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1.
Braz J Med Biol Res ; 53(1): e8669, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31859913

RESUMO

This study aimed to investigate the therapeutic effect of fasudil on treating experimental autoimmune neuritis (EAN). Twenty-four EAN mice were randomly assigned to fasudil treatment (Fasudil group) or saline treatment (EAN model group) for 28 days. Clinical symptom score was evaluated every other day; inflammatory cell infiltration, demyelination, anti-myelin basic protein (MBP), inflammatory cytokines, inducible nitric oxide synthase (iNOS), and arginase-1 were detected in sciatic nerves at day 28. Th1, Th2, Th17, and Tregs proportions in splenocytes were detected at day 28. Clinical symptom score was found to be attenuated in the Fasudil group compared to the EAN model group from day 12 to day 28. Sciatic nerve inflammatory cell counts by HE staining and demyelination by luxol fast blue staining were both reduced, while MBP was increased in the Fasudil group compared to the EAN model group at day 28. Interferon γ (IFN-γ) and interleukin (IL)-17 were reduced, while IL-4 and IL-10 were elevated in the Fasudil group at day 28. Sciatic nerve M1 macrophages marker iNOS was decreased while M2 macrophages marker arginase-1 was increased in the Fasudil group at day 28. CD4+IFN-γ+ (Th1) and CD4+IL-17+ (Th17) cell proportions were both decreased, CD4+IL-4+ (Th2) cell proportion was similar, while CD25+FOXP3+ (Treg) cell proportion in splenocytes was increased in the Fasudil group. In summary, fasudil presented a good therapeutic effect for treating EAN by attenuating Th1/Th17 cells and promoting Tregs activation as well as M2 macrophages polarization.


Assuntos
1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/análogos & derivados , Interferon gama/sangue , Interleucinas/sangue , Neurite Autoimune Experimental/tratamento farmacológico , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , 1-(5-Isoquinolinasulfonil)-2-Metilpiperazina/administração & dosagem , Animais , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Neurite Autoimune Experimental/sangue , RNA Mitocondrial , Reação em Cadeia da Polimerase em Tempo Real , Nervo Isquiático/efeitos dos fármacos , Nervo Isquiático/metabolismo , Fatores de Tempo
2.
Life Sci ; 239: 117021, 2019 Dec 15.
Artigo em Inglês | MEDLINE | ID: mdl-31678552

RESUMO

OBJECTIVES: Clematichinenoside AR (AR) is a saponin extracted for traditional Chinese medicine with the effects of improving the expression of tight junction (TJ) proteins and mediating anti-inflammatory activities. However, its effect on Crohn's disease (CD) is still unknown. We aimed to investigate the impact of AR on CD-like colitis and determine the mechanism underlying its effects. METHODS: Interleukin-10 gene knockout (Il-10-/-) mice (male, fifteen weeks old) with spontaneous colitis were allocated to the positive control and AR-treated (32 mg/kg AR administered every other day by gavage for 4 weeks) groups. Wild-type (WT) mice (male, fifteen weeks old) composed the negative control group. The effects of AR on intestinal barrier function and structure and T cell responses as well as the potential mechanisms underlying these effects were investigated. RESULTS: AR treatment significantly improved spontaneous colitis in Il-10-/- mice as demonstrated by reductions in the inflammatory score, disease activity index (DAI) and levels of inflammatory factors. The effects of AR on colitis in Il-10-/- mice were related to protecting intestinal barrier function and maintaining immune system homeostasis (regulatory T cell (Treg)/T helper 17 (Th17) cell balance). The anticolitis effect of AR may partly act by downregulating PI3K/Akt signaling. CONCLUSIONS: AR may have therapeutic potential for treating CD in humans.


Assuntos
Colite/tratamento farmacológico , Colite/genética , Interleucina-10/genética , Intestinos/patologia , Saponinas/uso terapêutico , Triterpenos/uso terapêutico , Animais , Translocação Bacteriana/efeitos dos fármacos , Colite/patologia , Citocinas/metabolismo , Intestinos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos
3.
APMIS ; 127(12): 789-796, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31512766

