus, Systemic; Male; Mice; Mice, SCID; Middle Aged; Tumor Necrosis Factor-alpha

The role of the synthetic immunomodulator AS101 on the production of interleukin-2 (IL-2) by spleen cells of mice with SLE was investigated. BALB/c female mice, in which SLE was induced by immunization with the pathogenic idiotype of anti-DNA antibody 16/6 Id were treated with AS101 for 7 weeks 2 and 4 months after induction of the disease. The ability of the splenocytes of the mice with SLE to produce IL-2 was restored after administration of AS101. This effect was particularly impressive when the 7-week AS101 treatment was initiated 4 months after immunization. Despite its beneficial effect on IL-2 production, AS101 exerted no influence on the titres of autoantibodies in the sera of the mice. It also had no effect on clinical parameters of SLE, such as the increased sedimentation rate, proteinuria and low white blood cell counts. Our data indicate that defective IL-2 production in SLE is probably secondary to other disease processes and is not necessarily associated with the production of autoantibodies in this disorder.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Antinuclear; Autoantibodies; Ethylenes; Female; Interleukin-2; Lupus Erythematosus, Systemic; Mice; Mice, Inbred BALB C; Receptors, Interleukin-2; Spleen; T-Lymphocytes; Tellurium

We studied the in vitro production of interleukin-2 (IL-2), the expression of IL-2 receptors, the absorption of IL-2, and spontaneously expanded suppressor cell function by mononuclear cells from 15 patients with systemic lupus erythematosus (SLE) and 15 healthy control subjects. These functions were studied in the presence or absence of AS-101, a recently described organotellurium compound with immunoregulatory properties. AS-101 was found to be non-toxic to cells from both patient and control groups; it increased the production of IL-2, elevated the percentage of Tac-positive cells even among cells that had been pre-treated with pronase, and ameliorated the absorption of IL-2. It also enhanced the suppressor cell function in cells from SLE patients. Since these functions are known to be defective in vitro in cells of SLE patients, and since preliminary testing of AS-101 in humans indicates that it is a safe drug, this immunoregulatory compound holds promise for a novel and effective treatment of SLE.

Topics: Adjuvants, Immunologic; Cells, Cultured; Ethylenes; Humans; Interleukin-2; Lupus Erythematosus, Systemic; Receptors, Interleukin-2; T-Lymphocytes; T-Lymphocytes, Regulatory; Tellurium