chiniofon and Autoimmune-Diseases

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

Linomide (roquinimex, LS 2616) is a quinoline-3-carboxamide with pleiotropic immune modulating capacity and it has therapeutic effects in several experimental animal models of autoimmune diseases. Linomide has been evaluated in clinical trials for multiple sclerosis, and was indeed shown to have disease inhibitory effects. However, due to unexpected side effects recorded in patients treated with Linomide, premature termination of clinical trials was required. The basic mechanism(s) of action of Linomide in inducing beneficial effects in autoimmune diseases is still elusive. Some experimental evidence indicates that Linomide influences the regulation of the cytokine profile, resulting in the inhibition of autoimmune and inflammation pathologies. This review focuses on Linomide applied in models for autoimmune and inflammation pathologies of the central and the peripheral nervous system, and summarises its very encouraging disease inhibitory effects and their potential pharmacological basis. The beneficial effects recorded with Linomide in both experimental and clinical trials emphasise the possible value of substances with Linomide-like activity for clinical use in autoimmune and inflammation pathologies in the near future.

Topics: Adjuvants, Immunologic; Animals; Autoimmune Diseases; Central Nervous System; Cytokines; Humans; Hydroxyquinolines; Immunity, Cellular; Peripheral Nervous System

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

Roquinimex-related 3-quinolinecarboxamide derivatives were prepared and evaluated for treatment of autoimmune disorders. The compounds were tested in mice for their inhibitory effects on disease development in the acute experimental autoimmune encephalomyelitis model and selected compounds in the beagle dog for induction of proinflammatory reaction. Structure-activity relationships are discussed. Compound 8c, laquinimod, showed improved potency and superior toxicological profile compared to the lead compound roquinimex (1b, Linomide) and was selected for clinical studies (currently in phase II).

Topics: Adjuvants, Immunologic; Animals; Autoimmune Diseases; Dogs; Encephalomyelitis, Autoimmune, Experimental; Female; Hydroxyquinolines; Mice; Mice, Inbred C57BL; Quinolones; Structure-Activity Relationship

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

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 (LS-2616, quinoline-3-carboxamide) has been reported to exert a diverse range of effects on the immune system. On one hand, this drug was found to stimulate the immune system and to enhance activities such as DTH or allograft rejection. On the other hand, linomide was shown to inhibit the induction of experimental autoimmune encephalomyelitis and myasthenia gravis, as well as the development of diabetes in non-obese diabetic (NOD) mice. Here we report the effects of linomide in animals immunized with uveitogenic retinal antigens. Treatment with linomide completely inhibited the development of experimental autoimmune uveoretinitis (EAU) in mice immunized with interphotoreceptor retinoid-binding protein and markedly suppressed EAU in rats immunized with S-antigen (S-Ag). In addition, linomide-treated rats exhibited reduced antibody production and lymphocyte proliferative response to S-Ag. In contrast to these suppressive activities, linomide treatment did not affect the development of adoptively transferred EAU in rats and moderately enhanced the DTH reactions to S-Ag in immunized rats in which EAU and other immune responses to this antigen were suppressed.

Topics: Adjuvants, Immunologic; Animals; Arrestin; Autoimmune Diseases; Female; Hydroxyquinolines; Hypersensitivity, Delayed; Immunization; Lymphocyte Activation; Male; Mice; Rats; Rats, Inbred Lew; Retinitis; Uveitis

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

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; Autoimmune Diseases; Bone Marrow Transplantation; Graft vs Host Disease; Humans; Hydroxyquinolines; Immunosuppression Therapy; Immunotherapy; Lymphocyte Depletion; T-Lymphocytes; Transplantation, Homologous

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

Linomide (LS-2616, quinoline-3-carboxamide) is a synthetic immunomodulator that stimulates natural killer cell activity and activates several lymphocytic subpopulations in experimental animals and humans. In this study we determined the effect of oral treatment with linomide on the development of experimental autoimmune encephalomyelitis, an animal model for immune-mediated human demyelinating disorders. Experimental autoimmune encephalomyelitis was induced in SJL/J mice and in an outbred strain of rats (Sabra) by subcutaneous injection of spinal cord homogenate in adjuvant followed by inoculation with Bordetella pertussis. Linomide was administered in drinking water, at an estimated dose of 50 to 100 mg/kg/day. None of the linomide-treated mice (0/41) and Sabra rats (0/15) developed any clinical or pathological signs of experimental autoimmune encephalomyelitis, whereas almost all control animals (48/53 and 18/19, respectively) were severely paralyzed and 64.5% died from the disease. Lymphocytes obtained from linomide-treated animals had reduced in vitro proliferative responses to guinea pig myelin basic protein, proteolipid protein of the myelin, and tuberculin-purified protein derivative, unlike antigen-independent proliferation which was rather unaffected. Natural killer cell activity (tested by a cytotoxic assay on radiolabeled YAC-1 target cells) was significantly enhanced in mice treated with linomide. Our results indicate that modulation of the immune system with linomide leads to complete inhibition of experimental autoimmune encephalomyelitis in the absence of systemic immunosuppression. Linomide could therefore be of use in future clinical trials for the treatment of human autoimmune demyelinating disorders.

