roquinimex and Lupus-Erythematosus--Systemic

NK cells are a subset of mononuclear cells which have long been suspected of playing an immunoregulatory role in the prevention of autoimmune diseases. Here, we briefly discuss the characteristics of NK cells--particularly what is known of their functional capabilities--and summarise the major findings from studies of NK cells in human and animals susceptible to three major autoimmune diseases: multiple sclerosis, systemic lupus erythematosus and type 1 (autoimmune) diabetes mellitus. In each case, we present the evidence for an association between disease and deficiencies in NK cells. The prospect of clinical interventions that stimulate NK cell activity are discussed and the current status described.

Topics: Animals; Autoimmune Diseases; Cell Differentiation; Cytokines; Diabetes Mellitus, Type 1; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Humans; Hydroxyquinolines; Interferons; Killer Cells, Natural; Lupus Erythematosus, Systemic; Mice; Multiple Sclerosis; Rats; Self Tolerance

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

Transferring parental splenocytes into unirradiated F1 mice induces a chronic graft-versus-host disease (GVHD), characterized by the production of Th2 cytokines and immunocomplex-mediated glomerulonephritis resembling systemic lupus erythematosus (SLE). The effects of H1521, a new derivative of 4-hydroxyquinoline-3-carboxamide, were investigated in chronic GVHD lupus model. H1521 was administered to chronic GVHD mice for 10 weeks. Nephritic symptoms were monitored and cytokine expression in the spleen was detected. To clarify the direct effect of H1521 on CD4(+) T cell, CD4(+) T cells were isolated and co-cultured with H1521 under neutral and Th1 or Th2 driving conditions in vitro. H1521 (32 mg/kg) reduced the incidence of proteinuria by 50% in chronic GVHD mice. Ameliorated lupus symptoms and improved renal histopathology damage were also observed. Administration of H1521 had little impact on Th1 cytokine IL-2 and IFN-gamma or Th2 cytokine IL-4 and IL-10 mRNA expression. In contrast, severely deficient IFN-gamma production by concanavalin A-stimulated spleen cells in chronic GVHD mice was completely restored by H1521. In accordance with this, decreased T-bet mRNA expression became normalized with H1521 (32 mg/kg) treatment. In addition, in vitro studies demonstrated that H1521 preferentially favored Th1 differentiation in CD4(+) T cell and promoted IFN-gamma secretion in Th1 differential CD4(+) T cell. However, IL-4 secretion in naive or Th2 differential CD4(+) T cell was unaffected by H1521. In conclusion, H1521 can induce Th1 cytokine profile in CD4(+) T cells and has possible therapeutic value in Th2-predominant immune diseases.

Topics: Adjuvants, Immunologic; Animals; Chronic Disease; Cytokines; Disease Models, Animal; Female; Graft vs Host Disease; Hydroxyquinolines; Lupus Erythematosus, Systemic; Mice; Mice, Inbred Strains; Th1 Cells; Th2 Cells

Nitric oxide is involved as a messenger molecule in a large number of physiologic and pathologic responses. Local generation of high nitric oxide output through the expression of the calcium-independent, cytokine-inducible form of nitric oxide synthase (iNOS) can result in either protective or damaging effects. The development of drugs that specifically suppress iNOS expression or inhibit its activity may therefore provide an excellent therapeutic tool for treatment of a diverse set of dysfunctions, including asthma, inflammatory processes, and autoimmune disease. We show compelling evidence that linomide, an immunomodulator known to ameliorate autoimmune diseases, prevents accumulation in the macrophages of mRNA encoding iNOS in mice injected with LPS. This effect is partially mediated by the blocking of TNF-alpha and IL-beta production by activated macrophages. Here, we also present evidence that kidneys from MRL/Mp-lpr/lpr mice express high iNOS levels when the mice develop glomerulonephritis. The administration of linomide to MRL/Mp-lpr/lpr mice significantly decreases iNOS mRNA levels and prevents the development of glomerulonephritis, extending the half-life of mice of this strain. This linomide effect is compatible with its role in preventing the development of autoimmune disease and extends its possible use to other pathologic manifestations associated with iNOS expression, such as the systemic lupus erythematosus-associated glomerulonephritis present in MRL/Mp-lpr/lpr mice.

Topics: Adjuvants, Immunologic; Animals; Enzyme Induction; Hydroxyquinolines; Kidney; Lipopolysaccharides; Lupus Erythematosus, Systemic; Macrophage Activation; Mice; Mice, Inbred MRL lpr; Nephritis; Nitric Oxide Synthase; Shock, Septic

The objective of this study was to assess the beneficial effects of an early administration of low dose linomide, a new immunomodulator, in an animal model of experimental systemic lupus erythematosus (SLE).. Experimental SLE was induced in naive BALB/c mice, by immunization with anti-DNA mAb (MIV-7). Control Mice immunized with irrelevant human IgM served as controls. The immunized mice were treated with linomide (0.1 mg/ml in the drinking water), four weeks prior to the first immunization, at an early stage of the disease induction (one month after boost injection), or at a later stage (3 months following boost immunization). The treatment duration was 3 months in all schedules. The follow-up studies continued for 8 weeks after discontinuation of the treatment. The presence in the serum of autoantibodies against ssDNA, dsDNA histones, phospholipids and an irrelevant autoantigen-pyruvate dehydrogenase, was determined by enzyme-linked immunosorbent assay (ELISA). The clinical parameters assessed included erythrocyte sedimentation rate, peripheral blood cell counts and proteinuria.. There was a 50-64% decrease in autoantibody levels in the sera of mice immunized with anti-DNA (MIV-7) mAb at the early stage of experimental SLE in mice which received linomide for a period of 3 months. No effect of linomide was noted in mice which received the drug during the later stages of experimental SLE when the disease was fully developed. Linomide had a preventive effect on the induction of experimental SLE in naive mice, when the treatment was initiated before the induction of the disease. This effect was abolished following cessation of the treatment.. Linomide proved to be effective at the early stages of induction of the experimental SLE. However, the autoantibody levels rose following discontinuation of the therapy.

Topics: Adjuvants, Immunologic; Animals; Antibodies, Antinuclear; Antibodies, Monoclonal; Autoimmune Diseases; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Hydroxyquinolines; Immunization, Passive; Lupus Erythematosus, Systemic; Mice; Mice, Inbred BALB C

Autoimmune (NZB X NZW) F1 female hybrid mice were treated with LS-2616, a recently developed substance with immunomodulating properties. Treatment was initiated at the age of 4 months (i.e. at the early stage of the disease) as well as at 7 months of age (i.e. after the development of established lupus-like disease). Control groups treated with cyclophosphamide and physiological saline were also studied. Beneficial therapeutic effects were obtained regardless of when the treatment was initiated and the dose of LS-2616 administered (1 and 8 mg/mouse/week). The effects of LS-2616 on longevity, splenomegaly and glomerulonephritis were pronounced and sometimes comparable to those of cyclophosphamide (1.8 mg/mouse/week). The results obtained suggest that LS-2616 may be useful in the treatment of autoimmune disease in man.

Topics: Animals; Autoimmune Diseases; Complement C3; Female; Hydroxyquinolines; Immunoglobulins; Lupus Erythematosus, Systemic; Lupus Nephritis; Mice