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1.
Int J Mol Sci ; 22(13)2021 Jun 26.
Artigo em Inglês | MEDLINE | ID: mdl-34206987

RESUMO

Hepatitis C virus (HCV) is one of the main triggers of chronic liver disease. Despite tremendous progress in the HCV field, there is still no vaccine against this virus. Potential vaccines can be based on its recombinant proteins. To increase the humoral and, especially, cellular immune response to them, more effective adjuvants are needed. Here, we evaluated a panel of compounds as potential adjuvants using the HCV NS5B protein as an immunogen. These compounds included inhibitors of polyamine biosynthesis and urea cycle, the mTOR pathway, antioxidants, and cellular receptors. A pronounced stimulation of cell proliferation and interferon-γ (IFN-γ) secretion in response to concanavalin A was shown for antioxidant N-acetylcysteine (NAC), polyamine biosynthesis inhibitor 2-difluoromethylornithine (DFMO), and TLR9 agonist CpG ODN 1826 (CpG). Their usage during the immunization of mice with the recombinant NS5B protein significantly increased antibody titers, enhanced lymphocyte proliferation and IFN-γ production. NAC and CpG decreased relative Treg numbers; CpG increased the number of myeloid-derived suppressor cells (MDSCs), whereas neither NAC nor DFMO affected MDSC counts. NAC and DFMO suppressed NO and interleukin 10 (IL-10) production by splenocytes, while DFMO increased the levels of IL-12. This is the first evidence of immunomodulatory activity of NAC and DFMO during prophylactic immunization against infectious diseases.


Assuntos
Acetilcisteína/farmacologia , Adjuvantes Imunológicos/farmacologia , Eflornitina/farmacologia , Hepatite C/imunologia , Imunidade Ativa/efeitos dos fármacos , Proteínas não Estruturais Virais/imunologia , Animais , Proliferação de Células , Células Cultivadas , Feminino , Imunogenicidade da Vacina/efeitos dos fármacos , Interferon gama/metabolismo , Interleucina-10/metabolismo , Interleucina-12/metabolismo , Camundongos , Camundongos Endogâmicos DBA , Células Supressoras Mieloides/efeitos dos fármacos , Células Supressoras Mieloides/imunologia , Óxido Nítrico/metabolismo , Oligodesoxirribonucleotídeos/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Vacinas contra Hepatite Viral/imunologia
2.
Nat Commun ; 12(1): 3611, 2021 06 14.
Artigo em Inglês | MEDLINE | ID: mdl-34127673

RESUMO

Yeast is an integral part of mammalian microbiome, and like commensal bacteria, has the potential of being harnessed to influence immunity in clinical settings. However, functional specificities of yeast-derived immunoregulatory molecules remain elusive. Here we find that while under steady state, ß-1,3-glucan-containing polysaccharides potentiate pro-inflammatory properties, a relatively less abundant class of cell surface polysaccharides, dubbed mannan/ß-1,6-glucan-containing polysaccharides (MGCP), is capable of exerting potent anti-inflammatory effects to the immune system. MGCP, in contrast to previously identified microbial cell surface polysaccharides, through a Dectin1-Cox2 signaling axis in dendritic cells, facilitates regulatory T (Treg) cell induction from naïve T cells. Furthermore, through a TLR2-dependent mechanism, it restrains Th1 differentiation of effector T cells by suppressing IFN-γ expression. As a result, administration of MGCP display robust suppressive capacity towards experimental inflammatory disease models of colitis and experimental autoimmune encephalomyelitis (EAE) in mice, thereby highlighting its potential therapeutic utility against clinically relevant autoimmune diseases.


Assuntos
Imunomodulação/efeitos dos fármacos , Imunomodulação/imunologia , Polissacarídeos/imunologia , Saccharomyces cerevisiae/metabolismo , beta-Glucanas/imunologia , Animais , Linfócitos T CD4-Positivos , Diferenciação Celular/efeitos dos fármacos , Colite/imunologia , Colite/patologia , Ciclo-Oxigenase 2 , Células Dendríticas/imunologia , Encefalomielite Autoimune Experimental , Glucanos , Proteínas de Homeodomínio/genética , Imunidade , Lectinas Tipo C , Mananas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Polissacarídeos/metabolismo , Polissacarídeos/farmacologia , Saccharomyces cerevisiae/genética , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th1 , Zimosan , beta-Glucanas/metabolismo , beta-Glucanas/farmacologia
3.
Int J Mol Sci ; 22(10)2021 May 13.
Artigo em Inglês | MEDLINE | ID: mdl-34068008

RESUMO

A major contributing factor in triple-negative breast cancer progression is its ability to evade immune surveillance. One mechanism for this immunosuppression is through ribosomal protein S19 (RPS19), which facilitates myeloid-derived suppressor cells (MDSCs) recruitment in tumors, which generate cytokines TGF-ß and IL-10 and induce regulatory T cells (Tregs), all of which are immunosuppressive and enhance tumor progression. Hence, enhancing the immune system in breast tumors could be a strategy for anticancer therapeutics. The present study evaluated the immune response of atovaquone, an antiprotozoal drug, in three independent breast-tumor models. Our results demonstrated that oral administration of atovaquone reduced HCC1806, CI66 and 4T1 paclitaxel-resistant (4T1-PR) breast-tumor growth by 45%, 70% and 42%, respectively. MDSCs, TGF-ß, IL-10 and Tregs of blood and tumors were analyzed from all of these in vivo models. Our results demonstrated that atovaquone treatment in mice bearing HCC1806 tumors reduced MDSCs from tumor and blood by 70% and 30%, respectively. We also observed a 25% reduction in tumor MDSCs in atovaquone-treated mice bearing CI66 and 4T1-PR tumors. In addition, a decrease in TGF-ß and IL-10 in tumor lysates was observed in atovaquone-treated mice with a reduction in tumor Tregs. Moreover, a significant reduction in the expression of RPS19 was found in tumors treated with atovaquone.


