RESUMEN

Tuberculosis (TB) caused by Mycobacterium tuberculosis is a health problem worldwide. Patients with pulmonary TB show a neuro-immune-endocrine imbalance characterized by an impaired cellular immunity together with increased plasma levels of cortisol, pro- and anti-inflammatory cytokines and markedly decreased dehydroepiandrosterone (DHEA) levels. Extending these findings, we now investigated the immune-endocrine profile of TB patients undergoing specific treatment. Patients (n = 24) were bled at diagnosis (T0), 2, 4, 6 months after treatment initiation and 3 months following its completion. At T0, TB patients showed increased plasma levels of interleukin-6 (IL-6), C reactive protein, interferon-gamma (IFN-γ) and transforming growth factor beta (TGF-ß). These mediators decreased during treatment, reaching levels similar to those from healthy controls (n = 26). Specific treatment led to an increased lymphoproliferative response along with clinical improvement. Newly diagnosed patients had low levels of DHEA, with increased cortisol amounts and cortisol/DHEA ratio, which normalized upon specific treatment. As regards glucocorticoid receptors (GR), TB patients at diagnosis presented a reduced mRNA GRα/GRß ratio in their peripheral blood mononuclear cells. Furthermore, multivariate analysis showed that cortisol/DHEA ratio was positively associated with inflammatory mediators for which this ratio may constitute a disease biomarker. Anti-mycobacterial treatment results in a better immune-endocrine scenario for the control of physiopathological processes accompanying disease development and hence implied in clinical recovery.

Asunto(s)

Antituberculosos/uso terapéutico , Regulación de la Expresión Génica/efectos de los fármacos , Leucocitos Mononucleares/efectos de los fármacos , Mycobacterium tuberculosis/efectos de los fármacos , Tuberculosis Pulmonar/tratamiento farmacológico , Adulto , Proteína C-Reactiva/genética , Proteína C-Reactiva/inmunología , Estudios de Casos y Controles , Deshidroepiandrosterona/sangre , Etambutol/uso terapéutico , Femenino , Regulación de la Expresión Génica/inmunología , Humanos , Hidrocortisona/sangre , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Isoniazida/uso terapéutico , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/microbiología , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/crecimiento & desarrollo , Mycobacterium tuberculosis/patogenicidad , Pirazinamida/uso terapéutico , Receptores de Glucocorticoides/genética , Receptores de Glucocorticoides/inmunología , Rifampin/uso terapéutico , Factor de Crecimiento Transformador beta/genética , Factor de Crecimiento Transformador beta/inmunología , Resultado del Tratamiento , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/microbiología , Tuberculosis Pulmonar/patología

RESUMEN

Tuberculosis (TB) is a major health problem requiring an appropriate cell immune response (IR) to be controlled. Since regulatory T cells (Tregs) are relevant in IR regulation, we analyzed Tregs variations throughout the course of TB treatment and its relationship with changes in immune-endocrine mediators dealing with disease immunopathology. The cohort was composed of 41 adult patients, 20 of them completing treatment and follow-up. Patients were bled at diagnosis (T0) and at 2 (T2), 4 (T4), 6 (T6), and 9 months following treatment initiation. Twenty-four age- and sex-matched healthy controls (HCo) were also included. Tregs (flow cytometry) from TB patients were increased at T0 (versus HCo P < 0.05), showing even higher values at T2 (versus T0 P < 0.01) and T4 (versus T0 P < 0.001). While IL-6, IFN-γ, TGF-ß (ELISA), and Cortisol (electrochemiluminescence, EQ) were augmented, DHEA-S (EQ) levels were diminished at T0 with respect to HCo, with cytokines and Cortisol returning to normal values at T9. Tregs correlated positively with IFN-γ (R = 0.868, P < 0.05) at T2 and negatively at T4 (R = -0.795, P < 0.05). Lowered levels of proinflammatory cytokines together with an increased frequency of Tregs of patients undergoing specific treatment might reflect a downmodulatory effect of these cells on the accompanying inflammation.

