RESUMO
Tuberculosis (TB) is one of the world's most pernicious diseases mainly due to immune evasion strategies displayed by its causative agent Mycobacterium tuberculosis (Mtb). Blood monocytes (Mos) represent an important source of DCs during chronic infections; consequently, the alteration of their differentiation constitutes an escape mechanism leading to mycobacterial persistence. We evaluated whether the CD16(+)/CD16(-) Mo ratio could be associated with the impaired Mo differentiation into DCs found in TB patients. The phenotype and ability to stimulate Mtb-specific memory clones DCs from isolated Mo subsets were assessed. We found that CD16(-) Mos differentiated into CD1a(+) DC-SIGN(high) cells achieving an efficient recall response, while CD16(+) Mos differentiated into a CD1a(-) DC-SIGN(low) population characterized by a poor mycobacterial Ag-presenting capacity. The high and sustained phosphorylated p38 expression observed in CD16(+) Mos was involved in the altered DC profile given that its blockage restored DC phenotype and its activation impaired CD16(-) Mo differentiation. Furthermore, depletion of CD16(+) Mos indeed improved the differentiation of Mos from TB patients toward CD1a(+) DC-SIGN(high) DCs. Therefore, Mos from TB patients are less prone to differentiate into DCs due to their increased proportion of CD16(+) Mos, suggesting that during Mtb infection Mo subsets may have different fates after entering the lungs.
Assuntos
Células Dendríticas/patologia , Monócitos/patologia , Receptores de IgG/metabolismo , Tuberculose/imunologia , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Adulto , Antígenos CD1/imunologia , Antígenos CD1/metabolismo , Diferenciação Celular/imunologia , Células Dendríticas/enzimologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Monócitos/enzimologia , Monócitos/imunologia , Monócitos/metabolismo , Mycobacterium tuberculosis/imunologia , Receptores de IgG/imunologia , Transdução de Sinais/imunologia , Transdução de Sinais/fisiologia , Tuberculose/enzimologia , Tuberculose/metabolismo , Tuberculose/microbiologia , Adulto Jovem , Proteínas Quinases p38 Ativadas por Mitógeno/imunologiaRESUMO
The interaction between immune complexes (IC) and the receptors for the Fc portion of IgG (FcgammaRs) triggers regulatory and effector functions in the immune system. In this study, we investigated the effects of IC on differentiation, maturation, and functions of human monocyte-derived dendritic cells (DC). When IC were added on day 0, DC generated on day 6 (IC-DC) showed lower levels of CD1a and increased expression of CD14, MHC class II, and the macrophage marker CD68, as compared with normally differentiated DC. The use of specific blocking FcgammaR mAbs indicated that the effect of IC was exerted mainly through their interaction with FcgammaRI and to a lesser extend with FcgammaRII. Immature IC-DC also expressed higher levels of CD83, CD86, and CD40 and the expression of these maturation markers was not further regulated by LPS. The apparent lack of maturation following TLR stimulation was associated with a decreased production of IL-12, normal secretion of IL-10 and CCL22, and increased production of CXCL8 and CCL2. IC-DC displayed low endocytic activity and a reduced ability to induce allogeneic T cell proliferation both at basal and LPS-stimulated conditions. Altogether, these data reveal that IC strongly affect DC differentiation and maturation. Skewing of DC function from Ag presentation to a proinflammatory phenotype by IC resembles the state of activation observed in DC obtained from patients with chronic inflammatory autoimmune disorders, such as systemic lupus erythematosus disease and arthritis. Therefore, the altered maturation of DC induced by IC may be involved in the pathogenesis of autoimmune diseases.