Assuntos
Anti-Infecciosos/farmacologia , Apresentação do Antígeno/imunologia , Atovaquona/farmacologia , Imunossupressão , Células Supressoras Mieloides/imunologia , Linfócitos T Reguladores/imunologia , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Apoptose , Proliferação de Células , Citocinas/metabolismo , Feminino , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos NOD , Camundongos SCID , Células Supressoras Mieloides/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
4.
Nat Commun ; 12(1): 2582, 2021 05 11.
Artigo em Inglês | MEDLINE | ID: mdl-33976133

RESUMO

Immune checkpoint blockers (ICBs) have failed in all phase III glioblastoma (GBM) trials. Here, we show that regulatory T (Treg) cells play a key role in GBM resistance to ICBs in experimental gliomas. Targeting glucocorticoid-induced TNFR-related receptor (GITR) in Treg cells using an agonistic antibody (αGITR) promotes CD4 Treg cell differentiation into CD4 effector T cells, alleviates Treg cell-mediated suppression of anti-tumor immune response, and induces potent anti-tumor effector cells in GBM. The reprogrammed GBM-infiltrating Treg cells express genes associated with a Th1 response signature, produce IFNγ, and acquire cytotoxic activity against GBM tumor cells while losing their suppressive function. αGITR and αPD1 antibodies increase survival benefit in three experimental GBM models, with a fraction of cohorts exhibiting complete tumor eradication and immune memory upon tumor re-challenge. Moreover, αGITR and αPD1 synergize with the standard of care treatment for newly-diagnosed GBM, enhancing the cure rates in these GBM models.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Glioblastoma/tratamento farmacológico , Proteína Relacionada a TNFR Induzida por Glucocorticoide/agonistas , Linfócitos T Reguladores/efeitos dos fármacos , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linhagem Celular Tumoral/transplante , Reprogramação Celular/efeitos dos fármacos , Reprogramação Celular/imunologia , Modelos Animais de Doenças , Feminino , Glioblastoma/imunologia , Humanos , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Memória Imunológica/efeitos dos fármacos , Masculino , Camundongos , Camundongos Knockout , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
5.
Methods Mol Biol ; 2285: 65-75, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33928543

RESUMO

CD4+ T helper (TH) cells are key mediators of immunity, and according to their effector functions, they can be divided into different subsets, namely, TH1, TH2, TH17, and TH22. In order to maintain systemic homeostasis and peripheral tolerance, CD4+ TH cells are counterbalanced by CD4+ T cells with regulatory properties, namely, Foxp3+ regulatory T cells (Foxp3+TREG) and TR1 cells. Here, we describe how to in vitro differentiate murine naïve CD4+ T cells toward helper (TH1, TH2, TH17, and TH22) and regulatory (Foxp3+TREG and TR1) cells.


Assuntos
Diferenciação Celular , Plasticidade Celular , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Animais , Anticorpos/farmacologia , Biomarcadores/metabolismo , Diferenciação Celular/efeitos dos fármacos , Plasticidade Celular/efeitos dos fármacos , Células Cultivadas , Técnicas de Cocultura , Citocinas/farmacologia , Citometria de Fluxo , Separação Imunomagnética , Camundongos Endogâmicos C57BL , Fenótipo , Projetos de Pesquisa , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/metabolismo , Fluxo de Trabalho
6.
Int J Mol Sci ; 22(8)2021 Apr 13.
Artigo em Inglês | MEDLINE | ID: mdl-33924467

RESUMO

Kurarinone is a flavanone, extracted from Sophora flavescens Aiton, with multiple biological effects. Here, we determine the therapeutic potential of kurarinone and elucidate the interplay between kurarinone and the autoimmune disease rheumatoid arthritis (RA). Arthritis was recapitulated by induction of bovine collagen II (CII) in DBA/1 mice as a collagen-induced arthritis (CIA) model. After the establishment of the CIA, kurarinone was given orally from day 21 to 42 (100 mg/kg/day) followed by determination of the severity based on a symptom scoring scale and with histopathology. Levels of cytokines, anti-CII antibodies, and the proliferation and lineages of T cells from the draining lymph nodes were measured using ELISA and flow cytometry, respectively. The expressional changes, including STAT1, STAT3, Nrf2, KEAP-1, and heme oxygenase-1 (HO-1) changes in the paw tissues, were evaluated by Western blot assay. Oxidative stress featured with malondiadehyde (MDA) and hydrogen peroxide (H2O2) activities in paw tissues were also evaluated. Results showed that kurarinone treatment reduced arthritis severity of CIA mice, as well as their levels of proinflammatory cytokines, TNF-α, IL-6, IFN-γ, and IL-17A, in the serum and paw tissues. T cell proliferation was also reduced by kurarinone even under the stimulation of CII and anti-CD3 antibody. In addition, kurarinone reduced STAT1 and STAT3 phosphorylation and the proportions of Th1 and Th17 cells in lymph nodes. Moreover, kurarinone suppressed the production of MDA and H2O2. All while promoting enzymatic activities of key antioxidant enzymes, SOD and GSH-Px. In the paw tissues, upregulation of Nrf-2 and HO-1, and downregulation of KEAP-1 were observed. Overall, kurarinone showed an anti-inflammatory effect by inhibiting Th1 and Th17 cell differentiation and an antioxidant effect exerted in part through activating the Nrf-2/KEAP-1 pathway. These beneficial effects in CIA mice contributed to the amelioration of their arthritis, indicating that kurarinone might be an adjunct treatment option for rheumatoid arthritis.


