RESUMO
Recurrent respiratory tract infections (RRTIs) are one of the most common pediatric diseases. Although the pathogenesis of pediatric RRTIs remains unknown, ineffective B cell-dominated humoral immunity has been considered as the core mechanism. During the course of pediatric RRTIs, B cell-dominated humoral immunity has changed from "protector" of respiratory system to "bystander" of respiratory tract infections. Under physiological condition, Tfh cells are essential for B cell-dominated humoral immunity, including regulating GC formation, promoting memory B cell (MB)/plasma cell (PC) differentiation, inducting immunoglobulin (Ig) class switching, and selecting affinity-matured antibodies. However, in disease states, Tfh cells are dysfunctional, which can be reflected by phenotypes and cytokine production. Tfh cell dysfunctions can cause the disorders of B cell-dominated humoral immunity, such as promoting B cell presented apoptosis, abrogating total Ig production, reducing MB/PC populations, and delaying affinity maturation of antigens-specific antibodies. In this review, we focused on the functions of B and Tfh cells in the homeostasis of respiratory system, and specifically discussed the disorders of humoral immunity and aberrant Tfh cell responses in the disease process of pediatric RRTIs. We hoped to provide some clues for the prevention and treatment of pediatric RRTIs.
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T-2 toxin is a mycotoxin with multiple toxic effects and has emerged as an important food pollutant. Microglia play a significant role in the toxicity of various neurotoxins. However, whether they participate in the neurotoxicity of T-2 toxin has not been reported. To clarify this point, an in vivo mouse model of T-2 toxin (4 mg/kg) poisoning was established. The results of Morris water maze and open-field showed that T-2 toxin induced learning and memory impairment and locomotor inhibition. Meanwhile, T-2 toxin induced microglial activation, while inhibiting microglia activation by minocycline (50 mg/kg) suppressed the toxic effect of the T-2 toxin. To further unveil the potential mechanisms involved in T-2 toxin-induced microglial activation, an in vitro model of T-2 toxin (0, 2.5, 5, 10 ng/mL) poisoning was established using BV-2 cells. Transcriptomic sequencing revealed lots of differentially expressed genes related to MAPK/NF-κB pathway. Western blotting results further confirmed that T-2 toxin (5 ng/mL) induced the activation of MAPKs and their downstream NF-κB. Moreover, the addition of inhibitors of NF-κB and MAPKs reversed the microglial activation induced by T-2 toxin. Overall, microglial activation may contribute a considerable role in T-2 toxin-induced behavioral abnormalities, which could be MAPK/NF-κB pathway dependent.
Assuntos
NF-kappa B , Toxina T-2 , Camundongos , Animais , NF-kappa B/metabolismo , Microglia , Toxina T-2/metabolismo , Transdução de Sinais , Regulação da Expressão Gênica , Lipopolissacarídeos/farmacologiaRESUMO
Inflammatory bowel diseases (IBDs), including ulcerative colitis and Crohn's disease, are characterized by chronic idiopathic inflammation of gastrointestinal tract. Although the pathogenesis of IBD remains unknown, intestinal immune dysfunction has been considered as the core pathogenesis. In the intestinal immune system, T helper 1 (Th1) and Th17 cells are indispensable for intestine homeostasis via preventing pathogenic bacteria invasion, regulating metabolism and functions of intestinal epithelial cells (IECs), and promoting IEC self-renewal. However, during the development of IBD, Th1 and Th17 cells acquire the pathogenicity and change from the maintainer of intestinal homeostasis to the destroyer of intestinal mucosa. Because of coexpressing interferon-γ and interleukin-17A, Th17 cells with pathogenicity are named as pathogenic Th17 cells. In disease states, Th1 cells impair IEC programs by inducing IEC apoptosis, recruiting immune cells, promoting adhesion molecules expression of IECs, and differentiating to epithelial cell adhesion molecule-specific interferon γ-positive Th1 cells. Pathogenic Th17 cells induce IEC injury by triggering IBD susceptibility genes expression of IECs and specifically killing IECs. In addition, Th1 and pathogenic Th17 cells could cooperate to induce colitis. The evidences from IBD patients and animal models demonstrate that synergistic action of Th1 and pathogenic Th17 cells occurs in the diseases development and aggravates the mucosal inflammation. In this review, we focused on Th1 and Th17 cell programs in homeostasis and intestine inflammation and specifically discussed the impact of Th1 and Th17 cell pathogenicity and their synergistic action on the onset and the development of IBD. We hoped to provide some clues for treating IBD.
