ABSTRACT
The debate on whether infection precipitates or prevents autoimmunity remains a contentious one. Recently the suggestion that some unknown microbe can be at the origin of some chronic inflammatory diseases has been countered by accumulating evidence that decreasing infection rates might have an important role to play in the rising prevalence of autoimmune disorders. The 'Hygiene Hypothesis' was initially postulated to explain the inverse correlation between the incidence of infections and the rise of allergic diseases, particularly in the developed world. Latterly, the Hygiene Hypothesis has been extended to also incorporate autoimmune diseases in general. Amongst the various infectious agents, a particular emphasis has been put on the interaction between parasitic worms and humans. Worm parasites have co-evolved with the mammalian immune system for many millions of years and during this time, they have developed extremely effective strategies to modulate and evade host defences and so maintain their evolutionary fitness. It is therefore reasonable to conclude that the human immune system has been shaped by its relationship with parasitic worms and this may be a necessary requirement for maintaining our immunological health. Fully understanding this relationship may lead to novel and effective treatments for a host of deleterious inflammatory reactions.
Subject(s)
Helminthiasis/immunology , Helminths/immunology , Inflammation/immunology , Animals , Autoimmune Diseases/epidemiology , Autoimmune Diseases/immunology , Autoimmune Diseases/therapy , Biological Evolution , Diabetes Mellitus, Type 1/immunology , Helminthiasis/epidemiology , Helminthiasis/parasitology , Host-Parasite Interactions/immunology , Humans , Hygiene , Inflammation/epidemiology , Inflammation/therapyABSTRACT
Concanavalin A (ConA)-induced hepatitis is a cell-mediated immunoinflammatory condition similar to human autoimmune hepatitis. We investigated the role of interleukin 12 (IL-12) in hepatitis induced in NMRI and C57/BL6 mice by a single injection of ConA. Recombinant murine IL-12 administered 24 hours and 1 hour prior to ConA exacerbated both transaminase activities in plasma and histologic signs of hepatitis. These markers of liver injury were significantly reduced by prophylactic, but not therapeutic treatment with anti-IL-12 monoclonal antibody (mAb). The disease-modulatory effects of IL-12 and anti-IL-12 mAb were associated with profound and reverse modifications of a ConA-induced increase in the circulating levels of IL-4, IL-6, interferon gamma (IFN-gamma) and tumor necrosis factor (TNF). Relative to control animals receiving ConA alone, the plasma levels of these cytokines were all augmented in IL-12/ConA-treated mice and diminished in anti-IL-12 mAb/ConA-treated mice. Anti-IFN-gamma mAb also impeded the appearance of IL-12/ConA-induced hepatitis. Thus, IL-12-induced production of IFN-gamma might play a role in mediating the hepatitis-inducing effect of ConA. However, IL-12p40-deficient C57/BL6 mice were as susceptible as wild-type controls to the hepatitis-inducing effect of ConA.
Subject(s)
Concanavalin A/toxicity , Hepatitis, Autoimmune/etiology , Interferon-gamma/physiology , Interleukin-12/physiology , Animals , Antibodies, Monoclonal/therapeutic use , Hepatitis, Autoimmune/prevention & control , Mice , Mice, Inbred C57BLABSTRACT
We have studied the impact of short-term treatment with interferon (IFN)-beta1b of relapsing remitting (RR) multiple sclerosis (MS) patients' blood levels of type 1 and type 2 cytokines such as IFN-gamma, interleukin (IL)-1beta, IL-2, IL-4, IL-6, IL-10 and tumour necrosis factor (TNF)-alpha. These cytokines were measured by solid-phase ELISA. Serum samples were obtained prior to, and 2 and 12 hours after beginning of the treatment and 48 h after the last of 5 s.c. injections with 8 million IU IFN-beta1b given on alternate days for 10 days. The treatment was found to increase the circulating levels of IL-2, IL-6, IL-10 and IFN-gamma at some of the time points considered, with the effect acquiring statistical significance for IL-6, IL-10 and IFN-gamma. The blood levels of IL-1beta, IL-4 and TNF-alpha remained below the limit of sensitivity of the assays at any of the time points considered. If this in vivo study mirrors the impact of IFN-beta1b on MS patients' immune cells, these data demonstrate an activation of the immune system upon early treatment with the drug that does not lead to either type 1 or type 2 cytokine prevalence.