Assuntos
Artrite Experimental/tratamento farmacológico , Artrite Experimental/imunologia , Flavonoides/uso terapêutico , Animais , Antioxidantes/metabolismo , Bovinos , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Galinhas , Colágeno Tipo II , Citocinas/sangue , Citocinas/metabolismo , Feminino , Flavonoides/farmacologia , Glutationa Peroxidase/metabolismo , Peróxido de Hidrogênio/metabolismo , Mediadores da Inflamação/metabolismo , Articulações/efeitos dos fármacos , Articulações/patologia , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Malondialdeído/metabolismo , Camundongos , Fator 2 Relacionado a NF-E2/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosforilação/efeitos dos fármacos , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/metabolismo , Superóxido Dismutase/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th1/efeitos dos fármacos , Células Th1/imunologia , Células Th17/efeitos dos fármacos , Células Th17/imunologia
7.
Molecules ; 26(8)2021 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-33920423

RESUMO

Immunotherapy is an effective therapeutic option for several cancers. In the last years, the introduction of checkpoint inhibitors (ICIs) has shifted the therapeutic landscape in oncology and improved patient prognosis in a variety of neoplastic diseases. However, to date, the selection of the best patients eligible for these therapies, as well as the response assessment is still challenging. Patients are mainly stratified using an immunohistochemical analysis of the expression of antigens on biopsy specimens, such as PD-L1 and PD-1, on tumor cells, on peritumoral immune cells and/or in the tumor microenvironment (TME). Recently, the use and development of imaging biomarkers able to assess in-vivo cancer-related processes are becoming more important. Today, positron emission tomography (PET) with 2-deoxy-2-[18F]fluoro-D-glucose ([18F]FDG) is used routinely to evaluate tumor metabolism, and also to predict and monitor response to immunotherapy. Although highly sensitive, FDG-PET in general is rather unspecific. Novel radiopharmaceuticals (immuno-PET radiotracers), able to identify specific immune system targets, are under investigation in pre-clinical and clinical settings to better highlight all the mechanisms involved in immunotherapy. In this review, we will provide an overview of the main new immuno-PET radiotracers in development. We will also review the main players (immune cells, tumor cells and molecular targets) involved in immunotherapy. Furthermore, we report current applications and the evidence of using [18F]FDG PET in immunotherapy, including the use of artificial intelligence (AI).


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Imunoterapia Adotiva/métodos , Neoplasias/diagnóstico por imagem , Neoplasias/terapia , Compostos Radiofarmacêuticos/síntese química , Inteligência Artificial , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Fluordesoxiglucose F18/administração & dosagem , Fluordesoxiglucose F18/química , Humanos , Inibidores de Checkpoint Imunológico/química , Inibidores de Checkpoint Imunológico/metabolismo , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/patologia , Neoplasias/genética , Neoplasias/imunologia , Tomografia por Emissão de Pósitrons/métodos , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Compostos Radiofarmacêuticos/administração & dosagem , Transdução de Sinais , 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 , Microambiente Tumoral/efeitos dos fármacos , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
8.
Am J Physiol Renal Physiol ; 320(5): F814-F825, 2021 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-33719572

RESUMO

Kidney infiltrating immune cells such as monocytes, neutrophils, and T cells play critical roles in renal ischemia-reperfusion (IR) injury and repair. Recently, the angiotensin II type 2 receptor (AT2R) has been implicated in protecting kidneys against injury and monocyte infiltration, particularly in chronic kidney disease. However, the role of AT2R in IR injury and repair phases and T cell modulation is unknown. To address this question, Sprague-Dawley rats were subjected to IR with or without AT2R agonist C21 treatment. IR caused early (2 h postreperfusion) renal functional injury (proteinuria, plasma urea, and creatinine) and enhanced immune cells (T cells and CD4 T cells) infiltration and levels of the proinflammatory cytokines monocyte chemoattractant protein-1, TNF-α, and IL-6. C21 treatment reversed these changes but increased the anti-inflammatory IL-10 level. On day 3, C21 treatment increased CD4+FoxP3+ (regulatory T cells) and CD4+IL-10+ cells and reduced kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin in the kidney compared with the IR control, suggesting the involvement of AT2R in kidney repair. These data indicate that AT2R activation protects the kidney against IR injury and immune cell infiltration in the early phase and modulates CD4 T cells toward the regulatory T cell phenotype, which may have long-term beneficial effects on kidney function.NEW & NOTEWORTHY The angiotensin II type 2 receptor agonist C21 has been known to have a renoprotective role in various kidney pathologies. C21 treatment (before renal ischemia) attenuated postischemic kidney injury, kidney dysfunction, and immune cell infiltration during the injury phase. Also, C21 treatment modulated the kidney microenvironment by enhancing anti-inflammatory responses mainly mediated by IL-10. During the repair phase, C21 treatment enhanced IL-10-secreting CD4 T cells and FoxP3-secreting regulatory T cells in Sprague-Dawley rats.