RESUMO

The aim was to examine anti-tumor necrosis factor α (anti-TNFα) therapy influence changes on Th17 and Th22 cells in patients with spondyloarthritis (SpA), and its correlation with changes in clinical and magnetic resonance imaging (MRI) activity and chronicity scores. The Th17 and Th22 cells were assessed at baseline, after 12 and 52 weeks of anti-TNFα therapy by flow cytometry (ClinicalTrials.gov NCT4682724). The percentages of both Th17 and Th22 cells were increased by 70% at baseline compared with healthy controls (both p < 0.01). During treatment, these two subsets increased further to be 170% (Th17) and 123% (Th22) above levels in healthy controls (both p < 0.01). The same subsets decrease their expression of IL-23R significantly during the observation period (p < 0.05). High levels of Th17 and Th22 cells at baseline were associated with the degree of chronic changes in the sacroiliac joints on MRI and a good clinical response to anti-TNFα treatment after one year. Plasma levels were not associated with clinical changes. Th17 cells, and Th22 subsets, increased during one year of anti-TNF-α therapy in SpA, regardless of their clinical improvement. This supports that both the Th17 and Th22 subsets could be involved in the progression in SpA.


Assuntos
Anti-Inflamatórios/uso terapêutico , Espondilartrite/tratamento farmacológico , Linfócitos T Auxiliares-Indutores/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Adulto , Anti-Inflamatórios/farmacologia , Feminino , Citometria de Fluxo , Humanos , Interleucina-17/metabolismo , Interleucinas/metabolismo , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Receptores de Interleucina/metabolismo , Espondilartrite/diagnóstico por imagem , Espondilartrite/imunologia , Espondilartrite/patologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Células Th17/efeitos dos fármacos , Células Th17/metabolismo , Resultado do Tratamento
4.
Toxicol Lett ; 316: 147-153, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31520700

RESUMO

Asthma is a common chronic inflammatory disease which severely reduces the quality of life in patients. Studies have demonstrated that both PM2.5 and cold stress contribute to the development of asthma. However, the combined effects of these two risking factors are unknown. In this study, we investigated the combined effects of PM2.5 exposure and cold stress (PMCS) on asthma, as well as the underlying mechanisms by using a murine model. After different exposures, the immune-pathological changes and redox states in groups were evaluated. Besides, the balance of TH1/TH2 cells and the acetylation levels of H3K9 and H3K14 in IL-4 gene promotor were detected. Our results showed that, compared with other exposures, PMCS led to an increased inflammation and redox levels in mice. It also significantly increased the percentage of TH2 T cells, which was correlated with hyperacetylation of H3K9 and H3K14 in IL-4 gene promoter in CD4+T cells. Furthermore, a significantly increased P300 and decreased HDAC1 were detected in CD4 + T cells in PMCS group. In conclusion, our findings demonstrated that PMCS exacerbated asthma in mice by increasing H3K9 and H3K14 acetylation in IL-4 gene promoter in CD4 + T cells, and P300 and HDAC1 might contribute to their combined effects.


Assuntos
Asma/induzido quimicamente , Temperatura Baixa/efeitos adversos , Histonas/metabolismo , Interleucina-4/metabolismo , Pulmão/efeitos dos fármacos , Material Particulado/toxicidade , Regiões Promotoras Genéticas , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Acetilação , Animais , Asma/genética , Asma/imunologia , Asma/metabolismo , Modelos Animais de Doenças , Proteína p300 Associada a E1A/metabolismo , Histona Desacetilase 1/metabolismo , Interleucina-4/genética , Interleucina-4/imunologia , Pulmão/imunologia , Pulmão/metabolismo , Masculino , Camundongos Endogâmicos BALB C , Ovalbumina , Tamanho da Partícula , Processamento de Proteína Pós-Traducional , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo
5.
Int Immunopharmacol ; 75: 105758, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31377589

RESUMO

OBJECTIVE: The present study aimed to investigate the functional role of bortezomib in the development of acute allograft rejection (AR) after renal transplant. METHODS: The mouse model of AR was established by allograft kidney transplant followed by the treatment of bortezomib. The serum cytokines, renal function, and the percentage of T follicular helper (Tfh) cells in CD4+ T cells were measured. The effect of miR-15b and interferon-regulatory factor 4 (IRF4) on Tfh cell proliferation and differentiation was assessed by cell transfection technology and CCK-8 assay. The interaction between miR-15b and IRF4 was assessed by luciferase reporter assay. RESULTS: Bortezomib relieved acute AR after renal transplant by suppressing Tfh cell proliferation and differentiation. Meanwhile, bortezomib treatment markedly increased miR-15b expression in AR renal tissues. The upregulation of miR-15b inhibited Tfh cell proliferation and differentiation by reducing IRF4. In addition, bortezomib ameliorated AR by suppressing Tfh cell proliferation and differentiation through miR-15b/IRF4 axis in vitro and in vivo. CONCLUSION: Our findings indicated the mechanism underlying the bortezomib in treating acute AR after renal transplant, and suggested the critical role of miR-15b in Tfh cell proliferation and differentiation, which provided a therapeutic target in attenuating acute AR.