Asunto(s)

Antituberculosos/uso terapéutico , Linfocitos T Reguladores/inmunología , Tuberculosis Pulmonar/tratamiento farmacológico , Tuberculosis Pulmonar/inmunología , Adulto , Antígenos CD4/metabolismo , Sulfato de Deshidroepiandrosterona/sangre , Femenino , Citometría de Flujo , Factores de Transcripción Forkhead/metabolismo , Humanos , Hidrocortisona/sangre , Interferón gamma/sangre , Subunidad alfa del Receptor de Interleucina-2/metabolismo , Interleucina-6/sangre , Pulmón/patología , Masculino , Persona de Mediana Edad , Factor de Crecimiento Transformador beta/sangre , Tuberculosis Pulmonar/patología , Adulto Joven

RESUMEN

Supernatants (SN) from cultures of peripheral blood mononuclear cells (PBMC) of tuberculosis (TB) patients inhibit dehydroepiandrosterone (DHEA) secretion by the adrenal cell line NCI-H295R. To analyze whether TGF-ß is involved in this effect, SN of PBMC from healthy controls or patients with severe TB infections, stimulated or not with Mycobacterium tuberculosis (Mtb SN), were added to adrenal cells under basal conditions or following stimulation with forskolin. Cortisol and DHEA concentrations were evaluated in supernatants of the adrenal cells cultured with or without the addition of anti-TGF-ß. Treatment with Mtb SN from TB inhibited DHEA production, and this effect was reversed when SN were treated with anti-TGF-ß. The increase in cortisol production induced by SN from TB patients was not affected by TGF-ß neutralization. Mediators released during the anti-TB immune response differentially modulate steroid production by adrenal cells, and TGF-ß is a cytokine implicated in the inhibition of DHEA production observed in TB.

Asunto(s)

Deshidroepiandrosterona/biosíntesis , Leucocitos Mononucleares/inmunología , Leucocitos Mononucleares/microbiología , Mycobacterium tuberculosis/inmunología , Factor de Crecimiento Transformador beta/antagonistas & inhibidores , Glándulas Suprarrenales/citología , Glándulas Suprarrenales/efectos de los fármacos , Glándulas Suprarrenales/metabolismo , Adulto , Estudios de Casos y Controles , Línea Celular , Colforsina/farmacología , Medios de Cultivo Condicionados , Deshidroepiandrosterona/metabolismo , Femenino , Interacciones Huésped-Patógeno/inmunología , Humanos , Hidrocortisona/biosíntesis , Técnicas In Vitro , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Pruebas de Neutralización , Tuberculosis Pulmonar/inmunología , Tuberculosis Pulmonar/microbiología

RESUMEN

We evaluated immune and endocrine status following antituberculosis treatment in HIV-negative patients with newly diagnosed tuberculosis (TB). Treatment led to a decrease in IL-6, IL-1ß, and C-reactive protein levels. Cortisol levels decreased throughout the anti-TB treatment, particularly after 4 months, but changes were less pronounced than those seen in proinflammatory mediators. Specific therapy resulted in increased dehydroepiandrosterone (DHEA) levels, which peaked after 4 months and started to decline after 6 months of treatment, reaching levels below those detected at inclusion. In contrast, in most patients, dehydroepiandrosterone sulfate (DHEAS) levels remained unchanged, although a trend toward increased concentrations was observed in a few cases 3 months after the treatment was finished. Specific therapy also resulted in more balanced cortisol/DHEA and cortisol/DHEAS ratios. Etiologic treatment involves favorable immune and endocrine changes, which may account for its beneficial effects.