Assuntos
Injúria Renal Aguda/prevenção & controle , Anti-Inflamatórios/farmacologia , Quimiotaxia de Leucócito/efeitos dos fármacos , Rim/efeitos dos fármacos , Receptor Tipo 2 de Angiotensina/agonistas , Traumatismo por Reperfusão/prevenção & controle , Sulfonamidas/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Tiofenos/farmacologia , Injúria Renal Aguda/imunologia , Injúria Renal Aguda/metabolismo , Injúria Renal Aguda/patologia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Rim/imunologia , Rim/metabolismo , Rim/patologia , Fenótipo , Ratos Sprague-Dawley , Receptor Tipo 2 de Angiotensina/metabolismo , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fatores de Tempo
9.
Front Immunol ; 12: 614320, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33708208

RESUMO

Heat shock proteins (Hsp) are constitutive and stress-induced molecules which have been reported to impact innate and adaptive immune responses. Here, we evaluated the role of Hsp70 as a treatment target in the imiquimod-induced, psoriasis-like skin inflammation mouse model and related in vitro assays. We found that immunization of mice with Hsp70 resulted in decreased clinical and histological disease severity associated with expansion of T cells in favor of regulatory subtypes (CD4+FoxP3+/CD4+CD25+ cells). Similarly, anti-Hsp70 antibody treatment led to lowered disease activity associated with down-regulation of pro-inflammatory Th17 cells. A direct stimulating action of Hsp70 on regulatory T cells and its anti-proliferative effects on keratinocytes were confirmed in cell culture experiments. Our observations suggest that Hsp70 may be a promising therapeutic target in psoriasis and potentially other autoimmune dermatoses.


Assuntos
Anticorpos/imunologia , Dermatite/etiologia , Dermatite/metabolismo , Suscetibilidade a Doenças , Proteínas de Choque Térmico HSP70/imunologia , Animais , Anticorpos/farmacologia , Biomarcadores , Biópsia , Citocinas/metabolismo , Dermatite/diagnóstico , Dermatite/tratamento farmacológico , Modelos Animais de Doenças , Suscetibilidade a Doenças/imunologia , Feminino , Proteínas de Choque Térmico HSP70/antagonistas & inibidores , Proteínas de Choque Térmico HSP70/genética , Imunização , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Camundongos , Proteínas Recombinantes , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Células Th17/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo
10.
Front Immunol ; 12: 577766, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33717062

RESUMO

Background: High-grade sarcomas are a heterogeneous group of aggressive tumors arising in bone and soft tissues. After relapse, treatment options are limited. The multi-targeted receptor tyrosine kinase inhibitors (TKIs) sunitinib and inhibitor of PD-1 (anti-PD-1) nivolumab have shown antitumor activity in selected subtypes. In this study, we examine the role of TKIs and PD-1 based therapy in in vitro cocultures of sarcoma. Methods: The human osteosarcoma (SaOS-2) and synovial sarcoma (SYO-1) cell lines were treated with sunitinib. After cell death and proliferation assessment, expression of PD-L1 was analyzed by flow cytometry. Sunitinib-treated sarcoma cells were cocultured with dendritic cells (DCs), and the phenotype of mature DCs was determined by flow cytometry. Mature DCs were cultured with autologous T cells. PD-1 expression on T cells, their proliferation, T regulatory cell (Tregs) induction and IFN-γ production, before and after nivolumab exposure, were analyzed. Results: Along with its anti-proliferative and direct pro-apoptotic effect on sarcoma cell lines, sunitinib prompted PD-L1 upregulation on sarcoma cells. Interestingly, sunitinib-treated sarcoma cells drive DCs to full maturation and increase their capacity to induce sarcoma-reactive T cells to produce IFN-γ. Conversely, no effect on T cell proliferation and T cell subpopulation composition was observed. Moreover, both bone and synovial sarcoma cell lines induced Tregs through DCs but sunitinib treatment completely abrogated Treg induction. Finally, sarcoma cell lines induced PD-1 upregulation on both effector T cells and Tregs when loaded into DCs, providing a rationale for using PD-1 blockade. Indeed, PD-1 blockade by nivolumab synergized with sunitinib in inducing IFN-γ-producing effector T cells. Conclusions: Taken together, our in vitro data indicate that the treatment of sarcoma cells with sunitinib can exert significant changes on immune cell subsets toward immune activation, leading to DC-based cross-priming of IFN-γ-producing effector T cells and reduced Treg induction. PD-1 blockade with nivolumab has a synergistic effect with sunitinib, supporting the use of TKI and anti-PD-1 approach in sarcomas, and perhaps in other cancers. DC-targeted drugs, including toll-like receptor 3 inhibitors and CD47 inhibitors, are under development and our preclinical model might help to better design their clinical application.