Assuntos
Bortezomib/uso terapêutico , Rejeição de Enxerto/tratamento farmacológico , Imunossupressores/uso terapêutico , Fatores Reguladores de Interferon/imunologia , Transplante de Rim , MicroRNAs/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Aloenxertos , Animais , Bortezomib/farmacologia , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Citocinas/sangue , Feminino , Rejeição de Enxerto/imunologia , Imunossupressores/farmacologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Linfócitos T Auxiliares-Indutores/imunologia
6.
Molecules ; 24(13)2019 Jul 05.
Artigo em Inglês | MEDLINE | ID: mdl-31284478

RESUMO

Dihydroartemisinin (DHA) is a derivative of the herb Artemisia annua L. that has prominent immunomodulatory activity; however, its underlying mechanism remains elusive. Inflammatory bowel disease (IBD) is an idiopathic inflammatory condition characterized as an autoimmune disorder that includes dysfunctions in the T helper (Th)/T regulatory cell (Treg) balance, which normally plays pivotal roles in immune homeostasis. The aim of this study was to explore the potential of DHA to ameliorate IBD by restoring the Th/Treg cell balance. To this end, we established mouse models of colitis induced by oxazolone (OXA) and 2,4,6-trinitro-benzene sulfonic acid (TNBS). We then treated mice with DHA at 4, 8, or 16 mg/kg/day. DHA treatment ameliorated colitis signs and reduced lymphocyte infiltration and tissue fibrosis. Moreover, DHA decreased the numbers of Th1 and Th17 cells and Th9 and Th22 cells in TNBS- or OXA-induced colitis, respectively, and increased Tregs in both models. DHA (0.8 mg/mL) also inhibited activated CD4+ T lymphocytes, which was accompanied by apoptosis induction. Moreover, it promoted heme oxygenase-1 (HO-1) production in vitro and in vivo, concomitant with CD4+ T cell apoptosis and restoration of the Th/Treg balance, and these effects were blocked by treatment with the HO-1 inhibitor Sn-protoporphyrin IX. Overall, these results suggest that DHA is a novel and valuable candidate for IBD therapy or Th/Treg immunoregulation.


Assuntos
Apoptose , Artemisininas/uso terapêutico , Heme Oxigenase-1/biossíntese , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/imunologia , Ativação Linfocitária/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Animais , Apoptose/efeitos dos fármacos , Artemisininas/farmacologia , Colite/induzido quimicamente , Colite/tratamento farmacológico , Colite/imunologia , Modelos Animais de Doenças , Indução Enzimática/efeitos dos fármacos , Doenças Inflamatórias Intestinais/enzimologia , Ativação Linfocitária/efeitos dos fármacos , Subpopulações de Linfócitos/efeitos dos fármacos , Subpopulações de Linfócitos/imunologia , Camundongos , Oxazolona , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/efeitos dos fármacos , Ácido Trinitrobenzenossulfônico
7.
Molecules ; 24(13)2019 Jul 04.
Artigo em Inglês | MEDLINE | ID: mdl-31277476

RESUMO

Advanced glycation end products (AGE), the most known aging biomarker, may cause "inflamm-aging" (i.e., chronic low-grade inflammation that develops with aging) in both aged and diabetes groups. However, the molecular bases of inflamm-aging remain obscure. We prepared AGE by incubating BSA (0.0746 mmol/L) + glucose (0.5 mol/L) at 37 °C in 5% CO2-95% air for 1-180 days. The lysine glycation in BSA-AGE reached 77% on day 30 and 100% after day 130, whereas the glycation of arginine and cysteine was minimal. The Nε-(carboxymethyl)-lysine content in BSA-AGE was also increased with increasing number of incubation days. The lectin-binding assay revealed that the glycation of BSA not only altered the conformational structure, but lost binding capacity with various lectins. An immunological functional assay showed that BSA-AGE > 8 µg/mL significantly suppressed normal human Th1 (IL-2 and IFN-γ) and Th2 (IL-10) mRNA expression, whereas AGE > 0.5 µg/mL enhanced monocyte IL-6 production irrelevant to cell apoptosis. The AGE-enhanced monocyte IL-6 production was via MAPK-ERK and MyD88-transduced NF-κBp50 signaling pathways. To elucidate the structure-function relationship of BSA-AGE-enhanced IL-6 production, we pre-preincubated BSA-AGE with different carbohydrate-degrading, protein-degrading, and glycoprotein-degrading enzymes. We found that trypsin and carboxypeptidase Y suppressed whereas ß-galactosidase enhanced monocyte IL-6 production. In conclusion, BSA-AGE exerted both immunosuppressive and pro-inflammatory effects that are the molecular basis of inflamm-aging in aged and diabetes groups.