Subject(s)
Cytokines/blood , Interferon-beta/therapeutic use , Interferon-gamma/blood , Interleukin-10/blood , Interleukin-6/blood , Multiple Sclerosis/drug therapy , Multiple Sclerosis/immunology , Adjuvants, Immunologic/administration & dosage , Adjuvants, Immunologic/therapeutic use , Adult , Female , Humans , Injections, Subcutaneous , Interferon beta-1a , Interferon beta-1b , Interferon-beta/administration & dosage , Interleukin-1/blood , Interleukin-2/blood , Interleukin-4/blood , Male , Multiple Sclerosis/blood , Reference Values , Time Factors , Tumor Necrosis Factor-alpha/analysisABSTRACT
We have studied the effects of either exogenously-administered interferon (IFN-)gamma or of a nonimmunogenic mouse IFN-gamma receptor-Immunoglobulin (IFN-gamma R-Ig) fusion protein on the development of Concanavalin (Con)A-induced hepatitis in NMRI mice. PBS-treated control mice injected with 20 mg/kg ConA developed classical serological and histological signs of hepatitis with elevation of transaminases in the blood and infiltration of the liver by mononuclear cells and neutrophils. Treating the mice with rat IFN-gamma 24 h prior to and 1 h after ConA-challenge markedly exacerbated these signs of hepatitis in a dose-dependent fashion. Moreover, mice injected with lower, non hepatitogenic, doses of ConA (10, 5 mg/kg) became fully susceptible to develop hepatitis upon similar treatment with IFN-gamma. Concordantly, ConA-induced hepatitis was abrogated by either IFN-gamma R-Ig fusion protein or anti-IFN-gamma mAb. These data provide further evidence for the central pathogenetic role of endogenous IFN-gamma in ConA-induced hepatitis and demonstrate the feasibility to prevent disease development by means of a non immunogenic IFN-gamma R-Ig fusion protein.
Subject(s)
Chemical and Drug Induced Liver Injury/immunology , Interferon-gamma/immunology , Liver/immunology , Receptors, Interferon/immunology , T-Lymphocytes/immunology , Animals , Antibodies, Monoclonal/immunology , CHO Cells , Chemical and Drug Induced Liver Injury/blood , Chemical and Drug Induced Liver Injury/pathology , Concanavalin A/administration & dosage , Cricetinae , Cytokines/blood , Cytokines/immunology , Immunoglobulins/genetics , Immunoglobulins/immunology , Interferon-gamma/pharmacology , Interleukin-4/immunology , Liver/injuries , Liver/pathology , Male , Mice , Rats , Receptors, Interferon/genetics , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/immunology , Interferon gamma ReceptorABSTRACT
Systemic lupus erythematosus (SLE)-prone female MRL-lpr / lpr (MRL-lpr) mice were treated with mouse or rat IFN-gamma under different experimental conditions, both prophylactically in 6- to 8 week-old animals and therapeutically in 12- to 18-week-old SLE-affected mice. It was found that IFN-gamma heterogeneously modulated the course of the disease in MRL-lpr mice. When administered prophylactically, IFN-gamma favorably modulated the histological, serological and clinical signs of the disease. Relative to untreated or PBS-treated control animals, the MRL-lpr mice which received IFN gamma were virtually free of inflammatory infiltration of the kidneys and the lungs, had lower levels of azotemia with reduction of both circulating IgG1, IgG2a and IgG3 and anti-double strand (ds) and single strand (ss) DNA antibodies, milder skin vasculitis, significantly reduced enlargement of their lymph nodes and lower weight of the spleens. IFN-gamma also lowered the rate of mortality of MRL-lpr mice. In contrast to these findings, therapeutically administered IFN-gamma worsened the course of the disease in MRL-lpr mice, which exhibited increased proteinuria, higher levels of IgG2a and IgG3 and anti-ds and -ss DNA antibodies, more aggressive nephritis and died at an earlier age than PBS-treated control mice. The dichotomic effect of IFN-gamma on disease manifestation in MRL-lpr mice offers new insights into the complex role of this cytokine in the regulation of systemic autoimmunity such as SLE.