Asunto(s)

Corticoesteroides/sangre , Mediadores de Inflamación/sangre , Tuberculosis Pulmonar/sangre , Tuberculosis Pulmonar/inmunología , Adulto , Antituberculosos/uso terapéutico , Proteína C-Reactiva/metabolismo , Estudios de Casos y Controles , Deshidroepiandrosterona/sangre , Sulfato de Deshidroepiandrosterona/sangre , Femenino , Humanos , Hidrocortisona/sangre , Interleucina-1beta/sangre , Interleucina-6/sangre , Masculino , Persona de Mediana Edad , Tuberculosis Pulmonar/tratamiento farmacológico , Adulto Joven

RESUMEN

This article describes the first use of heat-killed, borate-buffered preparations of aerobic actinomycetales to immunize pregnant animals in order to determine the effect on their pregnancy and fertility and the survival coefficients of their offspring. Pregnant rats received three injections of Gordonia bronchialis, Rhodococcus coprophylus or physiological saline and a proportion of their offspring were challenged with live Trypanosoma cruzi at the time of weaning. Levels of parasitemia and, in some animals, of the cytokines IFN-γ and IL-10 were measured. The progress of pregnancy, fertility and survival of offspring were unaffected by the maternal immunizations. The offspring of rats immunized with G. bronchialis displayed significantly reduced parasitemias, with increased levels of IFN-γ and reduced levels of IL-10, 4 days after challenge. The offspring of rats immunized with R. coprophylus displayed greater parasitemias than did those of the control group. These unexpected results are discussed and their causation considered.

Asunto(s)

Actinomycetales/inmunología , Enfermedad de Chagas/prevención & control , Factores Inmunológicos/administración & dosificación , Factores Inmunológicos/inmunología , Parasitemia/prevención & control , Trypanosoma cruzi/patogenicidad , Animales , Anticuerpos Antiprotozoarios/sangre , Enfermedad de Chagas/inmunología , Enfermedad de Chagas/parasitología , Modelos Animales de Enfermedad , Femenino , Bacteria Gordonia/inmunología , Interferón gamma/sangre , Interleucina-10/sangre , Masculino , Intercambio Materno-Fetal , Parasitemia/inmunología , Parasitemia/parasitología , Embarazo , Ratas , Rhodococcus/inmunología

RESUMEN

We have analyzed the expression of glucocorticoid receptor (GR) isoforms by real time RT-qPCR in PBMCs from 19 controls (HCo) and 28 TB patients (8 mild; 12 moderate; 8 severe), HIV(-) and similar sex and age distribution. mRNA hGRα/ß ratios were found higher in TB patients respect to those in HCo. However, when analyzing for disease severity such overall trend was at the expense of mild and moderate patients, with severe cases showing a lower mRNA hGRα/ß ratio with respect to the other patient groups. This suggested some degree of resistance to endogenous glucocorticoids in patients with severe TB, since hGRαα dimer mediates the biological functions of GC, with the GRß isoform acting as an inhibitor of GC activity. Levels of IL-6, IL-18, IFN-γ and Cortisol were significantly increased in severe and moderate cases, whereas DHEA values were found decreased in them (p<0.05 respect to HCo). Analysis on the relationship between plasma levels of these immuno-endocrine mediators with the mRNA expression of hGRα and hGRß showed that IL-6 was positively associated with hGRα in mild TB patients (p<0.01), whereas a negative correlation between IFN-γ and hGRß was observed in severe cases (p<0.01). As regard to hormones, DHEA was positively associated with hGRα in moderate and severe cases (p<0.01). This group also showed a negative correlation between hGRα and Cortisol/DHEA ratios (p<0.05). Changes in the systemic levels of cytokine and adrenal hormones are likely to affect GR expression in a differential fashion and according to the amount of pulmonary involvement.

Asunto(s)

Leucocitos Mononucleares/metabolismo , Receptores de Glucocorticoides/metabolismo , Tuberculosis/metabolismo , Adulto , Citocinas/sangre , Deshidroepiandrosterona/sangre , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Hidrocortisona/sangre , Leucocitos Mononucleares/inmunología , Masculino , Persona de Mediana Edad , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , ARN Mensajero/metabolismo , Receptores de Glucocorticoides/genética , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Índice de Severidad de la Enfermedad , Estadísticas no Paramétricas , Tuberculosis/genética , Tuberculosis/inmunología

