RESUMO
Cancer mice models are critical for immune-oncology research; they provide conditions to explore tumor immunoenviroment aiming to advance knowledge and treatment development. Often, research groups breed their own mice colonies. To assess the effect of C57BL/6 mice breeding nuclei in prostate cancer development and intratumoral macrophage populations, an isotransplantation experiment was performed. C57BL/6J mice from two breeding nuclei (nA and nB) were employed for prostate adenocarcinoma TRAMP-C1 cell implantation; tumor growth period and intratumoral macrophage profile were measured. BL/6nB mice (54%) showed tumor implantation after 69-day growth period while BL/6nA implantation reached 100% across tumor growth period (28 days). No difference in total macrophage populations was observed between groups within several tumoral regions; significantly higher M2 macrophage profile was observed in tumor microenvironments from both mice groups. Nevertheless, BL/6nB tumors showed around twice the population of M1 profile (11-27%) than BL6nA (4-15%) and less non-polarized macrophages. The M1:M2 average ratio was 1:8 for group A and 1:4 for B. Our results demonstrate different tumor progression and intratumoral macrophage populations among mice from the same substrain. Data obtained in this study shows the relevance of animal source renewal for better control of murine cancer model variables.
Assuntos
Modelos Animais de Doenças , Progressão da Doença , Macrófagos , Camundongos Endogâmicos C57BL , Neoplasias da Próstata , Microambiente Tumoral , Animais , Neoplasias da Próstata/patologia , Masculino , Camundongos , Macrófagos/imunologia , Linhagem Celular TumoralRESUMO
We recently reported that Tregs from long-term Belatacept-treated kidney transplant patients displayed an altered phenotype and impaired suppressive function compared to Tregs from healthy controls. However, it remains unknown whether ex vivo expansion of Tregs from patients who underwent long-term immunosuppression may be feasible to be used in their treatment. In this work, Tregs from Belatacept-treated patients were polyclonally expanded in vitro in the presence of rapamycin and IL-2. After four weeks of expansion, Tregs from patients expressed high levels of FOXP3, CD25, CTLA-4, Helios and CCR7, and showed strong suppressive activity, even in the presence of pro-inflammatory cytokines. However, FOXP3 TSDR demethylation remained lower in expanded Tregs from Belatacept-treated patients compared to healthy control Tregs. These data suggest that ex vivo expansion of Tregs from patients undergoing long-term immunosuppression may require the use of epigenetic modifying agents to stabilize FOXP3 expression to be considered as treatment in kidney transplant patients.
Assuntos
Abatacepte/uso terapêutico , Imunossupressores/uso terapêutico , Transplante de Rim , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Técnicas de Cultura de Células/métodos , Desmetilação/efeitos dos fármacos , Fatores de Transcrição Forkhead , Humanos , Hospedeiro Imunocomprometido , Fenótipo , Sirolimo/farmacologiaRESUMO
Airway inflammation is the most common hallmark of allergic asthma. Chemokine receptors involved in leukocyte recruitment are closely related to the pathology in asthma. CCR9 has been described as a homeostatic and inflammatory chemokine receptor, but its role and that of its ligand CCL25 during lung inflammation remain unknown. To investigate the role of CCR9 as a modulator of airway inflammation, we established an OVA-induced allergic inflammation model in CCR9-deficient mice. Here, we report the expression of CCR9 and CCL25 as early as 6 hours post-OVA challenge in eosinophils and T-lymphocytes. Moreover, in challenged CCR9-deficient mice, cell recruitment was impaired at peribronchial and perivenular levels. OVA-administration in CCR9-deficient mice leads to a less inflammatory cell recruitment, which modifies the expression of IL-10, CCL11, and CCL25 at 24 hours after OVA challenge. In contrast, the secretion of IL-4 and IL-5 was not affected in CCR9-deficient mice compared to WT mice. These results demonstrate for the first time that CCR9 and CCL25 expressions are induced in the early stages of airway inflammation and they have an important role modulating eosinophils and lymphocytes recruitment at the first stages of inflammatory process, suggesting that they might be a potential target to regulate inflammation in asthma.