Subject(s)
Autoimmunity , Interferon-gamma/immunology , Lupus Erythematosus, Systemic/immunology , Animals , Autoantibodies/immunology , Female , Interferon-gamma/pharmacology , Lupus Erythematosus, Systemic/etiology , Mice , Mice, Inbred MRL lpr , RatsABSTRACT
We evaluated the effects of recombinant human (rh) interleukin (IL)-11 on the development of spontaneous and cyclophosphamide-induced diabetes in female NOD mice. Prolonged treatment with rhIL-11 10 microg i.p. five consecutive times a week between the 4th and 22nd weeks of age significantly suppressed both development and cumulative incidence of type 1 diabetes. Disease protection was transient because most of the animals developed type 1 diabetes within 3 months of treatment withdrawal. In contrast, rhIL-11 failed to prevent type 1 diabetes when administered for the first time to euglycemic 18-week-old NOD mice. Most likely, this discrepancy was not due to age-dependent differences in the immunological responses of NOD mice to rhIL-11 because staphylococcus aureus enterotoxin B-induced tumor necrosis factor (TNF) and IL-12 production were equally suppressed by rhIL-11 in 12- and 25-week-old NOD mice. Relative to controls, NOD mice pretreated with rhIL-11 also showed significantly diminished blood levels of TNF, interferon-gamma, and IL-12 induced by anti-CD3 antibody and/or lipopolysaccharide. The results demonstrate that rhIL-11 has powerful anti-inflammatory effects that are capable of down-regulating early immunodiabetogenic pathways in NOD mice.
Subject(s)
Diabetes Mellitus, Type 1/prevention & control , Interleukin-11/therapeutic use , Aging , Animals , Blood Glucose/metabolism , Cyclophosphamide , Diabetes Mellitus, Type 1/chemically induced , Diabetes Mellitus, Type 1/genetics , Enterotoxins/toxicity , Female , Humans , Interleukin-12/biosynthesis , Interleukin-12/blood , Male , Mice , Mice, Inbred NOD , Recombinant Proteins/therapeutic use , Time Factors , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
A rat monoclonal antibody (mAb) that neutralizes mouse interleukin-12 (IL-12) was administered to female non-obese diabetic (NOD) mice of different ages to dismantle the role of endogenous IL-12 in murine autoimmune diabetogenesis. This mAb was effective in preventing clinical, but not histological signs of spontaneous diabetes when treatment was started early in life at the age of 4 weeks and consecutively continued for 10 weeks. Delaying commencement of anti-IL-12 mAb prophylaxis until the age of 18 weeks, when NOD mice suffer from advanced insulitis, was ineffective. Anti-IL-12 mAb did not influence the course of the accelerated model of diabetes induced by cyclophosphamide. These data prove that the pathogenetic role of endogenous IL-12 in NOD mouse diabetes is restricted to the very early diabetogenic events presumably occurring prior to insulitis development.
Subject(s)
Autoimmune Diseases/immunology , Diabetes Mellitus, Experimental/immunology , Interleukin-12/immunology , Animals , Antibodies, Monoclonal/therapeutic use , Diabetes Mellitus, Experimental/prevention & control , Female , Mice , Mice, Inbred NOD , RatsABSTRACT
Interferon (IFN)-gamma and interleukin (IL)-4 are prototypic type 1 and type 2 cytokines which are known to play pathogenetic and protective roles, respectively, in NOD mouse IDDM. The capacity of male NOD mice to produce more IL-4 and less IFN-gamma within the insulitic lesions than females has been suggested to contribute to their lower incidence of diabetes. In this study we have tested the effects of prolonged prophylactic treatment of male NOD mice with rat IFN-gamma, mouse IFN-gamma, anti-IL-4 monoclonal antibody (mAb) and recombinant murine soluble IL-4 receptor (smIL-4R) on the diabetogenic events leading to insulitis and diabetes. None of these treatments influenced spontaneous and/or cyclophosphamide-induced autoimmune diabetogenesis in male NOD mice. Control mice exhibited comparable histological signs of insulitis and incidence of diabetes to those treated with either mouse/rat IFN-gamma or specific IL-4 inhibitors. On the contrary, both clinical and histological signs of diabetes were suppressed by prophylactic treatment with anti-IFN-gamma mAb. These findings indicate that the autoimmune diathesis of male NOD mice towards IDDM cannot be augmented by manipulation of endogenous IFN-gamma or IL-4.