Assuntos
Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Inibidores de Checkpoint Imunológico/farmacologia , Imunomodulação/efeitos dos fármacos , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Sunitinibe/farmacologia , Apoptose/efeitos dos fármacos , Biomarcadores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Humanos , Imunofenotipagem , Interferon gama/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
11.
Front Immunol ; 12: 586220, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33763059

RESUMO

Type 1 diabetes (T1D) is a disorder of impaired glucoregulation due to lymphocyte-driven pancreatic autoimmunity. Mobilizing dendritic cells (DC) in vivo to acquire tolerogenic activity is an attractive therapeutic approach as it results in multiple and overlapping immunosuppressive mechanisms. Delivery of agents that can achieve this, in the form of micro/nanoparticles, has successfully prevented a number of autoimmune conditions in vivo. Most of these formulations, however, do not establish multiple layers of immunoregulation. all-trans retinoic acid (RA) together with transforming growth factor beta 1 (TGFß1), in contrast, has been shown to promote such mechanisms. When delivered in separate nanoparticle vehicles, they successfully prevent the progression of early-onset T1D autoimmunity in vivo. Herein, we show that the approach can be simplified into a single microparticle formulation of RA + TGFß1 with surface decoration with the T1D-relevant insulin autoantigen. We show that the onset of hyperglycemia is prevented when administered into non-obese diabetic mice that are at the mid-stage of active islet-selective autoimmunity. Unexpectedly, the preventive effects do not seem to be mediated by increased numbers of regulatory T-lymphocytes inside the pancreatic lymph nodes, at least following acute administration of microparticles. Instead, we observed a mild increase in the frequency of regulatory B-lymphocytes inside the mesenteric lymph nodes. These data suggest additional and potentially-novel mechanisms that RA and TGFß1 could be modulating to prevent progression of mid-stage autoimmunity to overt T1D. Our data further strengthen the rationale to develop RA+TGFß1-based micro/nanoparticle "vaccines" as possible treatments of pre-symptomatic and new-onset T1D autoimmunity.


Assuntos
Autoantígenos/imunologia , Autoimunidade/efeitos dos fármacos , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Fator de Crescimento Transformador beta1/farmacologia , Tretinoína/farmacologia , Animais , Células Dendríticas , Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/tratamento farmacológico , Composição de Medicamentos , Feminino , Insulina/metabolismo , Contagem de Linfócitos , Camundongos , Camundongos Endogâmicos NOD , Pâncreas/metabolismo , Pâncreas/patologia , Índice de Gravidade de Doença , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Fator de Crescimento Transformador beta1/química , Tretinoína/química
12.
Food Funct ; 12(7): 3191-3205, 2021 Apr 07.
Artigo em Inglês | MEDLINE | ID: mdl-33735338

RESUMO

Fructooligosaccharides (FOS) can change gut microbiota composition and play a protective role in food allergy (FA). Furthermore, the protective mechanism of FOS against FA is unclear. In this study, intestinal flora and tryptophan (Trp) metabolites were investigated in a mouse model with FA supplemented with FOS. Meanwhile, we injected aryl hydrocarbon receptor antagonists (AhR-A) into a mouse model of FA supplemented with FOS to investigate whether T helper cell (Th) 17/regulatory T (Treg) cell balance was affected. Our research studies showed that dietary intake of FOS provided moderate protection from the intestinal inflammation induced by ovalbumin (OVA). This protective effect disappeared in AhR-A mice. The OVA mice manifestations had significantly lower bacterial richness, when compared to the normal control (NC) mice. Among fecal bacteria, the abundance of Akkermansiaceae (family level) and Verrucomicrobia (phylum level) increased and Ruminococcacere (phylum level) decreased in the feces of allergic mice. These changes were reversed by FOS treatment. FOS modulated the gut microbiome profiles that were altered in OVA mice, which showed an increase in the abundance of Ruminococcacere (phylum level) and a decrease in the abundance of Akkermansiaceae (family level) and Verrucomicrobia (phylum level). Liquid chromatography/tandem mass spectrometry (LC-MS/MS) analysis of Trp metabolites showed significant reductions in the level of kynurenine (kyn) in the serum of OVA mice, as compared to NC and FOS mice. Conversely, the levels of Trp and 5-hydroxytryptamine (5-HT) were significantly increased in OVA mice. Correlation analysis revealed a negative relationship between the relative abundance of Verrucomicrobiae (class level) and Akkermansiaceae (family level) with kyn, and a positive relationship with 5-HT. FOS significantly reduced interleukin-17A (IL-17A) and retinoic acid-associated nuclear orphan receptor-γt (RORγt) in FOS mice but not in AhR-A mice. FOS increased the level of interleukin-10 (IL-10) and Forkhead box P3 (Foxp3) in FOS mice but not in AhR-A mice. These findings suggest that FOS ameliorates allergic symptoms and impacts Th17/Treg balance in mice by modulating the gut microbiota composition and Trp metabolites. FOS may serve as an effective tool for the treatment of FA by regulating immune and gut microbiota.