Although treatment methods have been comprehensively optimized, the death risk of inflammatory bowel disease (IBD) patients is higher than that of healthy control subjects and still gradually increasing. Even so, the pathogenesis of IBD remains poorly understood. A better understanding of the roles of T helper 1 and pathogenic T helper 17 cells in the pathogenesis of IBD may provide some promising clues for treating IBD.
Assuntos
Colite , Doenças Inflamatórias Intestinais , Animais , Células Th17 , Virulência , Doenças Inflamatórias Intestinais/patologia , Colite/patologia , Células Th1/metabolismo , Inflamação/patologia , Mucosa Intestinal/patologia , Interferon gama/metabolismoRESUMO
BACKGROUND: Menstrual cycle length (MCL) and ovarian response varies widely among women of childbearing age. They are provided with anti-Mu¨llerian hormone (AMH) cutoffs for "normal" and "weakened" ovarian responses, which give an early warning of the onset of decreased ovarian response. METHODS: This was a retrospective study in women aged 21 to 35 years with MCLs of 21-35 days receiving in vitro fertilization (IVF) treatment at Center for Reproductive Medicine from October 2018 to October 2021. Intergroup variables were balanced using propensity score matching based on age and BMI, and each case patient (patients with MCLs of 21-25 days) was matched with three control patients (patients with MCLs of 26-35 days). A receiver operating characteristic curve was used to calculate the AMH cutoff values. RESULTS: We included 135 patients with MCLs of 21-25 days and 405 matched control patients with MCLs of 26-35 days who received IVF treatment. The case group had significantly fewer retrieved oocytes, lower AMH values and higher initial and total Gonadotropin (Gn) levels during controlled ovarian hyperstimulation than the control group. The ovarian response began to decrease when AMH was < 3.5 ng/ml in the case group and < 2.7 ng/ml in the control group. CONCLUSION: In young women with MCLs of 21-35 days, short MCL was negatively correlated with AMH values and the number of oocytes retrieved. In patients with MCLs of 21-25 days and 26-35 days, the AMH cutoff values corresponding to the onset of decreased ovarian response were 3.5 ng/ml and 2.7 ng/ml, respectively.
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Hormônio Antimülleriano , Indução da Ovulação , Feminino , Humanos , Adulto , Estudos Retrospectivos , Pontuação de Propensão , Ovário , Fertilização in vitroRESUMO
BACKGROUND: Silicon dioxide nanoparticles (SiO2NPs) are widely used as additive in the food industry with controversial health risk. Gut microbiota is a new and hot topic in the field of nanotoxicity. It also contributes a novel and insightful view to understand the potential health risk of food-grade SiO2NPs in children, who are susceptible to the toxic effects of nanoparticles. METHODS: In current study, the young mice were orally administrated with vehicle or SiO2NPs solution for 28 days. The effects of SiO2NPs on the gut microbiota were detected by 16S ribosomal RNA (rRNA) gene sequencing, and the neurobehavioral functions were evaluated by open field test and Morris water maze. The level of inflammation, tissue integrity of gut and the classical indicators involved in gut-brain, gut-liver and gut-lung axis were all assessed. RESULTS: Our results demonstrated that SiO2NPs significantly caused the spatial learning and memory impairments and locomotor inhibition. Although SiO2NPs did not trigger evident intestinal or neuronal inflammation, they remarkably damaged the tissue integrity. The microbial diversity within the gut was unexpectedly enhanced in SiO2NPs-treated mice, mainly manifested by the increased abundances of Firmicutes and Patescibacteria. Intriguingly, we demonstrated for the first time that the neurobehavioral impairments and brain damages induced by SiO2NPs might be distinctively associated with the disruption of gut-brain axis by specific chemical substances originated from gut, such as Vipr1 and Sstr2. Unapparent changes in liver or lung tissues further suggested the absence of gut-liver axis or gut-lung axis regulation upon oral SiO2NPs exposure. CONCLUSION: This study provides a novel idea that the SiO2NPs induced neurotoxic effects may occur through distinctive gut-brain axis, showing no significant impact on either gut-lung axis or gut-liver axis. These findings raise the exciting prospect that maintenance and coordination of gastrointestinal functions may be critical for protection against the neurotoxicity of infant foodborne SiO2NPs.