RESUMEN

Earlier studies revealed that patients with tuberculosis (TB) have imbalanced immunoendocrine responses and that adrenal steroids [cortisol and dehydroepiandrosterone (DHEA)] can modify their specific cell-mediated immune response. Because most household contacts (HHCs) of contagious TB patients develop a subclinical and self-controlled process (latent TB), we studied some features of their immune and endocrine responses, particularly those related to the hypothalamic-pituitary-adrenal axis. Nineteen HHCs, 24 untreated TB patients (15 moderate, 9 advanced), and 18 healthy controls of similar age were studied. Patients had increased and reduced levels of cortisol and DHEA, respectively. DHEA levels were also reduced in HHCs. Stimulation of peripheral blood mononuclear cells (PBMC) with Mycobacterium tuberculosis sonicate resulted in increased in vitro lymphoproliferation in HHCs, while advanced patients showed the lowest response. Significantly higher amounts of interferon (IFN)-gamma were detected in supernatants from stimulated PBMC of HHCs when compared to controls and TB patients. Addition of cortisol to the cultures inhibited mycobacterial antigen-driven IFN-gamma production in all groups, although HHC supernatant contained significantly higher concentrations. In contrast, addition of DHEA to cultures of cells from HHCs resulted in increased IFN-gamma levels. These results suggest the existence of a particular immunoendocrine relation assuring a preserved IFN-gamma production in healthy housemates of TB patients.

Asunto(s)

Deshidroepiandrosterona/inmunología , Composición Familiar , Hidrocortisona/inmunología , Interferón gamma/biosíntesis , Mycobacterium tuberculosis/inmunología , Tuberculosis/inmunología , Tuberculosis/microbiología , Adolescente , Adulto , Anciano , Antígenos Bacterianos/inmunología , Estudios de Casos y Controles , Proliferación Celular/efectos de los fármacos , Deshidroepiandrosterona/sangre , Deshidroepiandrosterona/farmacología , Femenino , Glucocorticoides/farmacología , Humanos , Hidrocortisona/sangre , Leucocitos Mononucleares/citología , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/microbiología , Masculino , Persona de Mediana Edad , Mycobacterium tuberculosis/efectos de los fármacos , Sonicación , Tuberculosis/sangre

RESUMEN

OBJECTIVE: To analyze whether the cyclophosphamide (CYC) induced reestablishment of adjuvant arthritis (AA) in chronically Trypanosoma cruzi infected rats correlates with changes in the secretion of pro- and antiinflammatory cytokines by popliteal lymph node cells. METHODS: Inbred "l" rats infected with T. cruzi 90 days earlier and age matched controls were given CYC (25 mg/kg body weight) or physiologic saline 48 h before arthritis induction. Popliteal lymph node cells were collected at the time of AA induction (48 h after CYC treatment) or during the peak response, to study the concanavalin-A (ConA) or Mycobacterium tuberculosis-driven in vitro proliferation of several cytokines in their culture supernatants. Results. Infected rats given CYC were recovered from the otherwise decreased ConA induced proliferation seen at the time of peak AA. The CYC mediated reestablishment of AA in T. cruzi infected rats coexisted with an increased presence of tumor necrosis factor-a in supernatants from either antigen or ConA stimulated cultures as well as interleukin 12 (IL-12) in the latter case. CYC also lowered to normal the increased IL-10 levels from ConA stimulated cultures that the T. cruzi group displayed at the time of inducing AA. Conclusion. The process by which CYC restores the clinical expression of AA affects the balance between cytokines that influence the regulation of arthritis in favor of the inflammatory component.