Assuntos
Produtos Finais de Glicação Avançada/farmacologia , Interleucina-6/genética , Sistema de Sinalização das MAP Quinases , Monócitos/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Subunidade p50 de NF-kappa B/metabolismo , Soroalbumina Bovina/farmacologia , Linfócitos T Auxiliares-Indutores/metabolismo , Aminoácidos/metabolismo , Animais , Bovinos , Regulação da Expressão Gênica/efeitos dos fármacos , Glicoproteínas/metabolismo , Humanos , Interleucina-6/metabolismo , Lectinas/metabolismo , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Reação de Maillard/efeitos dos fármacos , Peso Molecular , Monócitos/efeitos dos fármacos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Células Th1/efeitos dos fármacos , Células Th1/metabolismo , Células Th2/efeitos dos fármacos , Células Th2/metabolismo
8.
J Neuroinflammation ; 16(1): 149, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324254

RESUMO

BACKGROUND: Unrestrained activation of Th1 and Th17 cells is associated with the pathogenesis of multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE). While inactivation of dynamin-related protein 1 (Drp1), a GTPase that regulates mitochondrial fission, can reduce EAE severity by protecting myelin from demyelination, its effect on immune responses in EAE has not yet been studied. METHODS: We investigated the effect of Mdivi-1, a small molecule inhibitor of Drp1, on EAE. Clinical scores, inflammation, demyelination and Drp1 activation in the central nervous system (CNS), and T cell responses in both CNS and periphery were determined. RESULTS: Mdivi-1 effectively suppressed EAE severity by reducing demyelination and cellular infiltration in the CNS. Mdivi-1 treatment decreased the phosphorylation of Drp1 (ser616) on CD4+ T cells, reduced the numbers of Th1 and Th17 cells, and increased Foxp3+ regulatory T cells in the CNS. Moreover, Mdivi-1 treatment effectively inhibited IFN-γ+, IL-17+, and GM-CSF+ CD4+ T cells, while it induced CD4+ Foxp3+ regulatory T cells in splenocytes by flow cytometry. CONCLUSIONS: Together, our results demonstrate that Mdivi-1 has therapeutic potential in EAE by modulating the balance between Th1/Th17 and regulatory T cells.


Assuntos
Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/patologia , Quinazolinonas/farmacologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Animais , Inibidores Enzimáticos/farmacologia , Feminino , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Dinâmica Mitocondrial/efeitos dos fármacos , Proteínas de Ligação a RNA/antagonistas & inibidores , Linfócitos T Auxiliares-Indutores/imunologia
9.
J Neurooncol ; 143(3): 429-436, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31152305

RESUMO

PURPOSE: Immunosuppression is one of hallmark features in many cancers including glioma. Triptolide, a natural compound purified from the Chinese herb Tripterygium wilfordii, has been reported to inhibit PD-L1 otherwise known as the B7 homolog 1 (B7-H1) expression in breast cancer. The purpose of this paper is to test the effects of Triptolide on T cell inhibition in glioma cells. METHODS: We labeled T cells and cocultured with Interferon-γ (IFN-γ) and Triptolide treated glioma cells. The effect on inhibition of T cells as well as subtypes of T cells was measured by Flow Cytometry. We also tested the expression of PD-L1 in six glioma cell lines. RESULTS: We found that Triptolide could reverse T cell inhibition especially CD4+ T cell and induced IFN-γ secretion. In addition, Triptolide could also induce interleukin-2 secretion and overcome interleukin-10 inhibition caused by glioma cells under IFN-γ treated condition. Triptolide could also down-regulate IFN-γ induced PD-L1 surface expression in glioma cells. CONCLUSIONS: These results suggest that Triptolide may be used to reverse CD4+ T cell inhibition caused by glioma cells and is an alternative candidate for targeting PD-L1, one of the checkpoint inhibitors for the treatment of glioma.