Subject(s)
Autoimmune Diseases/etiology , Diabetes Mellitus, Type 1/etiology , Interferon-gamma/toxicity , Interleukin-4/antagonists & inhibitors , Animals , Antibodies, Monoclonal/pharmacology , Autoantibodies/blood , Autoantibodies/immunology , Autoantigens/immunology , Autoimmune Diseases/chemically induced , Autoimmune Diseases/prevention & control , CHO Cells , Cricetinae , Cyclophosphamide/toxicity , Diabetes Mellitus, Type 1/chemically induced , Diabetes Mellitus, Type 1/prevention & control , Female , Genetic Predisposition to Disease , Immunoglobulin E/blood , Immunoglobulin E/immunology , Immunoglobulin G/blood , Immunoglobulin G/immunology , Interferon-gamma/antagonists & inhibitors , Interleukin-4/blood , Male , Mice , Mice, Inbred NOD , Rats , Receptors, Interleukin-4/physiology , Recombinant Proteins/pharmacology , Th2 Cells/immunologyABSTRACT
Interleukin (IL)-13 is a cytokine primarily produced by the T-helper (Th)-2 subset of lymphocytes that possesses powerful anti-inflammatory properties. Here, we have evaluated the impact of IL-13 treatment on development of type 1 diabetes in diabetes-prone nonobese diabetic (NOD) mice. Prolonged treatment with recombinant human IL-13 (hIL-13) markedly diminished the incidence of spontaneous type 1 diabetes in the mice. Female NOD mice treated from age 5-16 weeks with hIL-13 also showed significantly milder insulitis than control mice. The preventive action of hIL-13 was associated with a slight but significant change from a type 1 to a type 2 cytokine response. Accordingly, splenic lymphoid cells (SLC) from hIL-13-treated mice secreted less interferon (IFN)-gamma upon ex vivo stimulation with Concanavalin A than controls, and anti-CD3 monoclonal antibody-induced activation of T-cells in vivo resulted in lower blood levels of IFN-gamma and tumor necrosis factor-alpha and augmented blood levels of IL-4 in NOD mice pretreated with hIL-13. hIL-13 treatment also increased the blood levels of IgE and inhibited the transfer of type 1 diabetes by spleen cells from a diabetic donor to irradiated recipients. Taken together, these data add hIL-13 to the list of cytokines capable of downregulating immunoinflammatory diabetogenic pathways in NOD mice, and further support the concept that IL-4-related anti-inflammatory cytokines might have a role in the prevention of type 1 diabetes.
Subject(s)
Autoimmune Diseases/prevention & control , Diabetes Mellitus, Type 1/prevention & control , Interleukin-13/pharmacology , Mice, Inbred NOD/physiology , Animals , Cell Transplantation , Disease Progression , Female , Humans , Immunoglobulin E/blood , Inflammation/prevention & control , Interferon-gamma/antagonists & inhibitors , Interferon-gamma/blood , Interleukin-4/blood , Islets of Langerhans/drug effects , Islets of Langerhans/immunology , Mice , Spleen/cytology , Spleen/immunology , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
Experimental autoimmune thyroid disease (EAT) can be induced experimentally in mice following immunization with mouse thyroglobulin (mTg) and the adjuvants lipopolysaccharide (LPS) or complete Freund's adjuvant (CFA). EAT can also be transferred to naive recipients by CD4+ T cells from mTg-primed mice. Here we demonstrate a role for IL-12 in the development of EAT by the ability of neutralizing antibody to IL-12 to reduce disease severity and by the lack of significant levels of thyroid infiltration in IL-12p40-deficient mice following immunization with mTg and CFA. A single injection of 300 ng IL-12 at the time of initial immunization with mTg and LPS was able to increase the degree of thyroid infiltration. These data are all consistent with EAT being a Th1-mediated disease. Conversely, however, administration of IL-12 over a prolonged period markedly inhibited the induction of EAT by mTg and CFA and, if given to recipients, inhibited the transfer of EAT by mTg-primed lymph node cells. The development of an autoantibody response to mTg was also inhibited when IL-12 was administered throughout the experimental period, suggesting that sustained exposure to IL-12 can be immunosuppressive.