Asunto(s)

Antirreumáticos , Artritis Experimental/parasitología , Enfermedad de Chagas/complicaciones , Ciclofosfamida , Trypanosoma cruzi/inmunología , Animales , Antígenos/farmacología , Artritis Experimental/inducido químicamente , Artritis Experimental/inmunología , División Celular/efectos de los fármacos , División Celular/inmunología , Enfermedad de Chagas/inmunología , Enfermedad Crónica , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Interleucina-2/metabolismo , Ganglios Linfáticos/citología , Linfocitos/inmunología , Linfocitos/metabolismo , Masculino , Mitógenos/farmacología , Ratas , Ratas Endogámicas , Factor de Necrosis Tumoral alfa/metabolismo

RESUMEN

El fenómeno de inmunidad concomitante (IC) se define clásicamente como la capacidad que tiene un animal portador de un tumor progresor de inhibir el crecimiento de un segundo inóculo del mismo tumor. En dos líneas de ratas, que tienen distinto comportamiento al desafiarse con Sarcoma E 100 (SE 100), lnea IIMc: 90 por ciento de toma y 100 por ciento de regresión; línea "m": 100 por ciento de toma y muerte), se indujo IC a fin de establecer la participación del huésped en la generación de este fenómeno frente al mismo tumor. Las ratas recibieron el segundo desafío los días 3 ó 14, al igual que los respectivos grupos testigos. Los animales reinoculados el día 7 presentarón menor porcentagen de toma y menores superficies tumorales; además en las ratas IIMc se observó menor desarrollo del primer inóculo. El ensayo de Winn en ratas IIMc confirmó la presencia de células esplénicas (CE) comprometidas contra el SE 100 en los bazos de: ratas inmunes: portadoras de un solo tumor; de primer inóculo en crecimiento y segundo negativo en IC. En línea "m" el porcentagen de toma sólo fue menor en el grupo inoculado conjuntamente con el CE de ratas inmunes. Sólo un 10 por ciento (3/30) de ratas "m" pudieron inmunizarse contra el SE 100. Estos resultados perimitirían atribuir el fen¶meno de IC, en ratas IIMc, a mecanismos inmunitários y en ratas "m", de acuerdo a lo postulado por Gorelik, a un factor o factores liberados y/o inducidos por el primer tumor. Se sugiere que prevalecería uno u otro mecanismo según las características biológicas del huésped (AU)

Asunto(s)

Estudio Comparativo , Animales , Masculino , Ratas , Sarcoma Experimental/inmunología , Neoplasias del Bazo/inmunología , Inmunidad Celular , Siembra Neoplásica

RESUMEN

El fenómeno de inmunidad concomitante (IC) se define clásicamente como la capacidad que tiene un animal portador de un tumor progresor de inhibir el crecimiento de un segundo inóculo del mismo tumor. En dos líneas de ratas, que tienen distinto comportamiento al desafiarse con Sarcoma E 100 (SE 100), lnea IIMc: 90 por ciento de toma y 100 por ciento de regresión; línea "m": 100 por ciento de toma y muerte), se indujo IC a fin de establecer la participación del huésped en la generación de este fenómeno frente al mismo tumor. Las ratas recibieron el segundo desafío los días 3 ó 14, al igual que los respectivos grupos testigos. Los animales reinoculados el día 7 presentarón menor porcentagen de toma y menores superficies tumorales; además en las ratas IIMc se observó menor desarrollo del primer inóculo. El ensayo de Winn en ratas IIMc confirmó la presencia de células esplénicas (CE) comprometidas contra el SE 100 en los bazos de: ratas inmunes: portadoras de un solo tumor; de primer inóculo en crecimiento y segundo negativo en IC. En línea "m" el porcentagen de toma sólo fue menor en el grupo inoculado conjuntamente con el CE de ratas inmunes. Sólo un 10 por ciento (3/30) de ratas "m" pudieron inmunizarse contra el SE 100. Estos resultados perimitirían atribuir el fenômeno de IC, en ratas IIMc, a mecanismos inmunitários y en ratas "m", de acuerdo a lo postulado por Gorelik, a un factor o factores liberados y/o inducidos por el primer tumor. Se sugiere que prevalecería uno u otro mecanismo según las características biológicas del huésped

Asunto(s)

Animales , Masculino , Ratas , Neoplasias del Bazo/inmunología , Sarcoma Experimental/inmunología , Inmunidad Celular , Siembra Neoplásica