Assuntos
Antígeno B7-H1/antagonistas & inibidores , Linfócitos T CD4-Positivos/efeitos dos fármacos , Diterpenos/farmacologia , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Glioma/tratamento farmacológico , Interferon gama/farmacologia , Fenantrenos/farmacologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Antineoplásicos Alquilantes/farmacologia , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Técnicas de Cocultura , Regulação para Baixo , Compostos de Epóxi/farmacologia , Glioma/imunologia , Glioma/metabolismo , Humanos , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Células Tumorais Cultivadas
10.
Cell Mol Neurobiol ; 39(6): 883-898, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31140018

RESUMO

Increasing evidences have shown that resveratrol could protect the brain from ischemic injury; the mechanisms underlying its neuroprotective effects are multifactorial and not fully understood. It remains unclear whether resveratrol could exert neuroprotection through modulating gut-brain axis, which plays important roles in stroke pathology. In this study, C57BL/6 mice underwent middle cerebral artery occlusion (60 min) followed by reperfusion for 3 days. Resveratrol, when applied immediately after MCAO onset for 3 days, promoted Th1/Th2 balance towards Th2 polarization and skewed Treg/Th17 balance towards Treg in the small intestinal lamina propria (SI-LP), and decreased small intestinal pro-inflammatory cytokines expression through modulating intestinal flora at 3 days post-ischemia (dpi). Resveratrol attenuated cerebral ischemia-induced increase in the epithelial and vascular permeability of small intestine as evidenced by reduced evans blue extravasasion and decreased protein leakage by feces/plasma albumin ratio at 3 dpi. The blood levels of pro-inflammatory cytokines at 3 dpi were also attenuated by resveratrol due to inhibiting intestinal pro-inflammatory immunity and decreasing epithelial and vascular permeability. Resveratrol robustly protected against post-stroke inflammation-induced blood-brain barrier disruption not only in the cortex but also in the striatum at 3 dpi. Furthermore, resveratrol mediated smaller cerebral infarcts and less neurological deficits via decreasing the levels of pro-inflammatory cytokines in the peri-infarct area at 3 dpi. Our results for the first time demonstrated that resveratrol may inhibit systemic post-stroke inflammation and neuroinflammation via modulating intestinal flora-mediated Th17/Tregs and Th1/Th2 polarity shift in SI-LP, which may be one of the mechanisms underlying the neuroprotective effects of resveratrol.


Assuntos
Isquemia Encefálica/tratamento farmacológico , Encéfalo/patologia , Trato Gastrointestinal/patologia , Neuroproteção , Traumatismo por Reperfusão/tratamento farmacológico , Resveratrol/uso terapêutico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/patologia , Isquemia Encefálica/complicações , Isquemia Encefálica/imunologia , Isquemia Encefálica/fisiopatologia , Permeabilidade Capilar/efeitos dos fármacos , Citocinas/sangue , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Trato Gastrointestinal/efeitos dos fármacos , Inflamação/imunologia , Inflamação/patologia , Intestino Delgado/efeitos dos fármacos , Intestino Delgado/patologia , Masculino , Camundongos Endogâmicos C57BL , Modelos Biológicos , Neuroproteção/efeitos dos fármacos , Traumatismo por Reperfusão/complicações , Traumatismo por Reperfusão/imunologia , Traumatismo por Reperfusão/fisiopatologia , Resveratrol/farmacologia , Acidente Vascular Cerebral/sangue , Acidente Vascular Cerebral/complicações , Acidente Vascular Cerebral/tratamento farmacológico , Acidente Vascular Cerebral/fisiopatologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia
11.
PLoS One ; 14(4): e0215765, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31013298