Subject(s)
Autoimmune Diseases/immunology , Interleukin-12/immunology , Thyroid Diseases/immunology , Adoptive Transfer , Animals , Antibodies, Monoclonal , Autoimmune Diseases/etiology , Female , Freund's Adjuvant/administration & dosage , Gene Targeting , Immune Tolerance , Immunization , Interleukin-12/antagonists & inhibitors , Interleukin-12/genetics , Male , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Neutralization Tests , T-Lymphocytes/immunology , Thyroglobulin/administration & dosage , Thyroglobulin/immunology , Thyroid Diseases/etiologyABSTRACT
Down's syndrome (DS) is associated with several defects of both specific and non-specific immunity which may explain the enhanced susceptibility of DS subjects to viral and bacterial infections. In this study we have evaluated the effects of the new synthetic immunomodulator pidotimod in recurrent infections of the upper respiratory tract in a group of children with DS. It was an open trial vs untreated control, the pidotimod-treated group consisted of 14 subjects and the control group of 12. Pidotimod was administered at the dose of one 400 mg oral bottle/day for 90 days. There was a significant reduction in the frequency, severity and duration of infectious episodes in the pidotimod-treated group vs the untreated control group. The beneficial effects of pidotimod were also confirmed by a series of recordings made over the 90-day treatment period which showed a significant reduction in the number of days of fever, severity of the signs and symptoms of the acute episodes and use of antibiotics and antipyretic drugs. Pidotimod was well tolerated and no clinical, hematological or biochemical side-effects were noted.
Subject(s)
Down Syndrome/complications , Immunologic Factors/therapeutic use , Pyrrolidonecarboxylic Acid/analogs & derivatives , Respiratory Tract Infections/prevention & control , Thiazoles/therapeutic use , Adolescent , Child , Child, Preschool , Female , Humans , Immunologic Factors/pharmacology , Incidence , Male , Pyrrolidonecarboxylic Acid/pharmacology , Pyrrolidonecarboxylic Acid/therapeutic use , Recurrence , Respiratory Tract Infections/pathology , Severity of Illness Index , Thiazoles/pharmacology , ThiazolidinesABSTRACT
Rolipram is a type IV phosphodiesterase inhibitor endowed with powerful immunomodulatory properties. In this study, we evaluated the effects of this drug on the development of the T-cell-mediated hepatitis inducible in mice by concanavalin A. The results indicated that prophylactic treatment with either 5 or 10 mg/kg rolipram injected intraperitoneally 24 h and 1 h prior to intravenous (i.v.) challenge with 20 mg/kg concanavalin A successfully ameliorated serological and histological signs of liver damage, so that the treated mice showed lower transaminase levels in the plasma and milder mononuclear cell infiltration of the liver as compared to vehicle-treated controls. Moreover, this effect was associated with profound modifications of circulating levels of cytokines released after concanavalin A injection, with the blood levels of interferon-gamma and tumor necrosis factor-alpha being significantly lower and those of interleukin-10 higher than those of the control mice. In particular, the increased blood levels of interleukin-10 might play an important role in the anti-hepatitic effects of rolipram as coadministering this compound with anti-interleukin-10 monoclonal antibody significantly reduced its anti-inflammatory action. These results suggest that rolipram may be useful in the clinical setting for the treatment of cell-mediated immunoinflammatory diseases such as immunoinflammatory hepatitis.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Chemical and Drug Induced Liver Injury/prevention & control , Concanavalin A/antagonists & inhibitors , Phosphodiesterase Inhibitors/pharmacology , Pyrrolidinones/pharmacology , T-Lymphocytes/physiology , Animals , Antibodies, Monoclonal/pharmacology , Cell Movement/drug effects , Cytokines/metabolism , Interleukin-10/antagonists & inhibitors , Interleukin-10/metabolism , Leukocytes, Mononuclear/physiology , Male , Mice , Rolipram , Transaminases/bloodABSTRACT
One single intra-venous (i.v.) injection of Concanavalin A (Con A) into mice provokes a cell-mediated immunoinflammatory hepatitis. We have presently evaluated the immunopharmacological effects of exogenous interleukin (IL)-10 and the role of endogenous IL-10 in this model by using exogenous IL-10, anti-IL-10 monoclonal antibody (mAb) and mice with disrupted IL-10 gene (IL-10 KO mice). Whilst exogenous IL-10 administered in a prophylactic (1 h prior to Con A) and even "early" therapeutic fashion (30 min after Con A) reduced the elevation of transaminase activities in plasma in a dose-dependent manner, observed in control mice, these biochemical markers of liver injury were significantly increased both in IL-10 KO mice as well as in those receiving anti-IL-10 mAb. Interestingly, doses of Con A lower than 20 mg/kg that were only capable of inducing slight serological signs of hepatitis in mice, exerted marked hepatitic effects when administered to either anti-IL-10 mAb-treated mice or to IL-10 KO mice. The disease modulating effects of exogenous IL-10 and either genetical or pharmacologically-induced IL-10 deficiency were associated with profound and opposite modifications of the Con A-induced increase in the circulating levels of IFN-gamma and TNF-alpha. Relative to control animals, the blood levels of these cytokines were diminished in IL-10-treated mice and augmented in both IL-10 KO mice and anti-IL-10 mAb-treated mice. These results prove the physiological antiinflammatory role of endogenous IL-10 in Con A induced hepatitis and the beneficial effects of IL-10 treatment to prevent this condition.