Assuntos
Quimiocinas CC/metabolismo , Regulação da Expressão Gênica , Hipersensibilidade/metabolismo , Inflamação/metabolismo , Receptores CCR/metabolismo , Animais , Líquido da Lavagem Broncoalveolar , Separação Celular , Citocinas/metabolismo , Ensaio de Imunoadsorção Enzimática , Eosinófilos/citologia , Feminino , Citometria de Fluxo , Imunoglobulina E/sangue , Leucócitos/citologia , Pulmão/fisiopatologia , Linfócitos/citologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/citologiaRESUMO
In BALB/c adult mice, respiratory syncytial virus (RSV) infection enhances the degree of lung inflammation before and/or after ovalbumin (OVA) respiratory sensitization. However, it is unclear whether RSV infection in newborn mice has an effect on the immune response to OVA respiratory sensitization in adult mice. The aim of this study was to determine if RSV neonatal infection alters T CD4(+) population and lung inflammation during OVA respiratory sensitization in adult mice. BALB/c mice were infected with RSV on the fourth day of life and challenged by OVA 4 weeks later. We found that in adult mice, RSV neonatal infection prior to OVA sensitization reduces the CD4(+) CD25(+) and CD4(+) CD25(+) forkhead protein 3 (FoxP3)(+) cell populations in the lungs and bronchoalveolar lavage. Furthermore, it also attenuates the inflammatory infiltrate and cytokine/chemokine expression levels in the mouse airways. In conclusion, the magnitude of the immune response to a non-viral respiratory perturbation in adult mice is not enhanced by a neonatal RSV infection.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Subunidade alfa de Receptor de Interleucina-2/imunologia , Ovalbumina/imunologia , Pneumonia/imunologia , Infecções por Vírus Respiratório Sincicial/imunologia , Animais , Animais Recém-Nascidos , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/genética , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/imunologia , Imunização , Pulmão/imunologia , Pulmão/virologia , Camundongos , Camundongos Endogâmicos BALB C , Pneumonia/virologia , Vírus Sinciciais Respiratórios/imunologiaRESUMO
Allergic asthma is a chronic inflammatory disease characterized by the accumulation of eosinophils, Th2 cells and mononuclear cells in the airways, leading to changes in lung architecture and subsequently reduced respiratory function. We have previously demonstrated that CDIP-2, a chemokine derived peptide, reduced in vitro chemotaxis and decreased cellular infiltration in a murine model of allergic airway inflammation. However, the mechanisms involved in this process have not been identified yet. Now, we found that CDIP-2 reduces chemokine-mediated functions via interactions with CCR1, CCR2 and CCR3. Moreover, using bone marrow-derived eosinophils, we demonstrated that CDIP-2 modifies the calcium fluxes induced by CCL11 and down-modulated CCR3 expression. Finally, CDIP-2 treatment in a murine model of OVA-induced allergic airway inflammation reduced leukocyte recruitment and decreases production of cytokines. These data suggest that chemokine-derived peptides represent new therapeutic tools to generate more effective antiinflammatory drugs.
Assuntos
Anti-Inflamatórios/farmacologia , Peptídeos/farmacologia , Receptores CCR1/metabolismo , Receptores CCR2/metabolismo , Receptores CCR3/metabolismo , Alérgenos , Animais , Anti-Inflamatórios/uso terapêutico , Células CHO , Cálcio/metabolismo , Linhagem Celular Tumoral , Quimiotaxia/efeitos dos fármacos , Cricetulus , Citocinas/metabolismo , Eosinófilos/efeitos dos fármacos , Eosinófilos/fisiologia , Feminino , Humanos , Pulmão/efeitos dos fármacos , Pulmão/patologia , Linfonodos/citologia , Camundongos Endogâmicos BALB C , Ovalbumina , Peptídeos/uso terapêutico , Pneumonia/tratamento farmacológico , Pneumonia/patologia , Receptores CCR1/genética , Receptores CCR2/genética , Receptores CCR3/genética , Hipersensibilidade Respiratória/tratamento farmacológico , Hipersensibilidade Respiratória/patologiaRESUMO
Analysis of the mechanisms underlying the inflammatory response in amoebiasis is important to understand the immunopathology of the disease. Mucosal associated effector and regulatory T cells may play a role in regulating the inflammatory immune response associated to Entamoeba histolytica infection in the colon. A subpopulation of regulatory T cells has recently been identified and is characterized by the expression of the chemokine receptor CCR9. In this report, we used CCR9 deficient (CCR9(-/-)) mice to investigate the role of the CCR9(+) T cells in a murine model of E. histolytica intestinal infection. Intracecal infection of CCR9(+/+), CCR9(+/-) and CCR9(-/-) mice with E. histolytica trophozoites, revealed striking differences in the development and nature of the intestinal inflammatory response observed between these strains. While CCR9(+/+) and CCR9(+/-) mice were resistant to the infection and resolved the pathogen-induced inflammatory response, CCR9(-/-) mice developed a chronic inflammatory response, which was associated with over-expression of the cytokines IFN-γ, TNF-α, IL-4, IL-6 and IL-17, while IL-10 was not present. In addition, increased levels of CCL11, CCL20 and CCL28 chemokines were detected by qRT-PCR in CCR9(-/-) mice. E. histolytica trophozoites were identified in the lumen of the cecum of CCR9(-/-) mice at seven days post infection (pi), whereas in CCR9(+/+) mice trophozoites disappeared by day 1 pi. Interestingly, the inflammation observed in CCR9(-/-) mice, was associated with a delayed recruitment of CD4(+)CD25(+)FoxP3(+) T cells to the cecal epithelium and lamina propria, suggesting that this population may play a role in the early regulation of the inflammatory response against E. histolytica, likely through IL-10 production. In support of these data, CCR9(+) T cells were also identified in colon tissue sections obtained from patients with amoebic colitis. Our data suggest that a population of CCR9(+)CD4(+)CD25(+)FoxP3(+) T cells may participate in the control and resolution of the inflammatory immune response to E. histolytica infection.
