RESUMEN
Activation of T cells requires both TCR-specific ligation and costimulation through accessory molecules during T cell priming. IFNgamma is a key cytokine responsible for macrophage activation during Mycobacterium tuberculosis (Mtb) infection while IL-10 is associated with suppression of cell mediated immunity in intracellular infection. In this paper we evaluated the role of IFNgamma and IL-10 on the function of cytotoxic T cells (CTL) and on the modulation of costimulatory molecules in healthy controls and patients with active tuberculosis (TB). gamma-irradiated-Mtb (i-Mtb) induced IL-10 production from CD14(+) cells from TB patients. Moreover, CD3(+) T cells of patients with advanced disease also produced IL-10 after i-Mtb stimulation. In healthy donors, IL-10 decreased the lytic activity of CD4(+) and CD8(+) T cells whereas it increased gammadelta-mediated cytotoxicity. Furthermore, we found that the presence of IL-10 induced a loss of the alternative processing pathways of antigen presentation along with a down-regulation of the expression of costimulatory molecule expression on monocytes and macrophages from healthy individuals. Conversely, neutralization of endogenous IL-10 or addition of IFNgamma to either effector or target cells from TB patients induced a strong lytic activity mediated by CD8(+) CTL together with an up-regulation of CD54 and CD86 expression on target cells. Moreover, we observed that macrophages from TB patients could use alternative pathways for i-Mtb presentation. Taken together, our results demonstrate that the presence of IL-10 during Mtb infection might contribute to mycobacteria persistence inside host macrophages through a mechanism that involved inhibition of MHC-restricted cytotoxicity against infected macrophages.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Macrófagos/inmunología , Mycobacterium tuberculosis/inmunología , Linfocitos T Citotóxicos/inmunología , Tuberculosis Pulmonar/inmunología , Adulto , Anciano , Presentación de Antígeno/inmunología , Antígenos CD/inmunología , Antígeno B7-2 , Complejo CD3/inmunología , Antígenos CD40/inmunología , Humanos , Molécula 1 de Adhesión Intercelular/inmunología , Interferón gamma/inmunología , Interleucina-10 , Leucocitos Mononucleares/inmunología , Receptores de Lipopolisacáridos/inmunología , Activación de Linfocitos/inmunología , Glicoproteínas de Membrana/inmunología , Persona de Mediana EdadRESUMEN
Induction of Th1 cytokines, those associated with cell-mediated immunity, is critical for host defense against infection by intracellular pathogens, including mycobacteria. Signaling lymphocytic activation molecule (SLAM, CD150) is a transmembrane protein expressed on lymphocytes that promotes T cell proliferation and IFN-gamma production. The expression and role of SLAM in human infectious disease were investigated using leprosy as a model. We found that SLAM mRNA and protein were more strongly expressed in skin lesions of tuberculoid patients, those with measurable CMI to the pathogen, Mycobacterium leprae, compared with lepromatous patients, who have weak CMI against M. leprae. Peripheral blood T cells from tuberculoid patients showed a striking increase in the level of SLAM expression after stimulation with M. leprae, whereas the expression of SLAM on T cells from lepromatous patients show little change by M. leprae stimulation. Engagement of SLAM by an agonistic mAb up-regulated IFN-gamma production from tuberculoid patients and slightly increased the levels of IFN-gamma in lepromatous patients. In addition, IFN-gamma augmented SLAM expression on M. leprae-stimulated peripheral blood T cells from leprosy patients. Signaling through SLAM after IFN-gamma treatment of Ag-stimulated cells enhanced IFN-gamma production in lepromatous patients to the levels of tuberculoid patients. Our data suggest that the local release of IFN-gamma by M. leprae-activated T cells in tuberculoid leprosy lesions leads to up-regulation of SLAM expression. Ligation of SLAM augments IFN-gamma production in the local microenvironment, creating a positive feedback loop. Failure of T cells from lepromatous leprosy patients to produce IFN-gamma in response to M. leprae contributes to reduced expression of SLAM. Therefore, the activation of SLAM may promote the cell-mediated immune response to intracellular bacterial pathogens.
Asunto(s)
Glicoproteínas/biosíntesis , Inmunoglobulinas/biosíntesis , Interferón gamma/biosíntesis , Lepra/inmunología , Células TH1/inmunología , Anticuerpos/farmacología , Antígenos Bacterianos/inmunología , Antígenos CD , Células Cultivadas , Citocinas/farmacología , Glicoproteínas/genética , Humanos , Inmunoglobulinas/genética , Interferón gamma/inmunología , Interferón gamma/fisiología , Lepra/genética , Lepra/patología , Mycobacterium leprae/inmunología , ARN Mensajero/biosíntesis , Receptores de Superficie Celular , Miembro 1 de la Familia de Moléculas Señalizadoras de la Activación Linfocitaria , Regulación hacia ArribaRESUMEN
The Authors report the results on 20 patients affected by myasthenia gravis treated by radiotherapy following the method of Bollini (1945). This treatment obtained good results in 90% of the cases. There were no deaths during therapy nor "radiation disease". The advantages of this technique of radiotherapy in comparison to other methods of radiotherapy and to surgical and steroid therapy are presented and briefly discussed.
Asunto(s)
Miastenia Gravis/radioterapia , Adolescente , Hormona Adrenocorticotrópica/uso terapéutico , Adulto , Anciano , Femenino , Humanos , Masculino , Métodos , Persona de Mediana Edad , Miastenia Gravis/terapia , TimectomíaRESUMEN
Changes on specific radioactivity and levels of free nucleotides and polyamines in infarcted and borderline tissue of reperfused dog heart. The changes on specific radioactivity and levels of free nucleotides and polyamines, spermine and spermidine, of reperfused heart show a different behaviour of the anoxic myocardium. An increase of both specific activity and levels of free nucleotides and polyamines after 30 minutes of ischemia is observed. A longer period of anoxia (6 hours) causes a decreased synthesis and concentration of free nucleotides and polyamines. A remarkable recovery of specific activity of these compounds after reperfusion is noted. The borderline tissue shows a similar behaviour but with smaller changes. Therefore, in our experimental conditions, ischemia does not cause an irreversible alteration in protein synthesis mechanism of myocardial cells. In addition, the reperfusion may cause a recovery of biochemical mechanisms that control the functional capacity of the cell. The polyamine changes may postulate a central role of these amines in both anoxic and reperfused heart.