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Encéfalo/efeitos dos fármacos , Microbioma Gastrointestinal/efeitos dos fármacos , Microbioma Gastrointestinal/fisiologia , Nanopartículas/química , Dióxido de Silício/farmacologia , Animais , Microbioma Gastrointestinal/genética , Inflamação , Fígado/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neurônios , Dióxido de Silício/químicaRESUMO
Type 2 diabetes (T2D) and Alzheimer's disease (AD) share several common pathophysiological features. Huperzine A (Hup A), a Lycopodium alkaloid extracted from the Chinese herb moss Huperzia serrata, is a specific and reversible inhibitor of acetylcholinesterase, which is clinically used for the treatment of AD. In this study, we investigated whether Hup A improved the metabolic and cognitive functions in the high fat-induced (HFD) obese mice and genetic ob/ob mice. HFD and ob/ob mice were treated with Hup A (0.1, 0.3 mg · kg-1 · d-1, ig) for 3 months. Body weight was monitored and glucose tolerance tests were performed. Novel object recognition test and Morris water maze assay were conducted to evaluate the cognitive functions. We found that the Hup A treatment had no significant effect on peripheral metabolism of obese mice, whereas Hup A (0.1, mg · kg-1 · d-1) improved both the abilities of object recognition and spatial memory in HFD-fed mice, but not in ob/ob mice. Furthermore, Hup A treatment significantly upregulated the insulin and phosphorylated Akt levels in the cortex of HFD-fed mice, but not ob/ob mice. In addition, Hup A (0.3, mg · kg-1 · d-1) significantly decreased cortical ß-secretase (BACE1) expression. In conclusion, these results demonstrate that treatment with Hup A (0.1, mg · kg-1 · d-1) can effectively improve the cognitive functions, at least in diet-induced obese mice.
Assuntos
Alcaloides/farmacologia , Disfunção Cognitiva/tratamento farmacológico , Insulina/metabolismo , Obesidade/complicações , Sesquiterpenos/farmacologia , Alcaloides/administração & dosagem , Animais , Inibidores da Colinesterase/administração & dosagem , Inibidores da Colinesterase/farmacologia , Cognição/efeitos dos fármacos , Disfunção Cognitiva/etiologia , Dieta Hiperlipídica/efeitos adversos , Relação Dose-Resposta a Droga , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Obesos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Obesidade/tratamento farmacológico , Reconhecimento Psicológico/efeitos dos fármacos , Sesquiterpenos/administração & dosagem , Transdução de Sinais/efeitos dos fármacos , Memória Espacial/efeitos dos fármacosRESUMO
BACKGROUND: This study measured the change in connective tissue growth factor levels after the onset of unstable angina and ST-segment elevation myocardial infarction, and studied its correlation with peak creatine kinase-MB (CK-MB) enzyme. It also discussed the significance of myocardial fibrosis after myocardial infarction. To detect the serum levels of connective tissue growth factor in patients with ST-segment elevation myocardial infarction and its relationship with the maximum level of CK-MB. METHODS: We selected 50 patients with ST-segment elevation myocardial infarction and 50 patients with unstable angina. Connective tissue growth factor levels were examined 24 h, 2 d, 7 d, and 14 d after the onset of ST-segment elevation myocardial infarction, and within 24 h for unstable angina, using enzyme-linked immunosorbent assay (ELISA). The maximum level of CK-MB was detected by immunosuppression. RESULTS: The serum level of connective tissue growth factor in the unstable angina patients was 10.34 ± 2.00 ng/mL, and the levels in the ST-segment elevation myocardial infarction patients were 16.76 ± 3.17 ng/mL at 24 h, 29.87 ± 4.90 ng/mL at 2 d, 45.02 ± 8.35 ng/mL at 7 d, and 31.61 ± 4.40 ng/mL at 14 d. Compared with the unstable angina patients, the connective tissue growth factor levels in the ST-segment elevation myocardial infarction patients were significantly higher since day 1 (p < 0.01). The maximum level of CK-MB was correlated with connective tissue growth factor levels at 7 d (r = 0.859, p = 0.000). CONCLUSIONS: Connective tissue growth factor was significantly expressed in the ST-segment elevation myocardial infarction patients, indicating that it might play an important role in myocardial fibrosis.
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The success of adoptive CTL therapy for cancer depends on interactions between tumor-infiltrating CTLs and cancer cells as well as other cells and molecules in the tumor microenvironment. Tumor dendritic cells (DCs) comprise several subsets: CD103+CD11b- DC1 and CD11b+CD64- DC2, which originate from circulating precursors of conventional DCs, and CD11b+CD64+ DC3, which arise from monocytes. It remains controversial which of these subset(s) promotes intratumor CTL proliferation, expansion, and function. To address this issue, we used the Zbtb46-DTR-transgenic mouse model to selectively deplete DC1 and DC2 from tumors and lymphoid tissues. Wild-type and Zbtb46-DTR bone marrow chimeras were inoculated with B16 melanoma cells that express OVA and were treated with OT-1 CTLs. We found that depletion of DCs derived from precursors of conventional DCs in Zbtb46-DTR bone marrow chimeras abolished CTL proliferation and expansion in tumor-draining lymph nodes. By contrast, intratumor CTL accumulation, proliferation, and IFN-γ expression were unaffected by their absence. We found that adoptive cell therapy increases the frequency of monocyte-derived tumor DC3, which possess the capacity to cross-present tumor Ags and induce CTL proliferation. Our findings support the specialized roles of different DC subsets in the regulation of antitumor CTL responses.
