chiniofon and Diabetes-Mellitus--Type-1

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

Insulin-dependent diabetes mellitus (IDDM) is considered to be an autoimmune disorder characterized by destruction of the pancreatic beta-cells by auto-reacting lymphocytes. An attractive therapeutic approach to this disease would be to abrogate the autoimmune process at an early stage, thus preserving a critical mass of pancreatic beta-cells necessary for maintenance of normal glucose tolerance. Linomide (quinoline-3-carboxamide, Roquinimex, LS 2616), is a novel, orally absorbed, immunomodulatory drug that has been shown to be effective in various models of autoimmunity without causing non-specific immunosuppression. In this review, we describe the efficacy of Linomide for ameliorating the autoimmune process and diabetes in the non-obese diabetic (NOD) model of IDDM when administered at early stages of the disease. We also show that advanced disease in the NOD mouse can be treated effectively by combining Linomide with therapeutic modalities designed to increase pancreatic beta-cell mass. Subsequent clinical studies have shown that Linomide preserves beta-cell function in individuals with new-onset IDDM. Based on these data, Linomide or derivatives thereof might be useful for treatment of human IDDM.

Topics: Adjuvants, Immunologic; Animals; Autoimmune Diseases; Diabetes Mellitus, Type 1; Hydroxyquinolines; Mice; Mice, Inbred NOD

Topics: Adjuvants, Immunologic; Animals; Diabetes Mellitus, Type 1; Encephalomyelitis, Autoimmune, Experimental; Female; Humans; Hydroxyquinolines; Mice; Mice, Inbred NOD

The clinical use and mechanisms of action of technetium 99m pyrophosphate, gallium 67 citrate, and indium 111 oxine have been presented. The diagnosis of osteomyelitis in the lower extremity can often be made on the basis of clinical, laboratory, and conventional radiographic evaluations. In the case report of diabetic osteolysis, initial evaluations revealed osteomyelitis. The use of scanning involving leukocytes labeled with technetium and indium 111 oxine lessened the possibilities of an osseous infection. Studies show the sensitivity, specificity, and accuracy of scans using leukocytes labeled with indium 111 oxine to be superior to those of any other form of nucleotide imaging, but further clinical research is needed.

Topics: Adult; Diabetes Mellitus, Type 1; Diagnosis, Differential; Foot Diseases; Gallium Radioisotopes; Humans; Hydroxyquinolines; Indium Radioisotopes; Leukocytes; Male; Organometallic Compounds; Osteolysis; Osteomyelitis; Oxyquinoline; Radionuclide Imaging; Technetium

The quinoline-3-carboxamide, linomide, protects non-obese diabetic mice from diabetes. The effects of linomide on insulin needs and beta cell function were studied in recent juvenile Type I diabetes in a double-blind trial. Patients with recent onset diabetes were randomly assigned to treatment with a fixed dose of 2.5 mg linomide (42 patients) or placebo (21 patients) for 1 year, in addition to insulin and diet. Glycated haemoglobin was 10-15% lower at 9 months (p = 0.003) and 12 months (p < 0.05) in the linomide group. The insulin dose was 32-40% smaller in the linomide group at 3 (p < 0.03), 6 (p < 0.02), 9 (p < 0.001) and 12 months (p = 0.01). Insulin doses correlated negatively with C peptide values (p = 0.001-0.002). The trend for higher C peptide values in the linomide group did not reach significance. In a post hoc subgroup analysis performed in 40 patients (25 from the linomide group and 15 from the placebo group) who still had detectable residual beta cell function at entry, linomide was associated with 45-59% higher C peptide value at 6 months (p < 0.05), 9 months (p < 0.05) and 12 months (p < 0.05). The main adverse effects of linomide were mild transitory anaemia (45 vs 10% in the linomide and placebo groups), thrombocytopenia (24 vs 10%), and mild joint discomfort (45 vs 5%) with no clinical signs. In conclusion, low-dose linomide reduced the insulin needs in patients with juvenile Type I diabetes of recent onset and improved beta cell function in patients who still had detectable beta cell function at entry. These results support further clinical and experimental studies to define the effects of linomide in Type I diabetes provided the safety of linomide is reliably established.