Subject(s)
Chemical and Drug Induced Liver Injury/prevention & control , Concanavalin A/toxicity , Interleukin-10/deficiency , Interleukin-10/therapeutic use , Alanine Transaminase/blood , Animals , Antibodies, Monoclonal/adverse effects , Chemical and Drug Induced Liver Injury/etiology , Interferon-gamma/blood , Interferon-gamma/drug effects , Interleukin-10/immunology , Male , Mice , Mice, Inbred C57BL , Mice, Knockout , Time Factors , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/drug effectsABSTRACT
The serum levels of TGF-beta1, measured by solid-phase ELISA, were determined to be significantly augmented in patients with both relapsing remitting (RR) and secondary chronic progressive (CP) MS compared with sex- and age-matched healthy controls. Moreover, in RR MS patients, the blood levels of the cytokine were further augmented either during relapses or, in a rapid but reversible fashion, by s.c. injection with 8 million International Units (MIU) IFN-beta1b. Because TGF-beta1 possesses multiple anti-inflammatory activities, we hypothesize that the increase in its circulating levels in RR and CP MS patients might represent an endogenous anti-inflammatory mechanism aimed at counteracting ongoing immunoinflammatory events, and that IFN-beta may further potentiate this natural defensive apparatus.
Subject(s)
Adjuvants, Immunologic/therapeutic use , Interferon-beta/therapeutic use , Multiple Sclerosis/blood , Multiple Sclerosis/therapy , Transforming Growth Factor beta/blood , Enzyme-Linked Immunosorbent Assay , Female , Humans , Interferon beta-1a , Interferon beta-1b , Male , Recombinant Proteins/therapeutic use , RecurrenceABSTRACT
To gain further insights into the immunopharmacological mode of action of the immunosuppressant antibiotic deoxyspergualin (DSP), its effects were evaluated in murine lethal endo- and exotoxemia. These are two cytokine-mediated macrophage and T cell dependent immunoinflammatory conditions that can be induced in D-Galactosamine (D-Gal) presensitized mice by the injections with either LPS or SEB, respectively. The results show that prophylactic treatment with DSP (2.5 or 5 mg/kg bd.wt. 48, 24 and 2 h prior to challenge) neither improved the rate of survival, nor influenced the massive increase in the blood levels of tumor necrosis factor-alpha which followed the challenge with LPS or SEB. In sharp contrast, these clinical and seroimmunological events were both markedly counteracted by prophylactic treatment with sodium fusidate, another immunosuppressive agent used as control.
Subject(s)
Antibiotics, Antineoplastic/immunology , Antibiotics, Antineoplastic/pharmacology , Enterotoxins/toxicity , Guanidines/immunology , Guanidines/pharmacology , Lipopolysaccharides/toxicity , Tumor Necrosis Factor-alpha/metabolism , Animals , Endotoxemia/mortality , Endotoxemia/physiopathology , Female , Male , Mice , Mice, Inbred BALB C , Survival Rate , Time FactorsABSTRACT
Previous studies have shown that anti-gamma-interferon (IFN-gamma) antibody reduces the frequency of autoimmune IDDM in the DP-BB rat. We tested the effects of systemically administered recombinant rat IFN-gamma in both DP-BB and DR-BB rats. Unexpectedly, IFN-gamma markedly reduced the incidence of IDDM as compared with control rats when administered six times per week at a dosage of 280,000 U between ages 30-35 to 105 days or ages 60-64 to 105 days. A lower dosage (28,000 U on alternate days) was also protective when administered to DP-BB rats between birth and age 60 days. However, long-lasting protection against IDDM development over the 1-year study period was achieved only by the highest dosage of IFN-gamma administered from age 30 to 105 days. Ex vivo production of tumor necrosis factor-alpha from splenic lymphoid cells (SLCs) and peritoneal macrophages of the rats treated with IFN-gamma was comparable with that of controls; however, SLCs from the IFN-gamma-treated animals secreted lower amounts of IFN-gamma after stimulation with concanavalin A. IFN-gamma treatment also markedly reduced the frequency of phenotypically activated SLC-expressing class II antigens and interleukin-2 receptor. Finally, in agreement with the observed antidiabetogenic effects, exogenously administered IFN-gamma induced neither insulitis nor IDDM development in DR-BB rats, a subline of DP-BB rats in which autoimmune diabetes rarely occurs spontaneously but can be induced by administration of polyinosinic-polycytidilic acid.
