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PURPOSE: To evaluate the safety and efficacy of ocular cyclosporine in the prevention of the development of ocular graft versus host disease (oGVHD) in patients undergoing allogeneic hematopoietic stem cell transplantation (AHSCT) in comparison with historic data. DESIGN: We developed a longitudinal, observational, prospective nonrandomized study. We evaluated the feasibility of prophylactic use of topical cyclosporine A (CsA) to prevent or decrease the incidence of oGVHD and compared this with historic data. METHODS: Patients undergoing AHSCT were treated with prophylactic topical CsA for 12 months after engraftment, followed by serial ophthalmic evaluations, including the Schirmer test. RESULTS: Twenty patients were included. No serious adverse effects were reported. Poor adherence was documented in 15% of patients. In spite of observing extra-ocular GVHD (acute and chronic GVHD incidence of 50 and 45%, respectively), only 1 in 20 patients developed oGVHD over the 20-month follow-up for the entire cohort. No statistically significant difference was observed in the incidence of oGVHD when compared to a historical cohort. CONCLUSIONS: Topical CsA as a prophylactic measure for oGVHD, administered over a period of 1 year after grafting, is safe and feasible and may decrease the incidence of ophthalmic manifestations of GVHD. These findings must be confirmed in a randomized trial.
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Enfermedad Injerto contra Huésped , Trasplante de Células Madre Hematopoyéticas , Ciclosporina , Ojo , Humanos , Estudios ProspectivosRESUMEN
Background: Diagnosis of malignant pleural mesothelioma (MPM) remains a challenge, especially when resources in pathology are limited. The study aimed to evaluate cost-effective tumor markers to predict the probability of MPM in plasma samples in order to accelerate the diagnostic workup of the tissue of potential cases. Methods: We conducted a case-control study stratified by gender, which included 75 incident cases with MPM from three Mexican hospitals and 240 controls frequency-matched by age and year of blood drawing. Plasma samples were obtained to determine mesothelin, calretinin, and thrombomodulin using enzyme-linked immunosorbent assays (ELISAs). We estimated the performance of the markers based on the area under the curve (AUC) and predicted the probability of an MPM diagnosis of a potential case based on the marker concentrations. Results: Mesothelin and calretinin, but not thrombomodulin were significant predictors of a diagnosis of MPM with AUCs of 0.90 (95% CI: 0.85-0.95), 0.88 (95% CI: 0.82-0.94), and 0.51 (95% CI: 0.41-0.61) in males, respectively. For MPM diagnosis in men we estimated a true positive rate of 0.79 and a false positive rate of 0.11 for mesothelin. The corresponding figures for calretinin were 0.81 and 0.18, and for both markers combined 0.84 and 0.11, respectively. Conclusions: We developed prediction models based on plasma concentrations of mesothelin and calretinin to estimate the probability of an MPM diagnosis. Both markers showed a good performance and could be used to accelerate the diagnostic workup of tissue samples in Mexico.
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Biomarcadores de Tumor/análisis , Calbindina 2/sangre , Proteínas Ligadas a GPI/sangre , Mesotelioma/diagnóstico , Neoplasias Pleurales/diagnóstico , Anciano , Estudios de Casos y Controles , Femenino , Humanos , Neoplasias Pulmonares , Masculino , Mesotelina , Mesotelioma/sangre , México , Persona de Mediana Edad , Neoplasias Pleurales/sangreRESUMEN
In vivo control of Mycobacterium tuberculosis reflects the balance between host immunity and bacterial evasion strategies. Effector Th1 cells that mediate protective immunity by depriving the bacterium of its intracellular niche are regulated to prevent overexuberant inflammation. One key immunoregulatory molecule is Tim3. Although Tim3 is generally recognized to downregulate Th1 responses, we recently described that its interaction with Galectin-9 expressed by M. tuberculosis-infected macrophages stimulates IL-1ß secretion, which is essential for survival in the mouse model. Why IL-1ß is required for host resistance to M. tuberculosis infection is unknown. In this article, we show that IL-1ß directly kills M. tuberculosis in murine and human macrophages and does so through the recruitment of other antimicrobial effector molecules. IL-1ß directly augments TNF signaling in macrophages through the upregulation of TNF secretion and TNFR1 cell surface expression, and results in activation of caspase-3. Thus, IL-1ß and downstream TNF production lead to caspase-dependent restriction of intracellular M. tuberculosis growth.