Assuntos
Células Dendríticas/imunologia , Melanoma Experimental/imunologia , Neoplasias Cutâneas/imunologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Citotóxicos/transplante , Animais , Apresentação Cruzada/imunologia , Feminino , Imunoterapia Adotiva , Ativação Linfocitária/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Microambiente Tumoral/imunologiaRESUMO
BACKGROUND: The neutrophil to lymphocyte ratio (NLR) is an indicator of systemic inflammation and a prognostic marker in patients with acute coronary syndrome (ACS). This study aims to investigate the value of NLR to predict the in-hospital and long-term prognosis in patients with ST segment elevation myocardial infarction (STEMI) after percutaneous coronary intervention (PCI) by meta-analysis. METHOD: The studies related to the prognosis of NLR and STEMI patients published in the Pubmed, Embase, and Ovid databases before June 2017 were retrieved. The relevant data were extracted. Review Manager Version 5.3 was used for meta-analysis. RESULTS: A total of 14 studies of 10,245 patients with STEMI after PCI were included. A significant difference was observed for mortality (P < 0.001; relative risk (RR) 3.32; 95% confidence interval (CI) 2.45-4.49), hospital cardiac mortality(P < 0.001; RR 3.22; 95% CI 2.25-4.60), all mortality (P < 0.001; RR 3.23; 95% CI 2.28-4.57), major adverse cardiovascular events (MACE) (P < 0.001; RR 2.00; 95% CI 1.62-2.46), in-stent thrombosis (P < 0.001; RR 2.72 95% CI 1.66-4.44), nonfatal myocardial infarction(MI) (P < 0.001; RR 1.93; 95%CI 1.43-2.61), angina (P = 0.007; RR 1.67; 95%CI 1.15-2.41), advanced heart failure (AHF) (P < 0.001; RR 1.81; 95% CI 1.48-2.21), arrhythmia (P = 0.002; RR 1.38; 95% CI 1.13-1.69), no reflow (P < 0.001; RR 2.28; 95% CI 1.46-3.57), long-term all mortality (P < 0.001; RR 3.82; 95% CI 2.94-4.96), cardiac mortality (P = 0.004; RR 3.02; 95% CI 1.41-6.45), MACE (P < 0.001; RR 2.49; 95% CI 1.47-4.23), and nonfatal MI (P = 0.46; RR 1.32; 95% CI 0.63-2.75). CONCLUSIONS: Meta-analysis shows that NLR is a predictor of hospitalization and long-term prognosis in patients with STEMI after PCI, but requires further confirmation by large randomized clinical trials.
Assuntos
Linfócitos , Neutrófilos , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST/sangue , Infarto do Miocárdio com Supradesnível do Segmento ST/cirurgia , Idoso , Causas de Morte , Progressão da Doença , Feminino , Mortalidade Hospitalar , Humanos , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Intervenção Coronária Percutânea/efeitos adversos , Intervenção Coronária Percutânea/mortalidade , Valor Preditivo dos Testes , Recidiva , Fatores de Risco , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico , Infarto do Miocárdio com Supradesnível do Segmento ST/mortalidade , Fatores de Tempo , Resultado do TratamentoRESUMO
Dendritic cells (DC) play a pivotal role in the tumor microenvironment (TME). As the primary antigen-presenting cells in the tumor, DCs modulate anti-tumor responses by regulating the magnitude and duration of infiltrating cytotoxic T lymphocyte responses. Unfortunately, due to the immunosuppressive nature of the TME, as well as the inherent plasticity of DCs, tumor DCs are often dysfunctional, a phenomenon that contributes to immune evasion. Recent progresses in our understanding of tumor DC biology have revealed potential molecular targets that allow us to improve tumor DC immunogenicity and cancer immunotherapy. Here, we review the molecular mechanisms that drive tumor DC dysfunction. We discuss recent advances in our understanding of tumor DC ontogeny, tumor DC subset heterogeneity, and factors in the tumor microenvironment that affect DC recruitment, differentiation, and function. Finally, we describe potential strategies to optimize tumor DC function in the context of cancer therapy.
