ABSTRACT
The recommended chemotherapy for drug-sensitive tuberculosis (TB) consists of four different antibiotics administrated for 6 months. This long treatment leads to significant compliance problems and consequently to recrudescence of the disease and to the development of multidrug-resistant (MDR) strains. Thus, new alternatives are needed to shorten or simplify the treatment of TB. Antibodies have therapeutic effects in animal models of TB, so their use as adjuvants in drug-sensitive and MDR TB is an interesting alternative. To assess the effect of antibodies, BALB/c mice with active late disease 60 days after infection with drug-sensitive TB strain H37Rv were treated with intravenous immunoglobulin (IVIg), alone or in combination with conventional chemotherapy. When compared with control non-treated animals, IVIg alone produced a significantly decreased burden of pulmonary bacilli. This decrease was even greater when IVIg was used in combination with conventional chemotherapy. The combined therapy also significantly reduced tissue damage (pneumonia) when compared to infected animals treated only with antibiotics. IVIg treatment also caused decreased bacillary burdens in mice infected with an MDR strain. In vitro experiments suggested that improving phagocytosis by efficient opsonization is perhaps the principal mechanism of this beneficial therapeutic effect.
Subject(s)
Antitubercular Agents/administration & dosage , Combined Modality Therapy/methods , Drug Therapy/methods , Immunoglobulins, Intravenous/administration & dosage , Immunotherapy/methods , Mycobacterium tuberculosis/isolation & purification , Tuberculosis, Pulmonary/drug therapy , Animals , Bacterial Load , Disease Models, Animal , Lung/microbiology , Male , Mice, Inbred BALB C , Mycobacterium tuberculosis/drug effects , Treatment OutcomeABSTRACT
Antibodies have demonstrated having a protective effect in animal models of tuberculosis (TB). These experiments have considered the specificity of antigen recognition and the different isotypes and subclasses as significant contributors of this effect. However, the carbohydrate chain heterogeneity on the Fc region of IgG (Fc-IgG) can play an important role in modulating the immune response. Patients with TB usually have high titers of specific IgG; however, the carbohydrate associated with Fc-IgG usually lacks galactose. To assess the effect of this abnormal IgG in murine pulmonary TB, we evaluated the specificity of recognition to Mycobacterium tuberculosis antigens in vitro and protective effects in vivo comparing human intravenous immunoglobulin (IVIg) and IVIg treated with an endoglycosidase to remove the glycan residues (EndoS-treated IVIg). Our results showed similar antigen recognition. The study of distribution and kinetics of IVIg in serum and bronchial lavage after intraperitoneal (i.p.) administration in mice showed that IVIg circulates for 21 days. Finally, the protective effect of intact and EndoS-treated IVIg administered by i.p was studied in a murine model of progressive TB. IVIg treatment caused reduction in pulmonary bacilli loads, larger granulomas, and less pneumonia, while animals treated with EndoS-treated IVIg were not protected compared with control animals. Thus, IVIg has a protective activity in experimental pulmonary TB, and this effect requires intact Fc oligosaccharides.
Subject(s)
Immunoglobulin G/immunology , Immunoglobulin G/metabolism , Tuberculosis/immunology , Tuberculosis/metabolism , Animals , Antigens, Bacterial/immunology , Bronchoalveolar Lavage Fluid/immunology , Disease Models, Animal , Glycosylation , Humans , Immunoglobulin G/chemistry , Immunoglobulins, Intravenous/administration & dosage , Immunoglobulins, Intravenous/immunology , Immunoglobulins, Intravenous/pharmacokinetics , Infusions, Parenteral , Male , Mice , Mycobacterium tuberculosis/immunology , Polysaccharides/chemistry , Tuberculosis/pathology , Tuberculosis/prevention & control , Tuberculosis, Pulmonary/immunology , Tuberculosis, Pulmonary/metabolism , Tuberculosis, Pulmonary/pathology , Tuberculosis, Pulmonary/prevention & controlABSTRACT
BACKGROUND: Fibromyalgia (FM) is characterized by chronic, widespread muscular pain and tenderness and is generally associated with other somatic and psychological symptoms. Further, circulatory levels of proinflammatory cytokines (IL-1beta, TNF-alpha, and IL-6) may be altered in FM patients, possibly in association with their symptoms. Recently, rises in BMI have been suggested to contribute to increased circulating levels of proinflammatory cytokines in FM patients. Our aim was to measure the circulatory levels of proinflammatory cytokines to determine the influence of BMI on these levels in FM patients and healthy volunteers (HVs). In Spanish FM patients (n = 64) and HVs (n = 25), we measured BMI and serum concentrations of proinflammatory cytokines by capture ELISA. FINDINGS: There were significant differences in BMI levels between FM patients (26.40 +/- 4.46) and HVs (23.64 +/- 3.45) and significant increase in IL-6 in FM patients (16.28 +/- 8.13 vs 0.92 +/- 0.32 pg/ml) (P < 0.001). IL-1beta and TNF-alpha decreased in FM patients compared with HVs. By ANCOVA, there was no significant association between BMI and TNF-alpha (F = 0.098, p = 0.75) or IL-6 (F = 0.221, p = 0.63) levels in FM patients. CONCLUSIONS: Our analysis in FM patients of BMI as a covariate of proinflammatory cytokines levels showed that serum TNF-alpha and IL-6 levels are independent of BMI. Further studies are necessary to dissect these findings and their implication in future therapeutic approaches for FM patients.