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Caspasa 3/metabolismo , Interleucina-1beta/fisiología , Macrófagos/inmunología , Macrófagos/microbiología , Receptores del Factor de Necrosis Tumoral/metabolismo , Transducción de Señal/inmunología , Regulación hacia Arriba , Animales , Células Cultivadas , Activación Enzimática/inmunología , Humanos , Macrófagos/enzimología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Mycobacterium tuberculosis/inmunología , Receptores del Factor de Necrosis Tumoral/fisiología , Regulación hacia Arriba/inmunologíaRESUMEN
T cell Ig and mucin domain 3 (Tim3) is an inhibitory molecule involved in immune tolerance, autoimmune responses, and antiviral immune evasion. However, we recently demonstrated that Tim3 and Galectin-9 (Gal9) interaction induces a program of macrophage activation that results in killing of Mycobacterium tuberculosis in the mouse model of infection. In this study, we sought to determine whether the Tim3-Gal9 pathway plays a similar role in human pulmonary TB. We identified that pulmonary TB patients have reduced expression of Tim3 on CD14(+) monocytes in vivo. By blocking Tim3 and Gal9 interaction in vitro, we show that these molecules contribute to the control of intracellular bacterial replication in human macrophages. The antimicrobial effect was partially dependent on the production of IL-1ß. Our results establish that Tim3-Gal9 interaction activates human M. tuberculosis -infected macrophages and leads to the control of bacterial growth through the production of the proinflammatory cytokine IL-1ß. Data presented in this study suggest that one of the potential pathways activated by Tim3/Gal9 is the secretion of IL-1ß, which plays a crucial role in antimicrobial immunity by modulating innate inflammatory networks.
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Anticuerpos Bloqueadores/fisiología , Galectinas/fisiología , Activación de Macrófagos/inmunología , Macrófagos/inmunología , Macrófagos/microbiología , Proteínas de la Membrana/fisiología , Mycobacterium tuberculosis/inmunología , Transducción de Señal/inmunología , Adulto , Anciano , Anticuerpos Bloqueadores/biosíntesis , Femenino , Galectinas/antagonistas & inhibidores , Galectinas/inmunología , Receptor 2 Celular del Virus de la Hepatitis A , Humanos , Macrófagos/metabolismo , Masculino , Proteínas de la Membrana/antagonistas & inhibidores , Proteínas de la Membrana/inmunología , Persona de Mediana Edad , Mycobacterium tuberculosis/crecimiento & desarrollo , Mapeo de Interacción de ProteínasRESUMEN
INTRODUCTION: High HHV-8 viral load (VL) in Kaposi Sarcoma (KS) has been associated with Severe Immune Reconstitution Inflammatory Syndrome (Severe-IRIS-KS), which can occur after initiating cART, and leads to high mortality, particularly in patients with pulmonary involvement. We investigate if valganciclovir (as an anti-HHV-8 agent) initiated before cART reduces the mortality associated with Severe-IRIS-KS and the incidence of Severe-IRIS-KS. METHODS: Open-label parallel-group randomized clinical trial in AIDS cART naïve patients with disseminated KS (DKS) as defined by at least two of the following: pulmonary, lymph-node, or gastrointestinal involvement, lymphedema, or ≥30 skin lesions. In the experimental group (EG), patients received valganciclovir 900 mg BID four weeks before cART and continued until week 48; in the control group (CG), cART was initiated on week 0. Non-severe-IRIS-KS was defined as: an increase in the number of lesions plus a decrease of ≥one log10 HIV-VL, or an increase of ≥50cells/mm3 or ≥2-fold in baseline CD4+cells. Severe-IRIS-KS was defined as abrupt clinical worsening of KS lesions and/or fever after ruling out another infection following cART initiation, and at least three of the following: thrombocytopenia, anemia, hyponatremia, or hypoalbuminemia. RESULTS: 40 patients were randomized and 37 completed the study. In the ITT analysis, at 48 weeks, total mortality was the same in both groups (3/20), severe-IRIS-KS attributable mortality was 0/20 in the EG, compared with 3/20 in the CG (p = 0.09), similar to the per-protocol analysis: 0/18 in the EG, and 3/19 in the control group (p = 0.09). The crude incidence rate of severe-IRIS-KS was four patients developed a total of 12 episodes of Severe-IRIS-KS in the CG and two patients developed one episode each in the EG. Mortality in patients with pulmonary KS was nil in the EG (0/5) compared with 3/4 in the CG (P = 0.048). No difference was found between groups in the number of non-S-IRIS-KS events. Among survivors at week 48, 82% achieved >80% remission. CONCLUSIONS: Although mortality attributable to KS was lower in the EG the difference was not statistically significant.