RESUMO

Recent analyses of the genetics of peripheral T-cell lymphoma (PTCL) have shown that a large proportion of cases are derived from normal follicular helper (Tfh) T-cells. The sanroque mouse strain bears a mutation that increases Tfh cell number and heterozygous animals (Roquinsan/+) develop lymphomas similar to human Tfh lymphoma. Here we demonstrate the usefulness of Roquinsan/+ animals as a pre-clinical model of Tfh lymphoma. Long latency of development and incomplete penetrance in this strain suggests the lymphomas are genetically diverse. We carried out preliminary genetic characterisation by whole exome sequencing and detected tumor specific mutations in Hsp90ab1, Ccnb3 and RhoA. Interleukin-2-inducible kinase (ITK) is expressed in Tfh lymphoma and is a potential therapeutic agent. A preclinical study of ibrutinib, a small molecule inhibitor of mouse and human ITK, in established lymphoma was carried out and showed lymphoma regression in 8/12 (67%) mice. Using T2-weighted MRI to assess lymph node volume and diffusion weighted MRI scanning as a measure of function, we showed that treatment increased mean apparent diffusion coefficient (ADC) suggesting cell death, and that change in ADC following treatment correlated with change in lymphoma volume. We suggest that heterozygous sanroque mice are a useful model of Tfh cell derived lymphomas in an immunocompetent animal.


Assuntos
Antineoplásicos/administração & dosagem , Linfoma de Células T Periférico/tratamento farmacológico , Pirazóis/administração & dosagem , Pirimidinas/administração & dosagem , Administração Oral , Animais , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Heterozigoto , Humanos , Linfonodos/citologia , Linfonodos/diagnóstico por imagem , Linfonodos/efeitos dos fármacos , Linfoma de Células T Periférico/diagnóstico por imagem , Linfoma de Células T Periférico/genética , Imagem por Ressonância Magnética , Camundongos , Cultura Primária de Células , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/patologia , Resultado do Tratamento , Células Tumorais Cultivadas , Ubiquitina-Proteína Ligases/genética
12.
Toxicol Lett ; 311: 49-57, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31014974

RESUMO

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the most toxic congener of dioxins, is a persistent and ubiquitous environmental contaminant. Although the immunotoxic effects of TCDD have been reported, the mechanisms underlying these effects are still unclear. In this study, we have determined the toxic effects of TCDD on thymocytes and splenic T cells with in vitro cell culture systems. Magnetically isolated mouse splenic Th cells, Treg cells and the mixed spleen lymphocytes (SLC) were cultured and treated with TCDD and the differentiation of CD4 Th cells was determined by flow cytometery. Our results showed that different concentrations of TCDD caused immunotoxic effects through different toxicological mechanisms in both the purified mouse splenic Th cells and the mixed SLC. The low dose exposure to TCDD triggered regulatory effects in the immune system, while the high dose TCDD exposure resulted in severe immune toxicity. Notably, a decline of Treg subset was observed, suggesting an imbalanced immune regulation by TCDD treatment, as well as a possible decrease of TCDD's indirect effects on bystander immune cells. Our CD4 Th subset co-culture experiments showed that TCDD-induced pathobiology depended on immune cell balance, suggesting that cytokine-induced microenvironments further modulated toxic effects associated with TCDD exposure.


Assuntos
Diferenciação Celular/efeitos dos fármacos , Poluentes Ambientais/toxicidade , Dibenzodioxinas Policloradas/toxicidade , Baço/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Timócitos/efeitos dos fármacos , Animais , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Fatores de Transcrição Hélice-Alça-Hélice Básicos/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Microambiente Celular , Técnicas de Cocultura , Citocinas/imunologia , Citocinas/metabolismo , Relação Dose-Resposta a Droga , Ativação Linfocitária/efeitos dos fármacos , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fenótipo , Receptores de Hidrocarboneto Arílico/genética , Receptores de Hidrocarboneto Arílico/metabolismo , Baço/imunologia , Baço/metabolismo , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Timócitos/imunologia , Timócitos/metabolismo
13.
Proc Natl Acad Sci U S A ; 116(13): 6286-6291, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30862736

RESUMO

Disruption of mucosal immunity plays a critical role in the pathogenesis of inflammatory bowel disease, yet its mechanism remains not fully elucidated. Here, we found that activating transcription factor 3 (ATF3) protects against colitis by regulating follicular helper T (TFH) cells in the gut. The expression of ATF3 in CD4+ T cells was negatively correlated with the severity of ulcerative colitis in clinical patients. Mice with ATF3 deficiency in CD4+ T cells (CD4 cre Atf3 fl/fl ) were much more susceptible to dextran sulfate sodium-induced colitis. The frequencies of TFH cells, not other T cell subsets, were dramatically decreased in Peyer's patches from CD4 cre Atf3 fl/fl mice compared with Atf3 fl/fl littermate controls. The defective TFH cells significantly diminished germinal center formation and IgA production in the gut. Importantly, adoptive transfer of TFH or IgA+ B cells caused significant remission of colitis in CD4 cre Atf3 fl/fl mice, indicating the TFH-IgA axis mediated the effect of ATF3 on gut homeostasis. Mechanistically, B cell lymphoma 6 was identified as a direct transcriptional target of ATF3 in CD4+ T cells. In summary, we demonstrated ATF3 as a regulator of TFH cells in the gut, which may represent a potential immunotherapeutic target in colitis.