ABSTRACT
OBJECTIVE: To classify Mycobacterium leprae isolates from multiple areas in Mexico based on variable number of tandem repeats of 6 base within the rpoT gene and three single nucleotide polymorphism (SNP), and to analyse their geographic distribution in the context of the origin of leprosy in Mexico. RESULTS: Analysis for rpoT genotyping of 64 samples collected in the west and southwestern areas revealed that 46 isolates were of the 4 copy type and 18 isolates were of the 3 copy type. All samples from the eastern coastal area (n = 24) and from the Yucatan peninsula (n = 12) were of the 3 copy type. Six isolates from the west and southwestern area were SNP-type 1, 13 isolates were SNP-type 2 and 45 isolates were SNP-type 3. Nineteen of 24 isolates from the eastern coastal area were SNP-type 3 and one was SNP-type 4. Seven isolates from the Yucatan peninsula were SNP-type 3 and one was SNP-type 4. CONCLUSION: The difference of the proportion of each genotype between the western areas and the eastern areas indicated the expansion of leprosy through different paths in Mexico.
Subject(s)
Leprosy/microbiology , Mycobacterium leprae/genetics , Animals , Bacterial Proteins/chemistry , Bacterial Proteins/genetics , DNA, Bacterial/chemistry , DNA, Bacterial/genetics , Genetic Variation , Leprosy/epidemiology , Minisatellite Repeats , Polymorphism, Single Nucleotide , Sigma Factor/chemistry , Sigma Factor/geneticsABSTRACT
Major depressive disorder (MDD) is a psychiatric condition characterized by hypercortisolism and variations in circulatory cytokines. Previously it has been reported that administration of selective serotonin reuptake inhibitors (SSRI) in MDD patients modify cortisol and cytokine levels but these studies only evaluated changes over a short time period. This work reports the long-term effects of administration of SSRI on the cortisol levels and pro-/anti-inflammatory cytokine profile in a group of MDD patients treated for 52 weeks. A total of 31 patients diagnosed with MDD received anti depressant treatment with SSRI. HDRS and BDI were administered over a year, and levels of interleukin IL-1beta, IL-10, IL-2, IFN-gamma, IL-4, IL-13, and 24-h urine cortisol were determined at weeks (W) 0, 5, 20, 36 and 52 of treatment. Before treatment we found high levels of cortisol, IL-4, IL-13 (Th2) and IL-10 in MDD patients when compared with healthy volunteers. At W20 psychiatric scales indicated a remission of the depressive episode concomitantly with increments in IL-2 and IL-1beta but without changes in cortisol. Towards the end of the treatment (W52) we observed a significant reduction (p<0.01) in cortisol levels, with an increment in IL-1beta and IFN-gamma and a decrease in Th2 cytokines. Our results suggest that depressed patients only reach a partial reestablishment of HPA axis function after the long-term administration of SSRI.
Subject(s)
Antidepressive Agents/therapeutic use , Cytokines/blood , Depressive Disorder, Major/blood , Depressive Disorder, Major/drug therapy , Selective Serotonin Reuptake Inhibitors/therapeutic use , Adult , Analysis of Variance , Enzyme-Linked Immunosorbent Assay , Female , Humans , Hydrocortisone/blood , Longitudinal Studies , Male , Psychiatric Status Rating Scales , Radioimmunoassay/methods , Retrospective Studies , Time Factors , Young AdultABSTRACT
In Major Depressive Disorder (MDD), the neuroendocrine and immune systems interactions are impaired. We investigated the pro/anti-inflammatory Th1/Th2 cytokine balance in MDD patients and in non-depressed control group. The MDD subjects showed higher levels of cortisol and TNF-alpha, increased CD3+CD8+ and NK percentages, diminished B cell counts and no significant variations in CD3+CD4+ lymphocyte. Moreover, higher levels of IL-4 and IL-13 (Th2) and significantly lower measurements of IL-2 and IFN-gamma (Th1) cytokines were also observed in the MDD group. Overall, we propose that all these changes could be related to the elevated cortisol levels seen in the MDD patients. Further studies are necessary to explore these findings and its implication in future therapeutic approach of MDD patients.