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Anemia , Infecciones por VIH , Herpesvirus Humano 8 , Sarcoma de Kaposi , Humanos , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Valganciclovir/uso terapéutico , Terapia Antirretroviral Altamente Activa , Anemia/complicacionesRESUMEN
T-cell Immunoglobulin and Mucin Domain 3 (TIM-3) is an immune checkpoint receptor known to regulate T-cell activation and has been targeted for immunotherapy in cancer and other diseases. However, its expression and function in other cell types, such as macrophages, are poorly understood. This study investigated TIM-3 expression in human macrophages polarized to M1 (stimulated with IFN-γ and LPS) and M2 (stimulated with IL-4 and IL-13) phenotypes using an in vitro model. Our results show that M1 macrophages have a lower frequency of TIM-3+ cells compared to M2 macrophages at 48 and 72 hr poststimulation. Additionally, we observed differential levels of soluble ADAM 10, an enzyme responsible for TIM-3 release, in the supernatants of M1 and M2 macrophages at 72 hr. We also found that the TIM-3 intracellular tail might associate with lymphocyte-specific protein 1 (LSP-1), a protein implicated in cell motility and podosome formation. These findings enhance our understanding of TIM-3 function in myeloid cells such as macrophages and may inform the development of immunotherapies with reduced immune-related adverse effects.
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Receptor 2 Celular del Virus de la Hepatitis A , Macrófagos , Proteínas de Microfilamentos , Humanos , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Proteínas de Microfilamentos/metabolismoRESUMEN
Experimental models have shown that lipoproteins from Mycobacterium tuberculosis induce apoptosis via Toll-like receptor 2 (TLR2) in the THP-1 cell line and in monocyte-derived macrophages from healthy volunteers. We found an increased percentage of circulating monocytes in patients with tuberculosis (TB) in comparison to healthy controls. Patients with TB showed a higher TLR2 and TLR4 expression density on monocytes, and a higher proportion of TLR2(+) monocytes, as well as increased serum tumour necrosis factor-α level. In culture, monocytes from TB patients were more susceptible to death than monocytes from healthy controls. Moreover, death-susceptible monocytes were positive to both TLR2 and TLR4 at the start of culture. Freshly obtained monocytes from TB patients exhibited cleaved caspase 9 and denaturalized cytochrome c. For levels of caspase 8, apoptosis-regulating signal kinase 1, and phospho-p38 mitogen-activated protein kinase there was no difference between samples from TB patients and from healthy controls. The culture filtrate antigen extract from M. tuberculosis H37Rv strain induced the death of monocytes from patient with TB after a 4-hr incubation, which was abrogated by neutralizing antibodies for TLR2 but not TLR4. Similarly, Pam3CSK4, a synthetic agonist triacylated ligand to TLR2, also induced the death of monocytes, although it did not increase levels of cleaved caspase 9. Our findings suggest that monocytes from TB patients are more susceptible to death, probably through mitochondrial damage, and that cell death increases in the presence of mycobacterial antigen by a TLR2-dependent pathway.
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Apoptosis , Monocitos/fisiología , Mycobacterium tuberculosis/patogenicidad , Receptor Toll-Like 2/metabolismo , Tuberculosis/inmunología , Adulto , Antígenos Bacterianos/inmunología , Caspasa 9/metabolismo , Citocromos c/metabolismo , Femenino , Humanos , Masculino , Persona de Mediana Edad , Monocitos/citología , Monocitos/inmunología , Monocitos/metabolismo , Mycobacterium tuberculosis/inmunología , Mycobacterium tuberculosis/metabolismo , Receptor Toll-Like 4/metabolismo , Tuberculosis/metabolismo , Adulto JovenRESUMEN
The antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as well as the host immune response after vaccination and viral infection have shown to be highly heterogeneous. This is a case series study analysing humoral immune response and vaccination side effects after two doses of a BNT162b2 mRNA among healthcare workers (HCWs) in Mexico. All participants were scheduled for their two doses of mRNA BNT162b2 vaccine and provided information through a questionnaire: demographic characteristics, antibody serum titres and vaccination-related side effects. Blood samples were obtained for serology testing after the first and second doses of vaccine. No serious adverse effects due to vaccination were reported; nonetheless, non-medical HCWs reported more side effects after the second dose. The previous infection with SARS-CoV-2 boosted immune response after receiving the first vaccination (roughly 30 times higher than those without previous infection); nonetheless, after the second dose, the immune response did not show a higher titre as might be expected.