Subject(s)
Diabetes Mellitus, Experimental/prevention & control , Diabetes Mellitus, Type 1/prevention & control , Hypoglycemic Agents/pharmacology , Interferon-gamma/pharmacology , Aging/physiology , Animals , Concanavalin A/pharmacology , Diabetes Mellitus, Experimental/epidemiology , Diabetes Mellitus, Experimental/physiopathology , Diabetes Mellitus, Type 1/epidemiology , Diabetes Mellitus, Type 1/physiopathology , Dose-Response Relationship, Drug , Female , Histocompatibility Antigens Class II/analysis , Histocompatibility Antigens Class II/metabolism , Hypoglycemic Agents/administration & dosage , Hypoglycemic Agents/therapeutic use , Immunosuppressive Agents/pharmacology , Incidence , Injections, Intraperitoneal , Interferon-gamma/administration & dosage , Interferon-gamma/metabolism , Interferon-gamma/therapeutic use , Macrophages, Peritoneal/cytology , Macrophages, Peritoneal/metabolism , Male , Phenotype , Random Allocation , Rats , Rats, Inbred BB , Receptors, Interleukin-2/analysis , Receptors, Interleukin-2/metabolism , Recombinant Proteins , Spleen/cytology , Spleen/metabolism , Tacrolimus/pharmacology , Tumor Necrosis Factor-alpha/metabolismABSTRACT
Interleukin(IL)-13, a cytokine produced by T helper 2 (Th2) cells, is a powerful inhibitor of macrophage functions, including surface expression of CD14 and production of IL-1 and tumor necrosis factor (TNF)-alpha. We tested the effects of recombinant mouse(m)IL-13 in a neonatal mouse model of endotoxin shock; this is a macrophage-dependent condition, which is a model of neonatal sepsis in humans. mIL-13 (0.5 microgram/mouse) dramatically reduced the lethal effects of lipopolysaccharide (LPS) if administered either 24 or 4 h prior to or concomitantly with LPS challenge. This action might be mediated by multiple modulatory activities of IL-13 on LPS-induced cytokine secretion since, relative to control animals, the mice treated with mIL-13 had eight times lower peak blood levels of TNF. The IL-1 beta levels were also decreased, whereas increased levels of IL-6 and IL-10 were observed at several time points after LPS challenge.
Subject(s)
Animals, Newborn/immunology , Endotoxins/toxicity , Interleukin-13/therapeutic use , Shock, Septic/mortality , Shock, Septic/prevention & control , Adjuvants, Immunologic/therapeutic use , Animals , Cytokines/drug effects , Cytokines/metabolism , Female , Male , Mice , Mice, Inbred BALB C , Shock, Septic/immunologyABSTRACT
The role of endogenous interferon-gamma (IFN gamma) in the development of insulin-dependent diabetes mellitus (IDDM) in diabetes-prone BB rats was evaluated. Several groups of these animals were treated under different, experimental conditions with a purified polyclonal antibody (Ab), antirat IFN gamma. The results show that when administered at doses of 100 or 200 micrograms/week from the 30/33th until the 105th day of age, the anti-IFN gamma Ab reversibly reduced the incidence of IDDM compared to that in control rats treated with either irrelevant rabbit IgG or PBS. Moreover, when given up to the 105th day of age, these doses of anti-IFN gamma Abs exerted comparable preventive effects regardless of whether application started as early as within 24 h after birth or at the end of the prediabetic period (e.g. 70/75 days). In contrast, under none of the above experimental conditions did larger doses of anti-IFN gamma Ab (500 micrograms or 1 mg/week) exert antidiabetogenic effects in the BB rats. Apparently, this was due to the exuberant production of neutralizing Abs elicited by the large amount of the xenogeneic Ab injected. At histoimmunological analyses, the BB rats treated with 200 micrograms/ week anti-IFN gamma Abs from 30-80 days of age exhibited a milder insulitic process along with diminished spleen frequency of activated lymphoid cells (MHC class II and interleukin-2 receptor positive). Taken together, these results provide further in vivo evidence for the central pathogenic role of IFN gamma in BB rat IDDM and anticipate the usefulness of specific IFN gamma inhibitors in the prevention of the disease in the clinical setting. Defining novel and less immunogenic forms of specific IFN gamma inhibitors than xenogeneic Abs is important for improving the efficiency of anti-IFN gamma-oriented approaches.