Topics: Adjuvants, Immunologic; Animals; Autoimmune Diseases; Dose-Response Relationship, Drug; Encephalomyelitis, Autoimmune, Experimental; Female; Hydroxyquinolines; Killer Cells, Natural; Lymph Nodes; Lymphocytes; Mice; Rats; Spleen

MRL lpr/lpr mice develop a generalized autoimmune disease associated with a massive accumulation in the peripheral lymphoid organs of abnormal, phenotypically immature T cells. Both the lymphoadenopathy and the autoimmunity are thymus-dependent and likely to arise from an aberrant pathway of intrathymic differentiation. We here present the marked beneficial effects acquired in MRL lpr/lpr mice after in vivo administration of a novel immunomodulator called linomide. The highly altered pattern of thymic subpopulations in MRL lpr/lpr mice is normalized after linomide-treatment. Concomitantly, the peripheral T cell compartment, which in MRL lpr/lpr is highly deficient in producing and responding to IL-2, gains substantial functional reactivities. We propose that linomide acts by correcting the abnormal T cell development in autoimmune MRL lpr/lpr mice. This new immunomodulator may be a useful tool for providing insight into both the pathogenesis of autoimmune disorders and intrathymic differentiation.

Topics: Adjuvants, Immunologic; Animals; Autoimmune Diseases; Cell Count; Cell Differentiation; Hydroxyquinolines; Lymphocyte Activation; Mice; Mice, Mutant Strains; Phenotype; T-Lymphocyte Subsets; T-Lymphocytes

An autoimmune disease in MRL lpr/lpr (MRL/l) mice is associated with a plethora of T-cell abnormalities, one of them being impaired delayed-type hypersensitivity (DTH). Three immunomodulating drugs, cyclophosphamide (Cy), cyclosporin A (CsA) and LS 2616, all with beneficial effects on autoimmune diseases, have been examined with regard to their potential effects on DTH in female MRL/l mice and in healthy control mice. All three drugs, given as a single dose at the time of sensitization, increased DTH reactivity of oxazolone in healthy control mice, while only two of them, Cy and LS 2616, significantly augmented the defective DTH response in MRL/l mice.

Topics: Adjuvants, Immunologic; Animals; Autoimmune Diseases; Cyclophosphamide; Cyclosporins; Dermatitis, Contact; Female; Hydroxyquinolines; Mice; T-Lymphocytes

The autoimmune MRL/Mp-lpr/lpr (MRL/l) mouse spontaneously develops sialadenitis with a morphological and phenotypical pattern similar to that seen in human Sjögren's syndrome (SS). This makes the MRL/l mouse a suitable model for therapeutical studies of autoimmune sialadenitis. We have, by histological and immunohistochemical techniques, analyzed the therapeutical effect of treatment with LS2616, a recently synthesized oxokinolinamide derivative, on sialadenitis in submandibular glands of MRL/l mice. The results were compared with effects obtained after treatment with cyclophosphamide (CY) and physiologic saline. Administration of both LS2616 and CY to MRL/l mice has previously been found to result in prolongation of survival and amelioration of organ pathology. However, only CY treatment reduced sialadenitis, while LS2616 increased the semiquantitatively assessed focal inflammation of salivary glands in 6 months old mice. No differences in T-cell phenotypes of infiltrating lymphoid cells in salivary glands between different treatment regims could be noted. However, the frequency of B-cells in the sialadenitis was decreased in the CY treated group. In contrast, CY but not LS2616 treatment normalized expression of T-helper and cytotoxic T-cell phenotypes as well as reduced the B-cell portion in lymph nodes. It is concluded that CY treatment can suppress sialadenitis although both LS2616 and CY are effective in prolongation lifespan of MRL/l mice. This may implicate different immunopathogenic mechanisms for development of sialadenitis versus other organ lesions in the autoimmune disease of MRL/l mice.

Topics: Adjuvants, Immunologic; Animals; Autoimmune Diseases; Cyclophosphamide; Hydroxyquinolines; Male; Mice; Salivary Gland Diseases; Sialadenitis; Submandibular Gland Diseases

Autoimmune MRL/1 mice were treated with a recently developed substance with immunomodulating properties, LS-2616. Treatment was initiated at the age of 8 weeks, before the onset of clinically apparent disease, and at 16 weeks of age, after development of established lupus disease. Beneficial therapeutic effects were obtained, even when LS-2616 was administered at the lowest dose tested (1 mg/mouse/week) to 16-week-old mice. The effects of LS-2616 on longevity, as well as on development of lymphadenopathy, splenomegaly, glomerulonephritis, and vasculitis, were pronounced and were comparable with those of cyclophosphamide. The results obtained suggest a potential role for LS-2616 in the treatment of autoimmune disease in humans.

Topics: Adjuvants, Immunologic; Animals; Autoimmune Diseases; Cyclophosphamide; Drug Evaluation, Preclinical; Female; Glomerulonephritis; Hydroxyquinolines; Immunity; Lymphatic Diseases; Mice; Mice, Inbred Strains; Splenomegaly; Vasculitis

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