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The requirement for TLR signaling in the initiation of an Ag-specific Ab response is controversial. In this report we show that a novel OVA-expressing recombinant Salmonella vaccine (Salmonella-OVA) elicits a Th1-biased cell-mediated and serum Ab response upon oral or i.p. immunization of C57BL/6 mice. In MyD88(-/-) mice, Th1-dependent Ab responses are greatly reduced while Th2-dependent Ab isotypes are elevated in response to oral and i.p., but not s.c. footpad, immunization. When the T effector response to oral vaccination is examined we find that activated, adoptively transferred Ag-specific CD4(+) T cells accumulate in the draining lymph nodes, but fail to produce IFN-gamma, in MyD88(-/-) mice. Moreover, CD1d tetramer staining shows that invariant NKT cells are activated in response to oral Salmonella-OVA vaccination in wild-type, but not MyD88(-/-), mice. Treatment with neutralizing Ab to CD1d reduces the OVA-specific Ab response only in MyD88-sufficient wild-type mice, suggesting that both Ag-specific CD4 T cell and invariant NKT cell effector responses to Salmonella-OVA vaccination are MyD88 dependent. Taken together, our data indicate that the type of adaptive immune response generated to this live attenuated vaccine is regulated by both the presence of MyD88-mediated signals and vaccination route, which may have important implications for future vaccine design.
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Anticuerpos Antibacterianos/biosíntesis , Linfocitos T CD4-Positivos/inmunología , Isotipos de Inmunoglobulinas/biosíntesis , Factor 88 de Diferenciación Mieloide/deficiencia , Factor 88 de Diferenciación Mieloide/genética , Células T Asesinas Naturales/inmunología , Vacunas contra la Salmonella/administración & dosificación , Administración Oral , Animales , Anticuerpos Antibacterianos/sangre , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Femenino , Isotipos de Inmunoglobulinas/sangre , Inyecciones Intraperitoneales , Inyecciones Subcutáneas , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Factor 88 de Diferenciación Mieloide/fisiología , Células T Asesinas Naturales/metabolismo , Células T Asesinas Naturales/patología , Vacunas contra la Salmonella/genética , Vacunas contra la Salmonella/inmunología , Receptores Toll-Like/fisiología , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/inmunología , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/inmunologíaRESUMEN
RATIONALE: Invariant natural killer T (iNKT) cells are a unique subset of T cells that recognize lipid antigens presented by CD1d molecules. Recent studies have shown that iNKT cells can protect mice against Mycobacterium tuberculosis (Mtb) infection. We sought to determine whether pharmacological activation of iNKT cells by α-galactosylceramide (α-GalCer) could be used to treat tuberculosis (TB). OBJECTIVES: We hypothesized that α-GalCer, either alone or in combination with isoniazid, could be used to treat pulmonary TB. METHODS: The ability of α-GalCer-activated iNKT cells to suppress Mtb replication was evaluated using an in vitro coculture system. To test its potency in vivo, mice infected with virulent Mtb were treated with α-GalCer alone or in combination with isoniazid. MEASUREMENTS AND MAIN RESULTS: Quantitative colony-forming unit counts were compared for both experimental systems. Our results show that α-GalCer plus isoniazid controls bacterial growth better than α-GalCer or INH alone, and single or multiple α-GalCer administrations prolong the survival of the mice infected via the aerosol route. CONCLUSIONS: Our results demonstrate that α-GalCer administration can improve the outcome of Mtb infection, even when transmitted by the aerosol route. However, a combination of isoniazid and α-GalCer treatment has a synergistic effect on infection control. We conclude that more efficient treatment of TB will be achieved through a combination of classic chemotherapy and modulation of the host immune response.