Assuntos
Hipersensibilidade Alimentar/prevenção & controle , Oligossacarídeos/administração & dosagem , Animais , Modelos Animais de Doenças , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Oligossacarídeos/farmacologia , Ovalbumina , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Triptofano/metabolismo
13.
J Pharmacol Exp Ther ; 377(2): 273-283, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33658314

RESUMO

Cannabidiol (CBD) is a highly lipidic phytocannabinoid with remarkable anti-inflammatory effects. The aim of this study was to evaluate CBD's effects and mechanisms of action in the treatment of mice subjected to acute graft-versus-host disease (aGVHD). aGVHD was induced by the transplantation of bone marrow cells and splenocytes from C57BL-6j to Balb-c mice. The recipient mice were treated daily with CBD, and the treatment reduced mouse mortality by decreasing inflammation and injury and promoting immune regulation in the jejunum, ileum, and liver. Analysis of the jejunum and ileum showed that CBD treatment reduced the levels of C-C motif chemokine ligand (CCL) 2, CCL3, CCL5, tumor necrosis factor α, and interferon γ (IFNγ). CCL3 and IFNγ levels were also decreased in the liver. Mechanistically, CBD also increased the number of cannabinoid receptor type 2 (CB2) receptors on CD4+ and forkhead box P3+ cells in the intestine, which may explain the reduction in proinflammatory cytokines and chemokines. Antagonists of the CB2 receptor reduced the survival rates of CBD-treated mice, suggesting the participation of this receptor in the effects of CBD. Furthermore, treatment with CBD did not interfere with the graft-versus-leukemia response. CBD treatment appears to protect aGVHD mice by anti-inflammatory and immunomodulatory effects partially mediated by CB2 receptor interaction. Altogether, our study suggests that CBD represents an interesting approach in the treatment of aGVHD, with potential therapeutic applications in patients undergoing bone marrow transplantation. SIGNIFICANCE STATEMENT: This study provides for the first time a mechanism by which cannabidiol, a phytocannabinoid with no psychoactive effect, induces immunomodulation in the graft-versus-host disease. Enhancing intestinal cannabinoid receptor type 2 (CB2) receptor expression on CD4+ and forkhead box P3+ cells and increasing the number of these regulatory cells, cannabidiol decreases proinflammatory cytokines and increases graft-versus-host disease mice survival. This effect is dependent of CB2 receptor activation. Besides, cannabidiol did not interfere with graft-versus-leukemia response, a central response to avoid primary disease relapse.


Assuntos
Canabidiol/uso terapêutico , Doença Enxerto-Hospedeiro/tratamento farmacológico , Mucosa Intestinal/metabolismo , Leucemia/terapia , Receptor CB2 de Canabinoide/metabolismo , Animais , Transplante de Medula Óssea/efeitos adversos , Transplante de Medula Óssea/métodos , Canabidiol/farmacologia , Células Cultivadas , Quimiocinas CC/genética , Quimiocinas CC/metabolismo , Interferon gama/genética , Interferon gama/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Leucemia/imunologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Receptor CB2 de Canabinoide/agonistas , Receptor CB2 de Canabinoide/genética , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo
14.
Life Sci ; 276: 119395, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33781828

RESUMO

AIMS: STAT3 signaling is critical for Th17 development that plays an important role in multiple sclerosis pathogenesis. To evaluate the anti-inflammatory and regulatory T cells effects of JAK1/2 and STAT3 inhibition, we assessed the JAK 1/2 inhibitor ruxolitinib effects on Th17 cell/Tregs balance. MAIN METHODS: Ruxolitinib was administered to experimental autoimmune encephalomyelitis (EAE) mice via oral gavage, and its effects were assessed. The expression of pro-inflammatory and anti-inflammatory cytokines, including IL-17A and IL-10, were analyzed by real-time PCR. The frequency of Th17 cells and Tregs were evaluated by flow cytometry. KEY FINDING: Ruxolitinib ameliorated the EAE severity and decreased the proportion of Th17 cells and inflammatory markers levels. In contrast, the balance of Tregs and the level of anti-inflammatory cytokine were increased in ruxolitinib-treated mice. Furthermore, ruxolitinib markedly decreased the expression of Th17 related transcription factor, RORÉ£t, whereas FOXP3 expression associated with Treg differentiation was increased. SIGNIFICANCE: Our results show that ruxolitinib may be a promising therapeutic strategy for multiple sclerosis.


Assuntos
Citocinas/metabolismo , Modelos Animais de Doenças , Encefalomielite Autoimune Experimental/tratamento farmacológico , Esclerose Múltipla/tratamento farmacológico , Pirazóis/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Encefalomielite Autoimune Experimental/patologia , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Esclerose Múltipla/imunologia , Esclerose Múltipla/metabolismo , Esclerose Múltipla/patologia , Transdução de Sinais , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
15.
Life Sci ; 276: 119437, 2021 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-33789145

