RESUMO
Myeloid-derived suppressor cells (MDSCs) accumulate in tumor-bearing hosts and play a major role in tumor-induced immunosuppression, which hampers effective immuno-therapeutic approaches. ß-Glucans have been reported to function as potent immuno-modulators to stimulate innate and adaptive immune responses, which contributes to their antitumor property. Here, we investigated the effect of particulate ß-glucans on MDSCs and found that ß-glucan treatment could promote the differentiation of M-MDSCs (monocytic MDSCs) into a more mature CD11c(+) F4/80(+) Ly6C(low) population via dectin-1 pathway in vitro, which is NF-κB dependent, and the suppressive function of M-MDSCs was significantly decreased. Treatment of orally administered yeast-derived particulate ß-glucan drastically downregulated MDSCs but increased the infiltrated DCs and macrophages in tumor-bearing mice, thus eliciting CTL and Th1 responses, inhibiting the suppressive activity of regulatory T cells, thereby leading to the delayed tumor progression. We show here for the first time that ß-glucans induce the differentiation of MDSCs and inhibit the regulatory function of MDSCs, therefore revealing a novel mechanism for ß-glucans in immunotherapy and suggesting their potential clinical benefit.
Assuntos
Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/imunologia , Diferenciação Celular/efeitos dos fármacos , Polissacarídeos Fúngicos/farmacologia , Fatores Imunológicos/farmacologia , Células Mieloides/efeitos dos fármacos , beta-Glucanas/farmacologia , Administração Oral , Animais , Antígeno CD11c/genética , Antígeno CD11c/imunologia , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/patologia , Movimento Celular/efeitos dos fármacos , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/patologia , Polissacarídeos Fúngicos/isolamento & purificação , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fatores Imunológicos/isolamento & purificação , Terapia de Imunossupressão , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/patologia , Camundongos , Células Mieloides/imunologia , Células Mieloides/patologia , NF-kappa B/genética , NF-kappa B/imunologia , Saccharomyces cerevisiae/química , Baço/efeitos dos fármacos , Baço/imunologia , Baço/patologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/patologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia , beta-Glucanas/isolamento & purificaçãoRESUMO
BACKGROUND: ß-Glucans have been shown to function as a potent immunomodulator to stimulate innate and adaptive immune responses, which contributes to their anti-tumor property. However, their mechanisms of action are still elusive. Glucocorticoid-induced TNF receptor ligand (GITRL), a member of the TNF superfamily, binds to its receptor, GITR, on both effector and regulatory T cells, generates a positive co-stimulatory signal implicated in a wide range of T cell functions, which is important for the development of immune responses. METHODOLOGY/PRINCIPAL FINDINGS: In this study, we found that whole ß-glucan particles (WGPs) could activate dendritic cells (DCs) via dectin-1 receptor, and increase the expression of GITRL on DCs in vitro and in vivo. Furthermore, we demonstrated that the increased GITRL on DCs could impair the regulartory T cell (Treg)-mediated suppression and enhance effector T cell proliferation in a GITR/GITRL dependent way. In tumor models, DCs with high levels of GITRL were of great potential to prime cytotoxic T lymphocyte (CTL) responses and down-regulate the suppressive activity of Treg cells, thereby leading to the delayed tumor progression. CONCLUSIONS/SIGNIFICANCE: These findings suggest that particulate ß-glucans can be used as an immunomodulator to stimulate potent T cell-mediated adaptive immunity while down-regulate suppressive immune activity via GITR/GITRL interaction, leading to a more efficient defense mechanism against tumor development.
Assuntos
Carcinoma Pulmonar de Lewis/tratamento farmacológico , Carcinoma Pulmonar de Lewis/imunologia , Células Dendríticas/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Fatores de Necrose Tumoral/genética , beta-Glucanas/uso terapêutico , Animais , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/patologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Fatores Imunológicos/imunologia , Fatores Imunológicos/isolamento & purificação , Lectinas Tipo C/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Saccharomyces cerevisiae/química , Saccharomyces cerevisiae/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Fatores de Necrose Tumoral/imunologia , Regulação para Cima/efeitos dos fármacos , beta-Glucanas/imunologia , beta-Glucanas/isolamento & purificaçãoRESUMO
Follicular helper T (Tfh) cells are recognized as a distinct CD4(+) helper T-cell subset, which provides for B-cell activation and production of specific antibody responses, and play a critical role in the development of autoimmune disease. So far, only one study investigated the circulating Tfh cells increased in a subset of SLE patients. Since relatively little is known about the Tfh cells in rheumatoid arthritis (RA) patients, in this study, Tfh-cell frequency, related cytokine IL-21, and transcription factor Bcl-6 were investigated in 53 patients with RA and 31 health controls. Firstly, we found that the frequency of CD4(+)CXCR5(+)ICOS(high) Tfh cells was increased significantly in the peripheral blood of RA patients, compared with that in healthy controls. It is known that Tfh cells are critical for directing the development of an antibody response by germinal centers B cells; secondly, we observed that the Tfh-cell frequency is accompanied by the level of anti-CCP antibody in RA patients. Furthermore, expression of Bcl-6 mRNA and plasma IL-21 concentrations in RA patients was increased. Taken together, these findings have shown that the increased frequency of circulating Tfh cells is correlated with elevated levels of anti-CCP antibody, indicating the possible involvement of Tfh cells in the disease progression of RA.