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Antituberculosos/uso terapéutico , Galactosilceramidas/uso terapéutico , Isoniazida/uso terapéutico , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis Pulmonar/tratamiento farmacológico , Animales , Antígenos CD1d/inmunología , Quimioterapia Combinada , Femenino , Inmunomodulación , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Mycobacterium tuberculosis/inmunología , Células T Asesinas Naturales/inmunología , Resultado del Tratamiento , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/microbiologíaRESUMEN
Cellular immunity to Mycobacterium tuberculosis (Mtb) requires a coordinated response between the innate and adaptive arms of the immune system, resulting in a type 1 cytokine response, which is associated with control of infection. The contribution of innate lymphocytes to immunity against Mtb remains controversial. We established an in vitro system to study this question. Interferon-gamma is produced when splenocytes from uninfected mice are cultured with Mtb-infected macrophages, and, under these conditions, bacterial replication is suppressed. This innate control of bacterial replication is dependent on CD1d-restricted invariant NKT (iNKT) cells, and their activation requires CD1d expression by infected macrophages as well as IL-12 and IL-18. We show that iNKT cells, even in limiting quantities, are sufficient to restrict Mtb replication. To determine whether iNKT cells contribute to host defense against tuberculosis in vivo, we adoptively transferred iNKT cells into mice. Primary splenic iNKT cells obtained from uninfected mice significantly reduce the bacterial burden in the lungs of mice infected with virulent Mtb by the aerosol route. Thus, iNKT cells have a direct bactericidal effect, even in the absence of synthetic ligands such as alpha-galactosylceramide. Our finding that iNKT cells protect mice against aerosol Mtb infection is the first evidence that CD1d-restricted NKT cells mediate protection against Mtb in vivo.
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Interferón gamma/biosíntesis , Macrófagos/microbiología , Mycobacterium tuberculosis/inmunología , Células T Asesinas Naturales/inmunología , Tuberculosis/inmunología , Traslado Adoptivo , Análisis de Varianza , Animales , Antígenos CD1d/inmunología , Células Cultivadas , Femenino , Inmunidad Innata , Interleucina-12/inmunología , Interleucina-18/inmunología , Pulmón/microbiología , Activación de Linfocitos , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Mycobacterium tuberculosis/crecimiento & desarrollo , Células T Asesinas Naturales/metabolismo , Bazo/citología , Bazo/inmunología , Estadísticas no Paramétricas , Linfocitos T , Tuberculosis/microbiologíaRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disorder of unknown etiology. IPF is likely the result of complex interrelationships between environmental and host factors, although the genetic risk factors are presently uncertain. Because we have found that some MHC polymorphisms confer susceptibility to IPF, in the present study we aimed to evaluate the role of the MHC class I chain-related gene A (MICA) in the risk of developing the disease. MICA molecular typing was done by reference strand mediated conformation analysis in a cohort of 80 IPF patients and 201 controls. In addition, the lung cellular source of the protein was examined by immunohistochemistry, the expression of the MICA receptor NKG2D in lung cells by flow cytometry and soluble MICA by ELISA. A significant increase of MICA*001 was observed in the IPF cohort (OR = 2.91, 95% CI = 1.04-8.25; pC = 0.03). Likewise, the frequency of the MICA*001/*00201 genotype was significantly increased in patients with IPF compared with the healthy controls (OR = 4.72, 95% CI = 1.15-22.51; pC = 0.01). Strong immunoreactive MICA staining was localized in alveolar epithelial cells and fibroblasts from IPF lungs while control lungs were negative. Soluble MICA was detected in 35% of IPF patients compared with 12% of control subjects (P = 0.0007). The expression of NKG2D was significantly decreased in gammadelta T cells and natural killer cells obtained from IPF lungs. These findings indicate that MICA polymorphisms and abnormal expression of the MICA receptor NKG2D might contribute to IPF susceptibility.