Assuntos
Complexo Antígeno-Anticorpo/fisiologia , Diferenciação Celular/imunologia , Linhagem da Célula/imunologia , Células Dendríticas/citologia , Células Dendríticas/imunologia , Inibidores do Crescimento/fisiologia , Monócitos/citologia , Monócitos/imunologia , Animais , Complexo Antígeno-Anticorpo/sangue , Doenças Autoimunes/imunologia , Doenças Autoimunes/metabolismo , Doenças Autoimunes/patologia , Células Cultivadas , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Relação Dose-Resposta Imunológica , Inibidores do Crescimento/sangue , Humanos , Imunoglobulina G/metabolismo , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Lúpus Eritematoso Sistêmico/patologia , Ativação Linfocitária/imunologia , Teste de Cultura Mista de Linfócitos , Monócitos/metabolismo , Monócitos/patologia , Coelhos , Receptores de IgG/antagonistas & inibidores , Receptores de IgG/biossíntese , Receptores de IgG/fisiologia , Linfócitos T/imunologia , Fatores de TempoRESUMO
Although animals can be prophylactically immunized against the growth of tumor implants, most of the attempts to use immunotherapy to cause the regression of animal and human tumors once they become established have been unsuccessful. To understand the nature of this refractoriness we have studied a methylcholanthrene-induced and strongly immunogenic murine fibrosarcoma. In our model, the onset of this refractoriness was associated with the beginning of an immunosuppressive state known as "immunological eclipse" characterized by a loss of the antitumor immune response when tumor grows beyond a critical size. This immunological eclipse was accompanied by the emergence of a systemic inflammatory condition. Treatment of tumor-bearing mice with a single dose of a synthetic corticosteroid, dexamethasone (DX), reduced significantly all parameters of systemic inflammation and simultaneously reversed the immunological eclipse. The reversion of the eclipse upon DX treatment was not curative itself, but allowed an immunological therapy based in dendritic cells pulsed with tumor antigens, which was itself absolutely ineffective, to exert a significant inhibitory effect against an established growing tumor. The two-step schedule using an anti-inflammatory treatment to reverse the immunological eclipse plus a dendritic cell-based vaccination strategy aimed to stimulate the antitumor immune response, could serve eventually as a model of immunotherapy against animal and human tumors.
Assuntos
Vacinas Anticâncer/uso terapêutico , Células Dendríticas/imunologia , Fibrossarcoma/tratamento farmacológico , Tolerância Imunológica/imunologia , Sarcoma Experimental/tratamento farmacológico , Animais , Anti-Inflamatórios/imunologia , Anti-Inflamatórios/uso terapêutico , Vacinas Anticâncer/imunologia , Carcinógenos , Dexametasona/imunologia , Dexametasona/uso terapêutico , Intervalo Livre de Doença , Fibrossarcoma/induzido quimicamente , Fibrossarcoma/imunologia , Tolerância Imunológica/efeitos dos fármacos , Inflamação/tratamento farmacológico , Metilcolantreno , Camundongos , Camundongos Endogâmicos BALB C , Sarcoma Experimental/induzido quimicamente , Sarcoma Experimental/imunologiaRESUMO
Aunque existen vacunas para prevenir la aparición de tumores en animales de experimentación, la mayoría de los intentos por aplicar aquellas vacunas con fines terapéuticos contra tumores establecidos no han sido exitosos. Para comprender la naturaleza de esta refractariedad, estudiamos un tumor de ratón fuertemente inmunogénico inducido por el carcinógeno químico metilcolantreno. En nuestro modelo, el inicio de esta refractariedad coincidió con el comienzo de un estado de inmunosupresión conocido como "eclipse inmunológico" caracterizado por una pérdida o bloqueo de la respuesta inmune antitumoral después que el tumor ha superado cierto tamaño crítico. Este eclipse inmunológico fue acompañado por un proceso de inflamación sistémica en el organismo. El tratamiento de los ratones portadores de tumor con una única dosis del corticoide sintético dexametasona (DX) redujo los parámetros de inflamación sistémica e indujo la reversión del eclipse. Esta reversión no fue por sí misma curativa pero permitió que un tratamiento inmunológico basado en células dendríticas estimuladas con antígenos tumorales, que por sí solo era absolutamente ineficaz, pudiera ejercer un significativo efecto inhibidor sobre un tumor en crecimiento. El esquema de dos pasos que comprende, primero, un tratamiento antiinflamatorio para revertir el eclipse y segundo, una estrategia de vacunación basada en células dendríticas destinada a estimular la respuesta inmune antitumoral, podría servir, eventualmente, como un modelo de inmunoterapia contra tumores en animales y seres humanos.