Topics: Adjuvants, Immunologic; Adolescent; Adult; Antineoplastic Agents; C-Peptide; Child; Diabetes Mellitus, Type 1; Double-Blind Method; Female; Glycated Hemoglobin; Humans; Hydroxyquinolines; Hypoglycemic Agents; Insulin; Islets of Langerhans; Male

Islet β-cell dysfunction and aggressive macrophage activity are early features in the pathogenesis of type 1 diabetes (T1D). 12/15-Lipoxygenase (12/15-LOX) is induced in β-cells and macrophages during T1D and produces proinflammatory lipids and lipid peroxides that exacerbate β-cell dysfunction and macrophage activity. Inhibition of 12/15-LOX provides a potential therapeutic approach to prevent glycemic deterioration in T1D. Two inhibitors recently identified by our groups through screening efforts, ML127 and ML351, have been shown to selectively target 12/15-LOX with high potency. Only ML351 exhibited no apparent toxicity across a range of concentrations in mouse islets, and molecular modeling has suggested reduced promiscuity of ML351 compared with ML127. In mouse islets, incubation with ML351 improved glucose-stimulated insulin secretion in the presence of proinflammatory cytokines and triggered gene expression pathways responsive to oxidative stress and cell death. Consistent with a role for 12/15-LOX in promoting oxidative stress, its chemical inhibition reduced production of reactive oxygen species in both mouse and human islets in vitro. In a streptozotocin-induced model of T1D in mice, ML351 prevented the development of diabetes, with coincident enhancement of nuclear Nrf2 in islet cells, reduced β-cell oxidative stress, and preservation of β-cell mass. In the nonobese diabetic mouse model of T1D, administration of ML351 during the prediabetic phase prevented dysglycemia, reduced β-cell oxidative stress, and increased the proportion of anti-inflammatory macrophages in insulitis. The data provide the first evidence to date that small molecules that target 12/15-LOX can prevent progression of β-cell dysfunction and glycemic deterioration in models of T1D.

Topics: Animals; Arachidonate 12-Lipoxygenase; Arachidonate 15-Lipoxygenase; Blood Glucose; Cells, Cultured; Computer Simulation; Diabetes Mellitus, Type 1; Female; Humans; Hydroxyquinolines; Insulin-Secreting Cells; Isoxazoles; Lipoxygenase Inhibitors; Mice; Mice, Inbred NOD; Molecular Structure; Naphthalenes; Oxidative Stress; Protein Binding; Software; Thiophenes

Linomide prevents the development of autoimmune insulitis and insulin-deficient diabetes mellitus in female NOD mice. Linomide prevents development of autoimmune manifestations in other experimentally induced and spontaneous autoimmune diseases as well, but the mechanism of action is unknown. The present report summarizes our investigations on the effect of Linomide on different functional T cell subsets in NOD mice analyzed according to their cytokine profile. Supernatants from cultured splenocytes and peritoneal cells taken from Linomide-treated mice contained lower levels of TNFalpha, IL-1 beta, IFN gamma and IL-12 versus higher levels of IL-4, IL-6 and IL-10 in comparison with supernatants from cultures of untreated mice. Our results suggest that regulation of autoimmunity following oral Linomide administration in NOD mice induces a shift from Th(1) to Th(2) phenotype response, thereby preventing the development of diabetes by active cytokine-induced immunoregulation of T cell subsets, including downregulation of Th(1) and upregulation of Th(2).