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Antígenos de Histocompatibilidad Clase I/genética , Fibrosis Pulmonar Idiopática/genética , Subfamilia K de Receptores Similares a Lectina de Células NK/genética , Polimorfismo Genético , Adulto , Anciano , Estudios de Casos y Controles , Células Cultivadas , Femenino , Expresión Génica , Frecuencia de los Genes , Predisposición Genética a la Enfermedad , Genotipo , Antígenos HLA-B/genética , Antígenos de Histocompatibilidad Clase I/sangre , Humanos , Células Asesinas Naturales/metabolismo , Pulmón/metabolismo , Masculino , Persona de Mediana Edad , Subfamilia K de Receptores Similares a Lectina de Células NK/metabolismo , Análisis de Secuencia de ADN , Subgrupos de Linfocitos T/metabolismoRESUMEN
BACKGROUND AND OBJECTIVE: Specific CD8+ T-cell cytotoxicity has been recognized as being involved in the elimination of drug-susceptible tuberculosis (DS-TB). Given that there is currently no information on the cytotoxic effector functions of CD8+ T cells in multi-drug-resistant tuberculosis (MDR-TB), our objective was to analyse the cytotoxic activity, both basal and stimulated, of CD8+ T cells from MDR-TB patients and compare it with that of DS-TB patients, as well as purified protein derivative (PPD)+ and PPD- subjects. METHODS: Cytotoxic activity of CD8+ T cells from MDR-TB patients, DS-TB patients, PPD+ and PPD- subjects was measured by a colorimetric assay, using H37Rv culture filtrate protein as the antigenic stimulus. RESULTS: Twenty-eight subjects were studied (7 MDR-TB patients, 7 DS-TB patients, 7 PPD+ subjects and 7 PPD- subjects). In the presence of the antigenic stimulus, the cytotoxic activity of CD8+ T cells from MDR-TB patients (% lysis) increased from 6.7% to 59.6% (P < 0.001). In DS-TB patients lysis increased from 3.2% to 22.5% (P < 0.001), whereas in PPD+ subjects it increased from 2.7% to 12.0% (P < 0.001) and in PPD- subjects from 1.3% to 3.2% (P < 0.001). Basal cytotoxic activity was significantly higher for MDR-TB patients than PPD+ and PPD- subjects (P = 0.003), but not compared with that for DS-TB patients (P = 0.05). Stimulated cytotoxic activity was highest for MDR-TB patients. CONCLUSIONS: CD8+ T cells from MDR-TB patients showed an exaggerated cytotoxic activity after antigenic stimulation. Further studies are required to elucidate the role of this response in the immunopathogenesis of MDR-TB.
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Linfocitos T CD8-positivos/fisiología , Citotoxicidad Inmunológica/fisiología , Tuberculosis Resistente a Múltiples Medicamentos/inmunología , Tuberculosis Resistente a Múltiples Medicamentos/patología , Adulto , Antígenos Bacterianos/inmunología , Estudios de Casos y Controles , Técnicas de Cultivo de Célula , Femenino , Humanos , Hidrolasas/inmunología , Masculino , Persona de Mediana Edad , Tuberculina/inmunología , Adulto JovenRESUMEN
Pulmonary tuberculosis is currently considered a serious health problem worldwide. To understand tuberculosis infection we need to know the interaction between the host's immune response and the microorganism causing tuberculosis. Ample research has been carried out to identify new molecules and genes involved in the evasion mechanism of the host's immune response. This knowledge has generated the possibility that future therapeutic schemes will be designed to fight these particular molecules or genes. We reviewed recent experimental evidence on the mechanisms that will successfully fight against mycobacteria.
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Evasión Inmune , Mycobacterium tuberculosis/fisiología , Apoptosis , Genes MHC Clase II , Humanos , Necrosis , FagosomasRESUMEN
Plasminogen and plasmin are fundamental components of the fibrinolytic system that interact with microorganisms generating different immunopathological effects. The molecules of Mycobacterium tuberculosis interplaying with plasminogen have already been identified and characterized. In this work, we studied the effects of plasmin(ogen) bound toMycobacterium bovisCalmette-Guérin (BCG) on phagocytosis in THP1 macrophages as well as in granuloma formation and development on in vitrohuman granuloma model. For this purpose, BCG was coated with plasminogen and plasmin, obtained after activation of zymogen by tissue plasminogen activator. The results showed a significant reduction in the number of bacteria phagocytosed by macrophages in presence of plasminogen or plasmin on BCG surface. On the other hand, at 3 days BCG/plasminogen/plasmin induced an increase granuloma numbers with respect to those induced by uncoated bacteria. BCG/plasminogen/environments also showed a significant increase of IL-6 secretion. At 7 days, a reduced number of granulomas and an increased number of bacteria was observed with respect to uncoated BCG environment. Altogether, these results showed that plasmin(ogen) on the mycobacterial surface affects phagocytosis, granuloma development and the cytokine context, thus resulting in an increased number of bacteria in granulomas.