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Células Dendríticas/metabolismo , Neoplasias/metabolismo , Animais , Humanos , Imunidade , Modelos Biológicos , Neoplasias/imunologia , Neoplasias/patologiaRESUMO
Although dendritic cell (DC) dysfunction in cancer is a well-recognized consequence of cancer-associated inflammation that contributes to immune evasion, the mechanisms that drive this process remain elusive. Here, we show the critical importance of tumor-derived TLR2 ligands in the generation of immunosuppressive IL-10-producing human and mouse DCs. TLR2 ligation induced two parallel synergistic processes that converged to activate STAT3: stimulation of autocrine IL-6 and IL-10 and upregulation of their respective cell surface receptors, which lowered the STAT3 activation threshold. We identified versican as a soluble tumor-derived factor that activates TLR2 in DCs. TLR2 blockade in vivo improved intra-tumor DC immunogenicity and enhanced the efficacy of immunotherapy. Our findings provide a basis for understanding the molecular mechanisms of DC dysfunction in cancer and identify TLR2 as a relevant therapeutic target to improve cancer immunotherapy.
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Células Dendríticas/imunologia , Interleucina-10/imunologia , Interleucina-6/imunologia , Receptor 2 Toll-Like/imunologia , Animais , Linhagem Celular Tumoral , Humanos , Imunoterapia/métodos , Interleucina-10/metabolismo , Interleucina-6/metabolismo , Masculino , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neoplasias/imunologia , Neoplasias/metabolismo , Neoplasias/terapia , Transdução de Sinais , Receptor 2 Toll-Like/metabolismoRESUMO
Helicobacter pylori infects the human gastric mucosa causing a chronic infection that is the primary risk factor for gastric cancer development. Recent studies demonstrate that H. pylori promotes tolerogenic dendritic cell (DC) development indicating that this bacterium evades the host immune response. However, the signaling pathways involved in modulating DC activation during infection remain unclear. Here, we report that H. pylori infection activated the signal transducer and activator of transcription 3 (STAT3) pathway in murine bone marrow-derived DCs (BMDCs) and splenic DCs isolated ex vivo. Isogenic cagA-, cagE-, vacA- and urease-mutants exhibited levels of phosphoSTAT3 that were comparable to in the wild-type (WT) parent strain. H. pylori-infected BMDCs produced increased immunosuppressive IL-10, which activated STAT3 in an autocrine/paracrine fashion. Neutralization of IL-10 prevented H. pylori-mediated STAT3 activation in both BMDCs and splenic DCs. In addition, anti-IL-10 treatment of infected H. pylori-BMDCs was associated with increased CD86 and MHC II expression and enhanced proinflammatory IL-1ß cytokine secretion. Finally, increased CD86 and MHC II expression was detected in H. pylori-infected STAT3 knockout DCs when compared to WT controls. Together, these results demonstrate that H. pylori infection induces IL-10 secretion in DCs, which activates STAT3, thereby modulating DC maturation and reducing IL-1ß secretion. These findings identify a host molecular mechanism by which H. pylori can manipulate the innate immune response to potentially favor chronic infection and promote carcinogenesis.
Assuntos
Células Dendríticas/imunologia , Infecções por Helicobacter/imunologia , Helicobacter pylori/imunologia , Interleucina-10/metabolismo , Fator de Transcrição STAT3/metabolismo , Animais , Anticorpos Bloqueadores/farmacologia , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/microbiologia , Humanos , Evasão da Resposta Imune/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Interleucina-1beta/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator de Transcrição STAT3/genética , Transdução de Sinais/efeitos dos fármacosRESUMO
Dendritic cell (DC) homeostasis in peripheral tissues reflect a balance between DC generation, migration, and death. The current model of DC ontogeny indicates that pre-cDCs are committed to become terminal conventional DCs (cDCs). Here, we report the unexpected finding that proliferating immunostimulatory CD11c(+) MHC class II(+) cDCs derived from pre-cDCs can lose their DC identity and generate progeny that exhibit morphologic, phenotypic, and functional characteristics of regulatory macrophages. DC-derived-macrophages (DC-d-Ms) potently suppress T-cell responses through the production of immunosuppressive molecules including nitric oxide, arginase, and IL-10. Relative deficiency of granulocyte-macrophage colony stimulating factor (GM-CSF) provided a permissive signal for DC-d-M generation. Using a transgenic mouse model that allows tracking of CD11c(+) cells in vivo, we found that DC-d-M development occurs commonly in cancer, but not in lymphoid or nonlymphoid tissues under steady-state conditions. We propose that this developmental pathway serves as an alternative mechanism of regulating DC homeostasis during inflammatory processes.