Assuntos
Artrite Reumatoide/diagnóstico , Artrite Reumatoide/imunologia , Proteínas de Ligação a DNA/metabolismo , Interleucinas/biossíntese , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Idoso , Autoanticorpos/sangue , Circulação Sanguínea , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Humanos , Proteína Coestimuladora de Linfócitos T Induzíveis/metabolismo , Interleucinas/sangue , Interleucinas/genética , Masculino , Pessoa de Meia-Idade , Proteínas Proto-Oncogênicas c-bcl-6 , Receptores CXCR5/metabolismo , Regulação para CimaRESUMO
Rheumatoid arthritis (RA), a chronic autoimmune form of inflammatory joint disease, progressively affects multiple joints with pathological changes in the synovia, cartilage, and bone. Numerous studies have suggested a critical role for glucocorticoid-induced tumor necrosis factor receptor family-related protein (GITR) in the pathogenesis of autoimmune arthritis by modulating both innate and adaptive immune reactions, but the underlying mechanisms by which GITR activation promotes arthritic progression remain largely unclear. In this study, we found that collagen-induced arthritis mice treated with the ligand of GITR (GITRL) displayed an earlier onset of arthritis with a markedly increased severity of arthritic symptoms and joint damage, in which significantly increased Th17 cells in both spleen and draining lymph nodes were observed. Notably, results showed that a marked expansion of Th17 cells with increased RORγt mRNA expression was induced from naïve CD4(+) T cells when cultured with GITRL. Consistently, normal mice that were treated with GITRL were found to display a substantial expansion of splenic Th17 cells. Furthermore, we detected elevated serum levels of GITRL in patients with RA, which were positively correlated with an increase in interleukin-17 production. Taken together, the results from this study have revealed a new function of GITRL in exacerbating autoimmune arthritis via the enhancement of the expansion of Th17 cells.
Assuntos
Artrite Experimental/etiologia , Proteína Relacionada a TNFR Induzida por Glucocorticoide/fisiologia , Células Th17/patologia , Animais , Artrite Experimental/patologia , Linfócitos T CD4-Positivos/metabolismo , Diferenciação Celular , Divisão Celular/fisiologia , Proteína Relacionada a TNFR Induzida por Glucocorticoide/metabolismo , Proteína Relacionada a TNFR Induzida por Glucocorticoide/farmacologia , Humanos , Interleucina-17/metabolismo , Ligantes , Linfonodos/patologia , Masculino , Camundongos , Camundongos Endogâmicos DBA , Proteínas Recombinantes , Baço/patologia , Células Th17/metabolismoRESUMO
BACKGROUND: IL-4 is a cytokine that induces differentiation of naive helper T cells into Th2 cells. Once activated by IL-4, Th2 cells subsequently produce additional IL-4. OBJECTIVE: To examine the effect of IL-4 on IL-17 production and its effect in Collagen-Induced Arthritis (CIA) mice. METHOD: In this study, a chicken collagen-II-induced experimental arthritis (CIA) model was used in DBA/1 mice to investigate the relationship between IL-4 and IL-17 as well as other inflammatory factors. On the 38th day after the mice were induced with CIA, the expression of IL-17 and IL-4 as well as IFN-γ and IL-13 in sera of the mice was measured by QRT-PCR and ELISA. RESULT: The result of QRT-PCR analysis of IL-17 and IL-4 mRNA levels in the spleen showed that IL-17 is increased significantly at the onset of CIA in the spleen (p<0.01). Meanwhile, IL-17 is generally reduced at the peak of CIA but IL-4 is increased significantly at this peak in the spleen when the weight of the animal was taken into consideration (p<0.05). CONCLUSION: IL-4 can be involved in the production of IL-17 at especially the peak of CIA. These results imply that the inhibition of IL-17 may decrease the expression of IL-1ß and IL-6 production which will result in the aggravation of arthritis.