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Fibrinolisina/metabolismo , Granuloma/microbiología , Mycobacterium bovis/metabolismo , Fagocitosis/fisiología , Plasminógeno/metabolismo , Tuberculosis/microbiología , Células Cultivadas , Citocinas/biosíntesis , Granuloma/inmunología , Humanos , Macrófagos/microbiología , Mycobacterium bovis/aislamiento & purificación , Tuberculina , Tuberculosis/inmunología , Tuberculosis/metabolismoRESUMEN
CD8+ T cell-mediated immune response plays a major role in the clearance of virus-infected cells, including human papillomavirus (HPV). The effective treatment of women with normal cytology but persistent high risk-HPV infection or with low-grade intraepithelial lesions could take advantage of novel strategies based on vaccination with viral immunological targets with a wide spectrum of cross-protection. The helicase E1, expressed early during viral replication in HPV infection, is among the most conserved papillomavirus proteins, which makes it a good vaccine candidate. In the present study, we examined E1-specific CD8+ T cell and NK immune responses in a mouse model with α-galactosylceramide (α-GalCer) as an adjuvant. We found that mice immunized with E1 combined with α-GalCer elicited an E1-specific CD8+ T and NK cell cytotoxic responses, which correlated with growth inhibition of grafted melanoma B16-F0 cells expressing E1, both in prophylactic and therapeutic protocols.
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Vacunas contra el Cáncer/inmunología , Citotoxicidad Inmunológica , Galactosilceramidas/administración & dosificación , Proteínas Oncogénicas Virales/inmunología , Linfocitos T Citotóxicos/inmunología , Adyuvantes Inmunológicos/administración & dosificación , Animales , Femenino , Galactosilceramidas/inmunología , Papillomavirus Humano 18 , Humanos , Células Asesinas Naturales/inmunología , Melanoma Experimental/prevención & control , Melanoma Experimental/terapia , Melanoma Experimental/virología , Ratones , Ratones Endogámicos C57BL , Proteínas Oncogénicas Virales/administración & dosificación , Infecciones por Papillomavirus/inmunología , Infecciones por Papillomavirus/prevención & control , Infecciones por Papillomavirus/terapia , Trasplantes , Células Tumorales Cultivadas/inmunología , VacunaciónRESUMEN
Tuberculosis remains a serious threat worldwide. For this reason, it is necessary to identify agents that shorten the duration of treatment, strengthen the host immune system, and/or decrease the damage caused by the infection. Statins are drugs that reduce plasma cholesterol levels and have immunomodulatory, anti-inflammatory and antimicrobial effects. Although there is evidence that statins may contribute to the containment of Mycobacterium tuberculosis infection, their effects on peripheral blood mononuclear cells (PBMCs) involved in the immune response have not been previously described. Using PBMCs from 10 healthy subjects infected with M. tuberculosis H37Rv, we analyzed the effects of simvastatin on the treatment of the infections in an in vitro experimental model. Direct quantification of M. tuberculosis growth (in CFU/mL) was performed. Phenotypes and cell activation were assessed via multi-color flow cytometry. Culture supernatant cytokine levels were determined via cytokine bead arrays. The induction of apoptosis and autophagy was evaluated via flow cytometry and confocal microscopy. Simvastatin decreased the growth of M. tuberculosis in PBMCs, increased the proportion of NKT cells in culture, increased the expression of co-stimulatory molecules in monocytes, promoted the secretion of the cytokines IL-1ß and IL-12p70, and activated apoptosis and autophagy in monocytes, resulting in a significant reduction in bacterial load. We also observed an increase in IL-10 production. We did not observe any direct antimycobacterial activity. This study provides new insight into the mechanism through which simvastatin reduces the mycobacterial load in infected PBMCs. These results demonstrate that simvastatin activates several immune mechanisms that favor the containment of M. tuberculosis infection, providing relevant evidence to consider statins as candidates for host-directed therapy. They also suggest that future studies are needed to define the roles of statin-induced anti-inflammatory mechanisms in tuberculosis treatment.