Assuntos
Diferenciação Celular , Células Dendríticas/imunologia , Células Dendríticas/fisiologia , Macrófagos/citologia , Macrófagos/fisiologia , Animais , Animais Recém-Nascidos , Antígenos CD11/genética , Antígenos CD11/metabolismo , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/patologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Células Cultivadas , Células Dendríticas/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Masculino , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/patologia , Camundongos , Camundongos Congênicos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos TransgênicosRESUMO
TCRαß(+) CD3(+) CD4(-) CD8(-) NK1.1(-) double negative (DN) Tregs comprise 1-3% of peripheral T lymphocytes in mice and humans. It has been demonstrated that DN Tregs can suppress allo-, xeno- and auto-immune responses in an Ag-specific fashion. However, the mechanisms by which DN Tregs regulate immune responses remain elusive. Whether DN Tregs can regulate DCs has not been investigated previously. In this study, we demonstrate that DN Tregs express a high level of CTLA4 and are able to down-regulate costimulatory molecules CD80 and CD86 expressed on Ag-expressing mature DCs (mDCs). DN Tregs from CTLA4 KO mice were not able to downregulate CD80 and CD86 expression, indicating that CTLA4 is critical for DN Treg-mediated downregulation of costimulatory molecule expression on Ag-expressing mature DCs. Furthermore, DN Tregs could kill both immature and mature allogeneic DCs, as well as Ag-loaded syngeneic DCs, in an Ag-specific manner in vitro and in vivo, mainly through the Fas-FasL pathway. These data demonstrate, for the first time, that DN Tregs are potent regulators of DCs and may have the potential to be developed as a novel immune suppression treatment.
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Células Apresentadoras de Antígenos/metabolismo , Antígeno CTLA-4/metabolismo , Células Dendríticas/metabolismo , Linfócitos T Reguladores/metabolismo , Animais , Células Apresentadoras de Antígenos/imunologia , Células Apresentadoras de Antígenos/patologia , Antígeno B7-1/genética , Antígeno B7-1/metabolismo , Antígeno B7-2/genética , Antígeno B7-2/metabolismo , Antígeno CTLA-4/genética , Antígeno CTLA-4/imunologia , Células Cultivadas , Citotoxicidade Imunológica , Células Dendríticas/imunologia , Células Dendríticas/patologia , Regulação para Baixo , Humanos , Terapia de Imunossupressão , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologiaRESUMO
Cancers are often accompanied by inflammation, which can promote tumor growth, invasion, and metastases. We show that the tumor microenvironment induces the development of a Gr-1(+) conventional dendritic cell (cDC) subpopulation that is functionally defective. Gr-1(+)cDCs differentiated from recruited immediate precursors of cDCs, a process supported by the inflammatory cytokine milieu in tumors. Inhibition of Gr-1(+)cDC differentiation enhanced intratumor expansion of cytotoxic CD8(+) T cells (CTLs), resulting in suppression of tumor growth. Diphtheria toxin treatment of CD11c-diphtheria toxin receptor chimeras revealed the importance of intratumor cDCs in stimulating CTL proliferation in situ. Our study demonstrates a key role of intratumor cDCs in determining antitumor CTL responses and suggests that they may be an appropriate target for tumor immunotherapy.
Assuntos
Diferenciação Celular , Proliferação de Células , Células Dendríticas/imunologia , Interleucina-6/imunologia , Neoplasias Experimentais/imunologia , Linfócitos T Citotóxicos/imunologia , Microambiente Tumoral/imunologia , Animais , Diferenciação Celular/imunologia , Células Dendríticas/citologia , Células Dendríticas/metabolismo , Citometria de Fluxo , Ativação Linfocitária/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/metabolismo , Receptores de Quimiocinas/imunologia , Receptores de Quimiocinas/metabolismo , Linfócitos T Citotóxicos/metabolismo , Evasão Tumoral/imunologiaRESUMO
BACKGROUND AND AIM: Functional constipation is a common functional bowel disorder for which there is no reliable medical treatment. This study was designed to determine the therapeutic efficacy and safety of the Yun-chang capsule, a Chinese herbal formula, in the treatment of patients with functional constipation. METHODS: In our multi-center, prospective, double-blind, randomized, placebo-controlled, dose-escalation trial, patients with functional constipation received 70 mg of Yun-chang capsule plus 35 mg placebo (group A), 105 mg of Yun-chang capsule (group B), or 105 mg placebo (group C), three times daily for 2 weeks. The primary end-points were the changes in main symptom score and cumulative symptom score 2 weeks after the treatment. The secondary end-points were adverse events. RESULTS: A total of 140 patients were recruited and 132 met the inclusion criteria; 44 patients constituted each of the three treatment groups. Compared with patients in group C, patients in groups A and B had significant improvement in the main symptom score, cumulative symptom score, the change from baseline of the main symptom score, and the change from baseline of the cumulative symptom score at week 1 and week 2. The scores showed slight superiority of group B over group A at week 1 and week 2, although these differences were not statistically significant. There were no differences in adverse events. CONCLUSIONS: The Yun-chang capsule is efficacious and safe for the treatment of patients with functional constipation. Larger and longer-term trials are required to fully assess the benefits and safety of this treatment for functional constipation.