RESUMO

In Coronavirus disease 2019 (COVID-19), a decreased number of regulatory T (Treg) cells and their mediated factors lead to a hyperinflammatory state due to overactivation of the inflammatory cells and factors during the infection. In the current study, we evaluated the Nanocurcumin effects on the Treg cell population and corresponding factors in mild and severe COVID-19 patients. To investigate the Nanocurcumin effects, 80 COVID-19 patients (40 at the severe stage and 40 at the mild stage) were selected and classified into Nanocurcumin and placebo arms. In both the Nanocurcumin and placebo groups, the Treg cell frequency, the gene expression of Treg transcription factor forkhead box P3 (FoxP3), and cytokines (IL-10, IL-35, and TGF-ß), as well as the serum levels of cytokines were measured before and after treatment. In both mild and severe COVID-19 patients, Nanocurcumin could considerably upregulate the frequency of Treg cells, the expression levels of FoxP3, IL-10, IL-35, and TGF-ß, as well as the serum secretion levels of cytokines in the Nanocurcumin-treated group compared to the placebo group. The abovementioned factors were remarkably increased in the post-treatment with Nanocurcumin before pre-treatment conditions. By contrast, it has been observed no notable alteration in the placebo group. Our findings revealed the SinaCurcumin® effective function in a significant increase in the number of Treg cells and their mediated factors in the Nanocurcumin group than in the placebo group in both mild and severe patients. Hence, it would be an efficient therapeutic agent in rehabilitating COVID-19 infected patients.


Assuntos
COVID-19/tratamento farmacológico , Curcumina/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Adulto , Idoso , COVID-19/imunologia , COVID-19/virologia , Citocinas/efeitos dos fármacos , Citocinas/imunologia , Feminino , Fatores de Transcrição Forkhead/genética , Fatores de Transcrição Forkhead/metabolismo , Expressão Gênica/efeitos dos fármacos , Humanos , Interleucina-10/imunologia , Interleucinas/imunologia , Masculino , Pessoa de Meia-Idade , Nanomedicina/métodos , RNA Viral/metabolismo , SARS-CoV-2/efeitos dos fármacos , SARS-CoV-2/isolamento & purificação , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Fator de Crescimento Transformador beta/imunologia
16.
Nat Commun ; 12(1): 832, 2021 02 05.
Artigo em Inglês | MEDLINE | ID: mdl-33547304

RESUMO

The two T cell inhibitory receptors PD-1 and TIM-3 are co-expressed during exhausted T cell differentiation, and recent evidence suggests that their crosstalk regulates T cell exhaustion and immunotherapy efficacy; however, the molecular mechanism is unclear. Here we show that PD-1 contributes to the persistence of PD-1+TIM-3+ T cells by binding to the TIM-3 ligand galectin-9 (Gal-9) and attenuates Gal-9/TIM-3-induced cell death. Anti-Gal-9 therapy selectively expands intratumoral TIM-3+ cytotoxic CD8 T cells and immunosuppressive regulatory T cells (Treg cells). The combination of anti-Gal-9 and an agonistic antibody to the co-stimulatory receptor GITR (glucocorticoid-induced tumor necrosis factor receptor-related protein) that depletes Treg cells induces synergistic antitumor activity. Gal-9 expression and secretion are promoted by interferon ß and γ, and high Gal-9 expression correlates with poor prognosis in multiple human cancers. Our work uncovers a function for PD-1 in exhausted T cell survival and suggests Gal-9 as a promising target for immunotherapy.


Assuntos
Adenocarcinoma/terapia , Neoplasias do Colo/terapia , Galectinas/imunologia , Regulação Neoplásica da Expressão Gênica/imunologia , Proteína Relacionada a TNFR Induzida por Glucocorticoide/imunologia , Receptor Celular 2 do Vírus da Hepatite A/imunologia , Receptor de Morte Celular Programada 1/imunologia , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adenocarcinoma/mortalidade , Animais , Anticorpos/farmacologia , Antineoplásicos Imunológicos/farmacologia , Neoplasias do Colo/genética , Neoplasias do Colo/imunologia , Neoplasias do Colo/mortalidade , Galectinas/antagonistas & inibidores , Galectinas/genética , Proteína Relacionada a TNFR Induzida por Glucocorticoide/agonistas , Proteína Relacionada a TNFR Induzida por Glucocorticoide/genética , Receptor Celular 2 do Vírus da Hepatite A/genética , Humanos , Imunoterapia/métodos , Células Jurkat , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/mortalidade , Melanoma Experimental/terapia , Camundongos , Camundongos Endogâmicos BALB C , Receptor de Morte Celular Programada 1/genética , Ligação Proteica , Transdução de Sinais , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Neoplasias Cutâneas/terapia , Análise de Sobrevida , 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
18.
Biol Chem ; 402(2): 167-178, 2021 01 27.
Artigo em Inglês | MEDLINE | ID: mdl-33544473

RESUMO

Cancer recurrence presents a huge challenge in cancer patient management. Immune escape is a key mechanism of cancer progression and metastatic dissemination. CD25 is expressed in regulatory T (Treg) cells including tumor-infiltrating Treg cells (TI-Tregs). These cells specially activate and reinforce immune escape mechanism of cancers. The suppression of CD25/IL-2 interaction would be useful against Treg cells activation and ultimately immune escape of cancer. Here, software, web servers and databases were used, at which in silico designed small interfering RNAs (siRNAs), de novo designed peptides and virtual screened small molecules against CD25 were introduced for the prospect of eliminating cancer immune escape and obtaining successful treatment. We obtained siRNAs with low off-target effects. Further, small molecules based on the binding homology search in ligand and receptor similarity were introduced. Finally, the critical amino acids on CD25 were targeted by a de novo designed peptide with disulfide bond. Hence we introduced computational-based antagonists to lay a foundation for further in vitro and in vivo studies.