Topics: Adjuvants, Immunologic; Animals; Autoimmunity; Concanavalin A; Cytokines; Diabetes Mellitus, Type 1; Female; Hydroxyquinolines; Inflammation; Mice; Mice, Inbred NOD; Spleen; Th1 Cells; Th2 Cells

Linomide is a potent immunomodulator and has been reported to prevent type 1 diabetes mellitus in non-obese diabetic (NOD) mice and to reduce the incidence of other autoimmune diseases in animal models. The mechanisms of action seem to involve antigen expression by down regulation of macrophage activity and to antagonise the activation of Th1 cells during the cellular immune response. With the purpose to investigate the effect of Linomide on the incidence of spontaneous autoimmune thyroiditis (AIT) in female NOD mice we administered Linomide in drinking water (100 mg/kg/day) to NOD mice from 5th to 19th week of age. The mice were sacrificed at the end of week 19. None of the mice developed diabetes during the study period. The incidence of thyroiditis was evaluated on paraffin HE-stained sections and graduated on a scale from 0 to 4. Thirty-two percent of 37 mice treated with Linomide developed thyroiditis compared to 45% of 22 controls (p=0.31, chi2 =1.00). Among the mice who developed thyroiditis no difference in the degree of thyroiditis was found. Therefore no beneficial effect of Linomide on the incidence of spontaneous AIT in NOD mice could be demonstrated.

Topics: Adjuvants, Immunologic; Administration, Oral; Animals; Cell Movement; Diabetes Mellitus, Type 1; Female; Hydroxyquinolines; Incidence; Lymphocytes; Mice; Mice, Inbred NOD; Thyroid Gland; Thyroiditis, Autoimmune

Oral linomide, (quinoline-3-carboxamide), has been shown to prevent autoimmune insulitis, islet destruction, and diabetes in NOD mice treated at an early stage of the disease, but confers only partial protection in animals with advanced disease. Reg protein, the gene product of a complementary DNA isolated from a regenerating rat islet library, has been previously shown to induce expansion of beta-cell mass in pancreatectomized rats. To determine the effect of treatment combining immunomodulation and Reg protein on advanced autoimmune diabetes, we treated female NOD mice with oral linomide and i.p. Reg protein injections. In 14-week-old animals with less severe disease (glucose tolerant), treatment with each agent alone resulted in amelioration of diabetes, as did treatment with Reg alone in 5-week-old prediabetic mice. In 14-week-old animals with more severe disease (glucose intolerant), only treatment with the combination of both agents, but not that with each separately, resulted in amelioration of diabetes. Our study suggests that treatment aimed at abrogation of autoimmunity combined with expansion of beta-cell mass constitutes a potential therapeutic approach for treatment of insulin-dependent diabetes mellitus.

Topics: Adjuvants, Immunologic; Animals; Autoimmune Diseases; Blood Glucose; Calcium-Binding Proteins; Diabetes Mellitus, Type 1; Female; Glucose Tolerance Test; Hydroxyquinolines; Immunotherapy; Insulin; Islets of Langerhans; Lithostathine; Mice; Mice, Inbred NOD; Nerve Tissue Proteins; Pancreas

Linomide (quinoline-3-carboxamide), a well tolerated, orally administered compound was recently shown to be effective in the prevention and treatment of several autoimmune diseases in experimental animal models. We have investigated its effect on specific humoral immune responses directed to T-cell-dependent soluble or particulate antigens and to a T cell-independent antigen in several mouse strains. Linomide administered after antigen priming did not affect primary and secondary antibody responses directed to T-cell particulate antigens (SRBC) or soluble antigens given with or without complete Freund's Adjuvant (CFA). Linomide treatment given prior to antigen priming did not affect the antibody response to a soluble antigen (TNP-KLH) given with an adjuvant. In contrast, dose-dependent down regulation of primary antibody responses was observed when T cell-dependent (BSA-dextran) or T-cell-independent (TNP-Ficoll) antigens were administered in an immunogenic form without adjuvant after starting Linomide treatment. The primary anti-SRBC antibody response was also suppressed by high dose Linomide given prior to immunization although normal secondary responses were retained. It is worth noting that no immunosuppressive effects on antibody responses were found at low dose ranges which effectively reversed T cell dependent autoimmune manifestation.