Although animals can be prophylactically immunized against the growth of tumor implants, most of the attempts to use immunotherapy to cause the regression of animal and human tumors once they become established have been unsuccessful. To understand the nature of this refractoriness we have studied a methylcholanthrene-induced and strongly immunogenic murine fibrosarcoma. In our model, the onset of this refractoriness was associated with the beginning of an immunosuppressive state known as "immunological eclipse" characterized by a loss of the antitumor immune response when tumor grows beyond a critical size. This immunological eclipse was accompanied by the emergence of a systemic inflammatory condition. Treatment of tumor-bearing mice with a single dose of a synthetic corticosteroid, dexamethasone (DX), reduced significantly all parameters of systemic inflammation and simultaneously reversed the immunological eclipse. The reversion of the eclipse upon DX treatment was not curative itself, but allowed an immunological therapy based in dendritic cells pulsed with tumor antigens, which was itself absolutely ineffective, to exert a significant inhibitory effect against an established growing tumor. The two-step schedule using an anti-inflammatory treatment to reverse the immunological eclipse plus a dendritic cell-based vaccination strategy aimed to stimulate the anti-tumor immune response, could serve eventually as a model of immunotherapy against animal and human tumors.
Assuntos
Humanos , Animais , Camundongos , Anti-Inflamatórios/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Células Dendríticas/imunologia , Dexametasona/uso terapêutico , Fibrossarcoma/tratamento farmacológico , Terapia de Imunossupressão/métodos , Sarcoma Experimental/tratamento farmacológico , Anti-Inflamatórios/imunologia , Vacinas Anticâncer/imunologia , Intervalo Livre de Doença , Dexametasona/imunologia , Fibrossarcoma/imunologia , Inflamação/tratamento farmacológico , Camundongos Endogâmicos BALB C , Metilcolantreno/efeitos adversos , Sarcoma Experimental/imunologiaRESUMO
Aunque existen vacunas para prevenir la aparición de tumores en animales de experimentación, la mayoría de los intentos por aplicar aquellas vacunas con fines terapéuticos contra tumores establecidos no han sido exitosos. Para comprender la naturaleza de esta refractariedad, estudiamos un tumor de ratón fuertemente inmunogénico inducido por el carcinógeno químico metilcolantreno. En nuestro modelo, el inicio de esta refractariedad coincidió con el comienzo de un estado de inmunosupresión conocido como "eclipse inmunológico" caracterizado por una pérdida o bloqueo de la respuesta inmune antitumoral después que el tumor ha superado cierto tamaño crítico. Este eclipse inmunológico fue acompañado por un proceso de inflamación sistémica en el organismo. El tratamiento de los ratones portadores de tumor con una única dosis del corticoide sintético dexametasona (DX) redujo los parámetros de inflamación sistémica e indujo la reversión del eclipse. Esta reversión no fue por sí misma curativa pero permitió que un tratamiento inmunológico basado en células dendríticas estimuladas con antígenos tumorales, que por sí solo era absolutamente ineficaz, pudiera ejercer un significativo efecto inhibidor sobre un tumor en crecimiento. El esquema de dos pasos que comprende, primero, un tratamiento antiinflamatorio para revertir el eclipse y segundo, una estrategia de vacunación basada en células dendríticas destinada a estimular la respuesta inmune antitumoral, podría servir, eventualmente, como un modelo de inmunoterapia contra tumores en animales y seres humanos.(AU)
Although animals can be prophylactically immunized against the growth of tumor implants, most of the attempts to use immunotherapy to cause the regression of animal and human tumors once they become established have been unsuccessful. To understand the nature of this refractoriness we have studied a methylcholanthrene-induced and strongly immunogenic murine fibrosarcoma. In our model, the onset of this refractoriness was associated with the beginning of an immunosuppressive state known as "immunological eclipse" characterized by a loss of the antitumor immune response when tumor grows beyond a critical size. This immunological eclipse was accompanied by the emergence of a systemic inflammatory condition. Treatment of tumor-bearing mice with a single dose of a synthetic corticosteroid, dexamethasone (DX), reduced significantly all parameters of systemic inflammation and simultaneously reversed the immunological eclipse. The reversion of the eclipse upon DX treatment was not curative itself, but allowed an immunological therapy based in dendritic cells pulsed with tumor antigens, which was itself absolutely ineffective, to exert a significant inhibitory effect against an established growing tumor. The two-step schedule using an anti-inflammatory treatment to reverse the immunological eclipse plus a dendritic cell-based vaccination strategy aimed to stimulate the anti-tumor immune response, could serve eventually as a model of immunotherapy against animal and human tumors. (AU)