Assuntos
Subunidade alfa de Receptor de Interleucina-2/antagonistas & inibidores , Interleucina-2/antagonistas & inibidores , Peptídeos/farmacologia , RNA Interferente Pequeno/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Software , Bases de Dados Factuais , Humanos , Interleucina-2/química , Interleucina-2/imunologia , Subunidade alfa de Receptor de Interleucina-2/química , Subunidade alfa de Receptor de Interleucina-2/imunologia , Peptídeos/síntese química , Peptídeos/química , RNA Interferente Pequeno/síntese química , RNA Interferente Pequeno/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia
19.
Scand J Immunol ; 94(1): e13031, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33606277

RESUMO

Severe eosinophilic asthma (SEA) has been associated with T-helper type 2 (Th2) inflammatory response. A good understanding of T cell functions in asthma is important for therapy, especially in the choice of biological treatments for severe cases. Mepolizumab, an IL-5 antagonist, is indicated for the treatment of severe asthma. Regulatory T cells (Tregs) suppress inflammation by secreting cytokines that inhibit Th2 cell proliferation. We investigated peripheral Treg, CD4, CD8, CD19 and NK cell percentages and their relationship to clinical and functional parameters, including peripheral eosinophils, before and after anti-IL5 treatment. Subjects were 14 adult SEA patients (9 male, 54.1 ± 11.6 years), treated with mepolizumab, and 10 controls. T cells (CD4 and CD8), CD19, NK and Tregs were evaluated by flow cytometry. Comparison of lung function parameters before and after treatment with mepolizumab (T0 and T1) showed an increase in FEV1, FEV1/FVC ratio and a reduction in blood eosinophil percentages. CD8 and CD16/56+ CD3+ were significantly higher in SEA patients than controls (P = .04 and P = .03, respectively). A decrease in CD45+, CD8 + and CD16/56+ CD3+ cell percentages was observed between T0 and T1 (P = .02, P = .04, P = .03, respectively). A significant increase in Treg percentages (P = .0001) was recorded between T0 and T1. Mepolizumab therapy was found to modulate immune response, restoring immune balance in patients with SEA.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/imunologia , Eosinófilos/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Proliferação de Células/efeitos dos fármacos , Citocinas/imunologia , Feminino , Humanos , Inflamação/imunologia , Interleucina-5/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Células Th2/efeitos dos fármacos , Células Th2/imunologia
20.
Phytomedicine ; 84: 153519, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33640781

RESUMO

BACKGROUND: Gegen Qinlian decoction (GQ) is a traditional Chinese herbal prescription that has been widely used for the treatment of bacterial dysentery and enteric typhoid fever. Recently, GQ has been clinically reported to be a potential candidate for the treatment of ulcerative colitis (UC). However, the immunoregulatory function of GQ in the treatment of UC has not been fully elucidated. PURPOSE: This study focused on the role of immune imbalance in the pathogenesis of UC and the immunomodulatory effect of GQ in the treatment of UC. METHODS: The UC model was established by treating female mice with 3.0% dextran sulfate sodium (DSS) for 7 days, and GQ was orally administered at dosages of 1.5 and 7.5 g/kg/day. Inflammatory factors were detected by ELISA and qRT-PCR. Treg and Th17 cell dysregulation was analyzed by qRT-PCR, immunohistochemistry and flow cytometry. Proteins related to IL-6/JAK2/STAT3 signaling were detected by western blotting. RESULTS: GQ significantly alleviated the symptoms of UC mice and suppressed the activity of myeloperoxidase (MPO). Furthermore, the production of proinflammatory factors, such as IL-1ß, TNF-α and IL-6, was dramatically reduced after GQ administration. Furthermore, GQ improved the infiltration of Treg and Th17 cells into the colons and decreased the expression of inflammatory factors, such as TGF-ß1 and IL-17. The frequencies of Treg and Th17 cells in the Peyer's patches and spleen were reduced by GQ administration; however, GQ had no significant regulatory effect on normal mice. The western blotting results showed that GQ markedly suppressed the phosphorylation of JAK2 and STAT3 and decreased the transcription function of phosphorylated STAT3. CONCLUSIONS: Taken together, these results indicated that GQ alleviated DSS-induced UC by suppressing IL-6/JAK2/STAT3 signaling to restore Treg and Th17 cell homeostasis in colonic tissue.


Assuntos
Colite Ulcerativa/tratamento farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Linfócitos T Reguladores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Animais , Colite Ulcerativa/induzido quimicamente , Colite Ulcerativa/imunologia , Colite Ulcerativa/metabolismo , Colo/efeitos dos fármacos , Colo/imunologia , Colo/metabolismo , Colo/patologia , Sulfato de Dextrana/toxicidade , Medicamentos de Ervas Chinesas/química , Feminino , Homeostase/efeitos dos fármacos , Fatores Imunológicos/farmacologia , Interleucina-17/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Janus Quinase 2/metabolismo , Camundongos Endogâmicos C57BL , Peroxidase/metabolismo , Nódulos Linfáticos Agregados/efeitos dos fármacos , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Células Th17/imunologia
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