Topics: Animals; Antibody Formation; Antigen Presentation; Antigens, T-Independent; Autoantibodies; Autoantigens; Autoimmune Diseases; Dextrans; Diabetes Mellitus, Type 1; Drug Administration Schedule; Encephalomyelitis, Autoimmune, Experimental; Female; Ficoll; Freund's Adjuvant; Haptens; Hemocyanins; Hydroxyquinolines; Immunization; Immunologic Factors; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Mice, Inbred NOD; Myelin Basic Protein; Peptide Fragments; Serum Albumin, Bovine; Solubility; Trinitrobenzenes

Oral therapy with linomide protects prediabetic nonobese diabetic (NOD) mice from insulin-dependent diabetes mellitus. The mechanisms by which linomide exerts its protective effect are not fully understood. A decreased TCR-mediated activity of the GTP-GDP binding p21(ras) proto-oncogene is associated with prediabetes in NOD mice. However, the role of this signal transduction defect in the pathogenesis of autoimmune diabetes is not known. The TCR-mediated and protein kinase C-induced activations of p21(ras) were determined in mononuclear cells from lymph nodes of linomide-treated and untreated prediabetic NOD mice. TCR cross-linking by Con A induced an increase of 13 +/- 6.8% and a decrease of 0.8 +/- 1.8% in p21(ras) activity in the linomide-treated group and the untreated controls, respectively. Cell stimulation with PMA resulted in a 15 +/- 2% increase in p21(ras) activity in the linomide-treated mice and a 10 +/- 11.4% decrease in the untreated mice. Protein levels of p21(ras) and its regulatory elements, the GTPase-activating protein and the guanine nucleotide-releasing factor, mSOS, were comparable in both groups. We, therefore, conclude that prevention of autoimmune diabetes by linomide is associated with up-regulation of the p21(ras) T cell signal transduction defect in NOD mice.

Topics: Adjuvants, Immunologic; Animals; Diabetes Mellitus, Type 1; Female; Hydroxyquinolines; Male; Mice; Mice, Inbred NOD; Proto-Oncogene Proteins p21(ras); Receptors, Antigen, T-Cell; Up-Regulation

Topics: Adjuvants, Immunologic; Animals; Autoimmunity; Combined Modality Therapy; Diabetes Mellitus, Type 1; Female; Hydroxyquinolines; Islets of Langerhans Transplantation; Mice; Mice, Inbred NOD; Transplantation, Isogeneic

Oral administration of the synthetic immunomodulating drug quinoline-3-carboxamide (Linomide) in the drinking water to 5-week-old female non-obese diabetic (NOD) mice resulted in complete protection from insulitis and maintenance of normal glucose tolerance for over 40 weeks (impaired glucose tolerance: treated n = 2 of 18; control n = 17 of 18, p < 0.0001). Delayed administration of the drug at 16 weeks resulted in slowing of the progression to diabetes when assessed at 42 weeks (treated with diabetes n = 7 of 25; control with diabetes 25 of 43, p < 0.0234). No gross changes of immune system cell phenotype or function were observed in the Linomide-treated group. Adoptive transfer of spleen and lymph node cells from treated female NOD mice into sub-lethally irradiated male recipients failed to transfer diabetes, whereas a similar transfer of cells obtained from untreated age-matched controls resulted in diabetes in all secondary recipients (diabetes in control group n = 12 of 13; in Linomide group n = 0 of 11, p < 0.0001). Linomide pretreatment of the secondary recipients also inhibited the transfer of diabetes (diabetes in pretreated group n = 2 of 9, control group n = 12 of 13, p < 0.015), as did adoptive co-transfer of cell mixtures obtained from treated female NOD mice, free of diabetes, and from diabetic NOD female mice (diabetes in Linomide group n = 4 of 9; in control group 7 of 7, p < 0.0337).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adjuvants, Immunologic; Administration, Oral; Animals; Death; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Female; Hydroxyquinolines; Immunophenotyping; Immunotherapy, Adoptive; Islets of Langerhans; Lymph Nodes; Lymphocyte Activation; Lymphocyte Transfusion; Male; Mice; Mice, Inbred NOD; Spleen; Time Factors

Topics: Adolescent; Adult; Blood Platelets; Diabetes Mellitus, Type 1; Diabetic Nephropathies; Female; Graft Rejection; Humans; Hydroxyquinolines; Indium; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Organometallic Compounds; Oxyquinoline; Pancreas; Pancreas Transplantation; Radioisotopes; Radionuclide Imaging