Assuntos
Constipação Intestinal/tratamento farmacológico , Medicamentos de Ervas Chinesas/uso terapêutico , Fármacos Gastrointestinais/uso terapêutico , Fitoterapia , Extratos Vegetais/uso terapêutico , Adolescente , Adulto , Idoso , Cápsulas , China , Método Duplo-Cego , Medicamentos de Ervas Chinesas/administração & dosagem , Feminino , Fármacos Gastrointestinais/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/administração & dosagem , Guias de Prática Clínica como Assunto , Estudos Prospectivos , Resultado do TratamentoRESUMO
CD200 has been characterized as an important immunoregulatory molecule, increased expression of which can lead to decreased transplant rejection, autoimmunity, and allergic disease. Elevated CD200 expression has been reported to be associated with poor prognosis in a number of human malignancies. We have found that cells of the transplantable EMT6 mouse breast cancer line growing in vitro express low levels of CD200, but levels increase markedly during growth in immunocompetent mice. Similar increased in vivo expression does not occur in NOD-SCID.IL-2(gammar-/-) mice or mice with generalized over-expression of a CD200 transgene. In both mice, tumor growth occurs faster. Altered CD200 expression in control versus transgenic mice is accompanied by reproducible changes in tumor-infiltrating host cells, and altered cell composition in lymph nodes draining the tumor (DLN). Neutralization of expressed CD200 by anti-CD200mAbs leads to decreased tumor growth in immunocompetent mice, with improved detection of cytotoxic anti-tumor immune cells in DLN. Finally, we report that tumor growth in vivo can be monitored by levels of soluble CD200 (sCD200) in serum of tumor-bearing animals.
Assuntos
Antígenos CD/metabolismo , Neoplasias da Mama/imunologia , Animais , Anticorpos Monoclonais/administração & dosagem , Antígenos CD/sangue , Antígenos CD/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Membrana Celular/imunologia , Células Clonais , Citocinas/imunologia , Citotoxicidade Imunológica , Feminino , Imunocompetência , Subunidade gama Comum de Receptores de Interleucina/deficiência , Subunidade gama Comum de Receptores de Interleucina/genética , Subunidade gama Comum de Receptores de Interleucina/metabolismo , Linfonodos/imunologia , Linfócitos do Interstício Tumoral/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Camundongos Transgênicos , Fatores de Tempo , Carga TumoralRESUMO
The origin of dendritic cells (DCs) in tumors remains obscure. Recent studies indicate that conventional DCs (cDCs) in lymphoid tissues arise from a distinct population of committed cDC precursors (pre-cDCs) that originate in bone marrow and migrate via blood. In this study, we show that pre-cDCs are precursors for cDCs in tumors. Pre-cDCs from tumors, bone marrow, and spleen exhibit similar morphologic, immunophenotypic, and functional properties. Adoptive transfer studies show that bone marrow pre-cDCs migrate from blood into the tumor where they generate cDCs. The chemokine CCL3, which is markedly upregulated in tumors, promotes pre-cDC recruitment. Both pre-cDCs and their cDC progeny actively proliferate within the tumor. cDCs that arise from pre-cDCs in tumors express lower levels of CD11c and MHC class II as compared with those in spleen; however, there was no difference in their abilities to respond to maturation stimuli or activate Ag-specific lymphocytes in vitro. Our study provides the first evidence supporting a role for pre-cDCs in DC development in tumors and suggests a potential target for cancer immunotherapy.