Subject(s)
Cytokines/metabolism , Depressive Disorder, Major/metabolism , Depressive Disorder, Major/pathology , Th2 Cells/metabolism , Adolescent , Adult , Analysis of Variance , Case-Control Studies , Enzyme-Linked Immunosorbent Assay/methods , Female , Flow Cytometry/methods , Humans , Hydrocortisone/blood , Male , Middle Aged , Radioimmunoassay/methods , Statistics as TopicABSTRACT
DDT is still widely used in several parts of the world to control malaria, typhoid and dengue vectors, even though its use was banned in many countries based on toxicity data in wild life species. DDT has been shown to have immunotoxic effects in mice and to increase susceptibility to intracellular pathogens such as Mycobacterium leprae. However, little is known about the mechanisms underlying this effect. Activated macrophages play an important defensive role against intracellular pathogens, therefore our objective was to evaluate the effect of in vitro exposure to technical grade DDT (a mixture of three forms: 1,1,1-thricloro-2,2-bis(p-chlorophenyl)ethane (p,p'-DDT) (85%), o,p'-DDT (15%) and o,o'-DDT (trace amounts)), p,p'-DDT, 1,1-dicloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) and 1,1-dichloro-2,2-bis(p-chlorophenyl)ethane on the functional activation of J774A.1 macrophages and their capability to limit growth of intracellular pathogens, using Mycobacterium microti as a model. We evaluated cytotoxicity and the effect on cell proliferation of 2.5, 5.0 and 10 microg/ml of DDT compounds. Functional macrophage activity (NO(*) and O(2)(-) production, and mRNA expression of TNF-alpha, IL-1beta and iNO synthase) and the ability of treated cells to limit infection by M. microti in IFN-gamma-activated macrophages were evaluated in cells exposed to 2.5 microg/ml of DDT compounds. Doses of 5 and 10 microg/ml induced direct cytotoxic effects precluding meaningful analysis of the above parameters, whereas 2.5 microg/ml of all DDT compounds inhibited macrophage activity and reduced their ability to limit the intracellular growth of M. microti without inducing cytotoxicity. Technical grade DDT and p,p'-DDE were the more potent compounds. Therefore, exposure to DDT compounds could represent an important risk for infection development by those intracellular pathogens against which NO(*) and/or O(2)(-) production represent the main immune protective mechanism.
Subject(s)
DDT/toxicity , Macrophage Activation/drug effects , Mycobacterium Infections/immunology , Animals , Cell Division/drug effects , Cell Line , Cell Survival/drug effects , Dichlorodiphenyl Dichloroethylene/toxicity , Interleukin-1/biosynthesis , Isomerism , Mice , Nitric Oxide/toxicity , Nitric Oxide Synthase/biosynthesis , Nitric Oxide Synthase Type II , RNA, Messenger/biosynthesis , RNA, Messenger/genetics , Reverse Transcriptase Polymerase Chain Reaction , Tumor Necrosis Factor-alpha/biosynthesisABSTRACT
La lepra es una enfermedad multifactorial en la que la función que desempeña la respuesta inmunitaria es preponderante; sin embargo, la inmunología aún no ofrece explicación para la lepra TT, en la que la respuesta inmunitaria celular parece estar intacta. Existen investigaciones que indican que si bien la información genética del huésped no es determinante para el desarrollo de la enfermedad, sí lo es para el tipo de enfermedad que desarrollará el individuo
Subject(s)
Humans , Leprosy/immunology , Antibody Formation , Immunity, Cellular , Lepromin/administration & dosage , Mycobacterium leprae/immunologyABSTRACT
Las manifestaciones clínicas de la lepra van desde una pequeña mancha hipocrómica hasta los tipos deformantes. Se considera que la adquisición de la infección es multifactorial involucrando no sólo la presencia del bacilo sino también las características genéticas e inmunitarias del huésped. La lepra constituye un modelo único para estudiar los mecanismos inmunitarios en el hombre