Subject(s)
Antibodies/therapeutic use , Diabetes Mellitus, Type 1/prevention & control , Interferon-gamma/antagonists & inhibitors , Animals , Diabetes Mellitus, Type 1/immunology , Female , HLA-DR Antigens/analysis , Histocompatibility Antigens Class II/analysis , Immunoglobulin G/biosynthesis , Interferon-gamma/blood , Lymphocyte Activation , Male , Rabbits , Rats , Rats, Inbred BBABSTRACT
Previous studies have shown that in vivo treatment with antiinterferon-gamma (anti-IFNgamma) monoclonal antibodies (mAbs) prevents the development of autoimmune diabetes in NOD mice. Although these findings anticipate that specific anti-IFNgamma therapies may be useful for the prevention/treatment of human insulin-dependent diabetes mellitus, there are several reasons why the use of anti-IFNgamma mAb may be difficult in the clinical setting. With the aim to develop alternative forms of specific anti-IFNgamma therapies, we recently produced a nonimmunogenic form of the soluble IFNgamma receptor (sIFNgammaR) that binds and neutralizes murine IFNgamma with an affinity higher than that of anti-IFNgamma mAb. In this study we compared the efficacy of sIFNgammaR to that of two anti-IFNgamma mAbs (XMG 1.2 and AN-18) in the prevention of spontaneous and accelerated (cyclophosphamide-induced) forms of autoimmune diabetes in NOD mice. The results show that in the spontaneous model, sIFNgammaR could prevent histological and clinical signs of autoimmune diabetes as efficiently as the two mAbs. Under ex vivo conditions, sIFNgammaR exhibited a more powerful modulatory effect than XMG 1.2 mAb on cytokine secretion from splenic lymphoid cells, which resulted in a significant reduction of Concanavalin A-induced IL-2 secretion and an augmented release of both unstimulated and lipopolysaccharide-induced IL-6. Moreover, although both mAbs were immunogenic and elicited formation of high titers of anti-rat IgG, sIFNgammaR did not induce antibody formation. Unexpectedly, in the cyclophosphamide-induced model, sIFNgammaR turned out to be less effective than either of the two anti-IFNgamma mAbs. Taken together, these data support the role of IFNgamma in the pathogenesis of NOD mice, but, more importantly, suggest that a nonimmunogenic approach is possible to the diminution of the effects of IFNgamma in this model.
Subject(s)
Diabetes Mellitus, Type 1/prevention & control , Receptors, Interferon/physiology , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/pharmacology , Antibody Formation , Cyclophosphamide , Diabetes Mellitus, Type 1/chemically induced , Diabetes Mellitus, Type 1/genetics , Female , Interferon-gamma/immunology , Mice , Mice, Inbred NOD , Solubility , T-Lymphocytes, Regulatory/physiology , T-Lymphocytes, Regulatory/transplantation , Time FactorsABSTRACT
The serum levels of the heterodimeric cytokine IL-12 were measured by solid-phase ELISA in a group of healthy subjects, multiple sclerosis (MS) patients with secondary chronic progressive course of the disease and patients suffering from other neurological diseases (OND). Serum levels of IL-12 higher than 5 pg/ml (limit of sensitivity of the assay) were only found in 2/30 (6.7%) of the healthy subjects and none of the 8 subjects with OND. In contrast, IL-12 was found in the majority of CPMS patients' sera (10/15, 66.7%) with values ranging between 5.5 and 18.6 pg/ml. These results are suggestive for an up-regulated production of IL-12 in CPMS.