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Obstructive sleep apnea syndrome (OSAS) is an independent and modifiable risk factor for cardiovascular diseases; however, the pathophysiological mechanisms underlying this association are not yet fully understood. Intermittent hypoxemia, one of the physiological markers of OSAS, is characterized by transient periods of oxygen desaturation followed by reoxygenation. The cycles of hypoxia-reoxygenation are associated with oxidative stress that, in turn, triggers the activation of pathways that lead to cardiovascular damage. These pathways include an increased chemoreflex sensitivity that induces the over-activation of the sympathetic nervous system, decreased baroreflex sensitivity, the activation of systemic inflammation pathways mediated primarily by the nuclear transcriptional factor kappaB that favors the development of atherosclerosis through the synthesis of cytokines and the expression of adhesion molecules, endothelial dysfunction with a decreased availability of nitric oxide, dyslipidemia, insulin resistance and stimulation of the renin-angiotensin system. Other mechanisms proposed include arousals that increase sympathetic activity and exaggerated intrathoracic pressure changes that generate high transmural pressure. Most of these mechanisms respond favorably to treatment with CPAP. A better understanding of the mechanisms of cardiovascular damage opens the possibility of instituting new treatments that will contribute to limiting the cardiovascular consequences associated with OSAS.
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Enfermedades Cardiovasculares/etiología , Apnea Obstructiva del Sueño/fisiopatología , Animales , Aterosclerosis/etiología , Aterosclerosis/fisiopatología , Barorreflejo/fisiología , Enfermedades Cardiovasculares/fisiopatología , Moléculas de Adhesión Celular/fisiología , Presión de las Vías Aéreas Positiva Contínua , Citocinas/fisiología , Dislipidemias/etiología , Dislipidemias/fisiopatología , Humanos , Hipoxia/etiología , Hipoxia/fisiopatología , Inflamación/etiología , Inflamación/fisiopatología , Resistencia a la Insulina , FN-kappa B/metabolismo , Óxido Nítrico/metabolismo , Estrés Oxidativo , Presión , Ratas , Ratas Sprague-Dawley , Reflejo Anormal , Sistema Renina-Angiotensina/fisiología , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/metabolismo , Apnea Obstructiva del Sueño/terapia , Sistema Nervioso Simpático/fisiopatologíaRESUMEN
A variety of receptors perform the function of attenuating or inhibiting activation of cells in which they are expressed. Examples of these kinds of receptors include TIM-3 and PD-1, among others that have been widely studied in cells of lymphoid origin and, though to a lesser degree, in other cell lines. Today, several studies describe the function of these molecules as part of the diverse mechanisms of immune tolerance that exist in the immune system. This review analyzes the function of some of these proteins in monocytes and macrophages and as well as their participation as inhibitory molecules or elements of immunological tolerance that also act in innate defense mechanisms. We chose the receptors TIM-3, PD-1, CD32b, and CD200R because these molecules have distinct functional characteristics that provide examples of the different regulating mechanisms in monocytes and macrophages.
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Antígenos de Superficie/metabolismo , Receptor 2 Celular del Virus de la Hepatitis A/metabolismo , Macrófagos/inmunología , Monocitos/inmunología , Receptores de Superficie Celular/metabolismo , Receptores de IgG/metabolismo , Animales , Humanos , Tolerancia Inmunológica , Inmunidad Innata , Activación de Macrófagos , Receptores de Orexina , Receptor de Muerte Celular Programada 1/metabolismo , Transducción de SeñalRESUMEN
Tuberculosis is one of the 10 leading causes of death in the world. The current treatment is based on a combination of antimicrobials administered for six months. It is essential to find therapeutic agents with which the treatment time can be shortened and strengthen the host immune response against Mycobacterium tuberculosis. M. tuberculosis needs cholesterol to infect and survive inside the host, but the progression of the infection depends to a large extent on the capacity of the immune response to contain the infection. Statins inhibit the synthesis of cholesterol and have pleiotropic effects on the immune system, which have been associated with better results in the treatment of several infectious diseases. Recently, it has been reported that cells treated with statins are more resistant to M. tuberculosis infection, and they have even been proposed as adjuvants in the treatment of M. tuberculosis infection. The aim of this review is to summarize the immunopathogenesis of tuberculosis and its mechanisms of evasion and to compile the available scientific information on the effect of statins in the treatment of tuberculosis.