roquinimex and Disease-Models--Animal

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

Topics: Animals; Disease Models, Animal; Graft Rejection; Graft Survival; Guanidines; Heart Transplantation; Hydroxyquinolines; Immunosuppressive Agents; Rats; Transplantation, Heterologous; Transplantation, Homologous

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

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

A series of linomide-related quinoline-3-carboxamides and their analogues was prepared and evaluated for antinephritic activities. The 6-MeS derivative 7a was highly effective in two nephritis models, namely chronic graft-versus-host disease and autoimmune MRL/l mice.

Topics: Amides; Animals; Antibodies, Antinuclear; Autoimmune Diseases; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Graft vs Host Disease; Mice; Mice, Inbred MRL lpr; Nephritis; Proteinuria; Quinolines; Structure-Activity Relationship

A series of quinoline-3-carbothioamides and their analogues was prepared via four synthetic routes and evaluated for their antinephritic and immunomodulating activities. The optimal compound 9g strongly inhibited the T-cell independent antibody production in mice immunized with TNP-LPS and was highly effective in two nephritis models, namely chronic graft-versus-host disease and autoimmune MRL/l mice.

Topics: Adjuvants, Immunologic; Administration, Oral; Animals; Antibody Formation; Autoimmune Diseases; Disease Models, Animal; Dogs; Graft vs Host Disease; Half-Life; Immunization; Mice; Nephritis; Proteinuria; Quinolines; Structure-Activity Relationship; Thioamides

A significant reduction of the pan T lymphocytes as well as CD4+ and CD8 subsets of cells in the gut mucosa of the septic rats has previously been demonstrated. In contrast, the populations of major histocompatibility complex (MHC) class II-positive cells and macrophages increased. The aim of this study was to evaluate if the immunomodulator Linomide influenced the immune cell distribution in the small intestinal mucosa in sepsis and, furthermore, if these changes coincide with changes in the concentration of tumor necrosis factor-alpha (TNF-alpha) in plasma or ascites. Polymicrobial sepsis was induced in rats by cecal ligation and puncture (CLP). Three different experimental groups were used: CLP, Linomide p.o. + CLP, and Linomide i.p.+ CLP, with adequate controls. Specimens were taken from the small bowel for immunohistologic staining and grading of mucosal injury. The following monoclonal antibodies were used: W3/25, OX8, R73, OX6, and ED1. All slides were examined by one "blinded" examiner. Mucosal injury was graded from 0 to 5. The immunostained tissues were also analyzed by an automatic color-based image system. All controls had a normal appearance of the mucosa (grade 0-1), whereas the septic animals had a median grade of III (II-IV) mucosal injury. Linomide i.p. + CLP decreased mucosal damage to median I (0-IV, P < 0.05). Linomide had no effects on the immune cell distribution in controls. In CLP rats, a significant reduction in both CD4+ and CD8+ T lymphocytes as well as an increased number of macrophages and MHC class II-positive cells was seen in the villi as compared with sham-operated controls (P < 0.05). Linomide attenuated these changes for CD8+ and T lymphocytes and macrophages. Sepsis caused increased concentrations of TNF-alpha in portal blood and ascites 3 h from CLP induction. This increase was attenuated by Linomide.

Topics: Adjuvants, Immunologic; Animals; Ascitic Fluid; Disease Models, Animal; Hydroxyquinolines; Immunohistochemistry; Intestinal Mucosa; Intestine, Small; Male; Rats; Rats, Wistar; Sepsis; Tumor Necrosis Factor-alpha

Five years after the identification of the von Hippel-Lindau (VHL) gene, physicians, scientists and concerned VHL family members met to review the current state of knowledge on the diagnosis and treatment of VHL and to summarize the latest information on the biochemistry of the VHL protein (pVHL). The NIH and University of Pennsylvania groups reported the detection of germ-line mutations in 100% (93 of 93) of VHL families studied. Several studies determined the frequency of VHL germ-line mutations in individuals with a single manifestation of VHL without a family history of VHL. National groups to improve the diagnosis and treatment of individuals with VHL disease have been established in Great Britain, Denmark, France, Holland, Italy, Japan, Poland, and the United States. Evidence for the existence of genes that modify the expression of VHL was presented. The VHL protein appears to have several distinct functions: (a) down-regulation of hypoxia-inducible mRNAs; (b) proper assembly of the extracellular fibronectin matrix; (c) regulation of exit from the cell cycle; and (d) regulation of expression of carbonic anhydrases 9 and 12.