Assuntos
Modelos Animais de Doenças , Disenteria Amebiana/imunologia , Entamoeba histolytica/imunologia , Receptores CCR/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Quimiocina CCL11/genética , Quimiocina CCL11/imunologia , Quimiocina CCL11/metabolismo , Quimiocina CCL20/genética , Quimiocina CCL20/imunologia , Quimiocina CCL20/metabolismo , Quimiocinas CC/genética , Quimiocinas CC/imunologia , Quimiocinas CC/metabolismo , Disenteria Amebiana/metabolismo , Disenteria Amebiana/parasitologia , Entamoeba histolytica/fisiologia , Citometria de Fluxo , Fatores de Transcrição Forkhead/imunologia , Fatores de Transcrição Forkhead/metabolismo , Expressão Gênica , Humanos , Mediadores da Inflamação/imunologia , Mediadores da Inflamação/metabolismo , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-17/imunologia , Interleucina-17/metabolismo , Subunidade alfa de Receptor de Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Interleucina-4/imunologia , Interleucina-4/metabolismo , Interleucina-6/imunologia , Interleucina-6/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores CCR/genética , Receptores CCR/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Trofozoítos/imunologia , Trofozoítos/fisiologia , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismoRESUMO
Vanadium (V) is a transition metal found in air adsorbed onto suspended particles. As a result, urban populations are often exposed to this element as a constituent of particulate matter (PM). One aspect of the myriad toxicities that might arise from these exposures is altered immune responses. Previous reports from the laboratory reported modifications in splenic architecture - with germinal center hyperplasia and a suppressed humoral immune response - in mice that had been exposed to vanadium agents via inhalation. This paper reports a decrease in the presence of the CD11c surface marker on mouse thymic dendritic cells (DC) as a result of host exposure to vanadium (here, in the form of vanadium pentoxide; V(2)O(5)) over a period of 4 weeks. All results were obtained using immunohistochemistry and flow cytometry. It is surmised that this decrease might induce a dysfunction, including possible negative selection of T-cells, which could increase the presence of autoreactive clones in the exposed host. Such an outcome could, in turn, increase the risk for development of autoimmune reactions in different organs specifically, and of autoimmune diseases in general in these V-exposed hosts.
Assuntos
Poluentes Atmosféricos/efeitos adversos , Doenças Autoimunes/etiologia , Antígeno CD11c/imunologia , Células Dendríticas/efeitos dos fármacos , Exposição Ambiental/efeitos adversos , Timo/efeitos dos fármacos , Vanádio/efeitos adversos , Animais , Doenças Autoimunes/imunologia , Separação Celular , Células Cultivadas , Células Dendríticas/imunologia , Regulação para Baixo , Citometria de Fluxo , Inalação , Masculino , Camundongos , Camundongos Endogâmicos , Timo/imunologiaRESUMO
Activins and inhibins are members of the transforming growth factor-ß superfamily that have been considered crucial regulators of cell processes, such as differentiation, proliferation and apoptosis, in different cell types. Initial studies about the function of activin A in the immune system focused on the regulation of hematopoiesis in the bone marrow under homeostatic and inflammatory conditions. Recent data provide a more comprehensive understanding about the role of activins/inhibins in the immune system. Novel findings included in this review point out the important requirement of activin/inhibin signaling to maintain the balance between homeostatic and inflammatory signals that are required for the optimal development and function of immune cells. The purpose of this review is to highlight the versatile nature of activins/inhibins as key regulators of both the innate and adaptive immune responses.
Assuntos
Ativinas/imunologia , Imunidade Adaptativa , Imunidade Inata , Inibinas/imunologia , Transdução de Sinais/fisiologia , Ativinas/metabolismo , Animais , Medula Óssea/metabolismo , Hematopoese/fisiologia , Humanos , Inibinas/metabolismo , Leucócitos/imunologia , Camundongos , Fagócitos/imunologia , Fator de Crescimento Transformador beta/metabolismoRESUMO
Members of the transforming growth factor beta (TGF-beta) superfamily are soluble factors that regulate a variety of functional responses including proliferation, differentiation, apoptosis and cell cycle, among others, depending not only on the cell type and its differentiation state, but also on the milieu of cytokines present. All three members of this superfamily: TGF-betas, bone morphogenetic proteins (BMPs) and Activins, have been shown to be expressed in the thymus suggesting their potential role as regulators of the T lymphocyte differentiation process. Although initial reports described the role of TGF-beta in controlling specific checkpoints during thymocyte development, recent data has provided new evidence on the role of BMPs and Activins in this process. This review provides new insights on the function of members of the TGF-beta superfamily at different stages of thymocyte development.