Assuntos
Diferenciação Celular/imunologia , Movimento Celular/imunologia , Células Dendríticas/imunologia , Neoplasias Experimentais/imunologia , Células-Tronco/imunologia , Animais , Carcinoma Pulmonar de Lewis/imunologia , Carcinoma Pulmonar de Lewis/patologia , Linhagem Celular Tumoral , Técnicas de Cocultura , Neoplasias do Colo/imunologia , Neoplasias do Colo/patologia , Células Dendríticas/classificação , Células Dendríticas/patologia , Masculino , Melanoma Experimental/imunologia , Melanoma Experimental/patologia , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Neoplasias Experimentais/patologia , Transplante de Células-Tronco , Células-Tronco/patologiaRESUMO
BACKGROUND: Although there are some Chinese herbal medicines in treatment of constipation, but no multi-center randomized controlled trials have been carried out to prove their effectiveness. OBJECTIVE: To evaluate the safety and efficacy of Yunchang Capsule in treatment of functional constipation with deficiency of both qi and yin and internal accumulation of poisonous pathogenic factors syndrome, and to explore the clinical dosage. DESIGN, SETTING, PARTICIPANTS AND INTERVENTIONS: A randomized, double-blinded controlled, multicenter trial was conducted. A total of 240 patients with functional constipation from West China Hospital of Sichuan University, Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, the First Affiliated Hospital of Tianjing University of Traditional Chinese Medicine and Fujian Academy of Traditional Chinese Medicine were randomly divided into three groups: low dose group (80 cases), high dose group (80 cases) and control group (80 cases). Patients in the low dose group were treated with two pills (0.35 g/pill) of Yunchang Capsule and one pill of Yunchang Capsule simulant for three times daily; patients in the high dose group were treated with three pills (0.35 g/pill) of Yunchang Capsule for three times daily; and patients in the control group were treated with three pills (0.35 g/pill) of Biantong Capsule for three times daily. The therapeutic course was 14 days. MAIN OUTCOME MEASURES: Clinical symptoms, syndromes, and adverse effects were observed before and after the treatment, and blood, urine and stool tests, hepatorenal function and electrocardiogram were also examined. RESULTS: Two cases were excluded, eleven cases were lost to follow-up, and there were 234 patients entered to intention-to-treat (ITT) analysis. After the treatment, the therapeutic effects were calculated by full analysis set (FAS) and per-protocol population set (PPS) analysis respectively. The effects on functional constipation in FAS showed the response rates in the low dose, high dose and control groups were 86.25% (69/80), 82.90% (63/76), and 70.52% (55/78) respectively, and PPS analysis showed the response rates were 85.71% (66/77), 83.56% (61/73), and 70.13% (54/77) respectively. There were no significant differences among the three groups (P>0.05). The effects on traditional Chinese medicine syndrome in FAS showed the response rates in the low dose, high dose and control groups were 78.75% (63/80), 69.74% (53/76), and 67.95% (53/78) respectively, and PPS analysis showed the response rates were 77.92% (60/77), 69.87%(51/73), and 67.53% (52/77) respectively. There were also no significant differences among the three groups (P>0.05). No severe adverse events were observed. CONCLUSION: Both low dose and high dose of Yunchang Capsule are effective and safe in treatment of functional constipation with deficiency of both qi and yin and internal accumulation of poisonous pathogenic factors syndrome.
Assuntos
Constipação Intestinal/tratamento farmacológico , Medicina Tradicional Chinesa , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Medicina Tradicional Chinesa/efeitos adversos , Medicina Tradicional Chinesa/métodos , Qi , Síndrome , Resultado do TratamentoRESUMO
Fibrinogen-like protein 2 (FGL2) is a multifunctional protein, which has been implicated in the pathogenesis of allograft and xenograft rejection. Previously, FGL2 was shown to inhibit maturation of BM-derived DC and T-cell proliferation. The mechanism of the immunosuppressive activity of FGL2 remains poorly elucidated. Here, we focus on identification of FGL2-specific receptor(s) and their ability to modulate APC activity and allograft survival. Using flow cytometry and surface plasmon resonance analysis, we show that FGL2 binds specifically to Fc gamma receptor (FcgammaR)IIB and FcgammaRIII receptors, which are expressed on the surface of APC, including B lymphocytes, macrophages and DC. Antibody to FcgammaRIIB and FcgammaRIII, or deficiency of these receptors, abrogated FGL2 binding. FGL2 inhibited the maturation of BMDC from FcgammaRIIB+/+ mice but not from FcgammaRIIB(-/-) mice and induced apoptosis in the FcgammaRIIB+ mouse B-cell line (A20) but not the A20IIA1.6 cell line that does not express FcgammaRIIB. Recombinant FGL2 infused into FcgammaRIIB+/+ (C57BL/6J, H-2b) mice but not FcgammaRIIB(-/-) mice inhibited rejection of fully mismatched BALB/cJ (H-2d) skin allografts. The identification of specific receptor binding has important implications for the pathogenesis of immune-mediated disease and suggests a potential for targeted FGL2 therapy.