Topics: Animals; Carcinoma, Renal Cell; Central Nervous System Neoplasms; Cystadenoma, Papillary; Disease Models, Animal; DNA Mutational Analysis; Exons; Genes, Lethal; Genetic Testing; Genotype; Hemangioblastoma; Hemangioma; Humans; Hydroxyquinolines; Kidney Neoplasms; Ligases; Mice; Mice, Knockout; Mice, Nude; Neoplasms; Neovascularization, Pathologic; Nephrectomy; Pancreatic Neoplasms; Paraganglioma; Phenotype; Polymerase Chain Reaction; Proteins; Radiosurgery; Retinal Neoplasms; Trophoblasts; Tumor Suppressor Proteins; Ubiquitin-Protein Ligases; von Hippel-Lindau Disease; Von Hippel-Lindau Tumor Suppressor Protein

The drug Linomide is an immunomodulator showing marked down-regulation of several experimental autoimmune diseases. In this study, its effect on three different experimental models of thyroid disease and on spontaneous infiltration of salivary glands (sialoadenitis), was investigated. Although very effective at preventing thyroid infiltrates in mice immunized with mouse thyroglobulin and complete Freund's adjuvant and in spontaneous models of thyroiditis and sialoadenitis, it completely failed to modify experimental autoimmune thyroiditis (EAT) induced in mice immunized with mouse thyroglobulin and lipopolysaccharide. There was no significant shift in the observed isotypes of anti-mouse thyroglobulin antibodies and only anti-mouse thyroglobulin antibodies in the spontaneous model were completely down-modulated by the drug. One surprising fact to emerge was that Linomide-treated donor mice, although protected from thyroid lesions themselves, were still able to transfer EAT showing that they must have been effectively primed while being treated with Linomide. It is possible that the drug down modulated EAT by interfering with the trafficking of primed effector cells.

Topics: Adjuvants, Immunologic; Animals; Autoimmune Diseases; Disease Models, Animal; Drug Administration Schedule; Female; Freund's Adjuvant; Hydroxyquinolines; Lipopolysaccharides; Lymph Nodes; Male; Mice; Mice, Inbred CBA; Mice, Inbred NOD; Sialadenitis; Thyroglobulin; Thyroiditis, Autoimmune

Both Linomide (quinoline-3-carboxamide) and tolerization with self-antigens have been demonstrated to successfully ameliorate demyelinating disease in experimental autoimmune encephalomyelitis (EAE). Based on the autoimmune hypothesis of multiple sclerosis (MS), both agents have been tested in clinical trials but have been found to be toxic or not efficacious. We investigated the efficacy of these immunomodulators in an alternative experimental model of MS, a virus-induced demyelinating disease. Oral administration of Linomide to Theiler's virus-infected mice beginning either at time of infection or at day 15 post-infection (p.i.) resulted in an increased percentage of spinal cord quadrants with demyelination. Administration of Linomide beginning at day 15 p.i. increased lesion size as compared to infected control-treated mice. Treatment with 80 mg kg(-1) day(-1) of Linomide beginning at the time of infection significantly increased the number of Theiler's murine encephalomyelitis virus (TMEV)-positive cells mm(-2) of spinal cord white matter. There were no differences in the amount of remyelination between mice treated with Linomide or water. However, chronically infected mice treated with Linomide had severely reduced spontaneous vertical activity as measured using a activity wheel. Oral tolerization of mice with mouse or bovine myelin had no effect on virus-induced demyelination or virus antigen expression. The contrasting results obtained between the TMEV model and the autoimmune model of demyelination do not support recent reports suggesting that the underlying mechanism of demyelination in the Theiler's model is autoimmune.

Topics: Adjuvants, Immunologic; Administration, Oral; Animals; Cattle; Disease Models, Animal; Female; Hydroxyquinolines; Immune Tolerance; Mice; Mice, Inbred Strains; Multiple Sclerosis; Myelin Sheath; Poliomyelitis; Theilovirus; Treatment Failure

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

Topics: Adjuvants, Immunologic; Animals; Autoimmune Diseases; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Hydroxyquinolines; Mice; Multiple Sclerosis; Rats