Assuntos
Fator 3 Ativador da Transcrição/imunologia , Fator 3 Ativador da Transcrição/farmacologia , Colite/tratamento farmacológico , Colite/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Fator 3 Ativador da Transcrição/genética , Fator 3 Ativador da Transcrição/metabolismo , Transferência Adotiva , Animais , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Colite/patologia , Colite Ulcerativa , Colo/patologia , Sulfato de Dextrana/efeitos adversos , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Homeostase , Imunidade nas Mucosas/imunologia , Imunoglobulina A , Imunoterapia , Camundongos , Nódulos Linfáticos Agregados/imunologia , Subpopulações de Linfócitos T
14.
Diabetes ; 68(6): 1240-1250, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30894366

RESUMO

Multiple studies of B- and T-cell compartments and their response to stimuli demonstrate alterations in established type 1 diabetes (T1D). Yet it is not known whether these alterations reflect immune mechanisms that initiate islet autoimmunity, promote disease progression, or are secondary to disease. To address these questions, we used samples from the TrialNet Pathway to Prevention study to investigate T-cell responses to interleukin (IL)-2 and regulatory T cell-mediated suppression, the composition of the B-cell compartment, and B-cell responses to B-cell receptor and IL-21 receptor engagement. These studies revealed stage-dependent T- and B-cell functional and immune phenotypes; namely, early features that differentiate autoantibody-positive at-risk first-degree relatives (FDRs) from autoantibody-negative FDRs and persisted through clinical diagnosis; late features that arose at or near T1D diagnosis; and dynamic features that were enhanced early and blunted at later disease stages, indicating evolving responses along the continuum of T1D. We further explored how these specific phenotypes are influenced by therapeutic interventions. Our integrated studies provide unique insights into stable and dynamic stage-specific immune states and define novel immune phenotypes of potential clinical relevance.


Assuntos
Linfócitos B/imunologia , Diabetes Mellitus Tipo 1/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adolescente , Adulto , Doenças Assintomáticas , Autoanticorpos/imunologia , Subpopulações de Linfócitos B/imunologia , Linfócitos B/efeitos dos fármacos , Criança , Progressão da Doença , Feminino , Humanos , Memória Imunológica/imunologia , Interleucina-2/farmacologia , Masculino , Fenótipo , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Interleucina-21/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Adulto Jovem
15.
Nat Commun ; 10(1): 1376, 2019 03 26.
Artigo em Inglês | MEDLINE | ID: mdl-30914642

RESUMO

IL-9-producing CD4+ (Th9) cells are a subset of CD4+ T-helper cells that are endowed with powerful antitumor capacity. Both IL-4 and TGF-ß have been reported to be indispensable for Th9 cell-priming and differentiation. Here we show, by contrast, that Th9 cell development can occur in the absence of TGF-ß signaling. When TGF-ß was replaced by IL-1ß, the combination of IL-1ß and IL-4 efficiently promoted IL-9-producing T cells (Th9IL-4+IL-1ß). Th9IL-4+ IL-1ß cells are phenotypically distinct T cells compared to classic Th9 cells (Th9IL-4+TGF-ß) and other Th cells, and are enriched for IL-1 and NF-κB gene signatures. Inhibition of NF-κB but not TGF-ß-signaling negates IL-9 production by Th9IL-4+IL-1ß cells. Furthermore, when compared with classic Th9IL-4+TGF-ß cells, Th9IL-4+IL-1ß cells are less exhausted, exhibit cytotoxic T effector gene signature and tumor killing function, and exert a superior antitumor response in a mouse melanoma model. Our study thus describes an alternative pathway for Th9 cell differentiation and provides a potential avenue for antitumor therapies.


Assuntos
Interleucina-1beta/farmacologia , Interleucina-4/farmacologia , Linfopoese/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Fator de Crescimento Transformador beta/farmacologia , Animais , Diferenciação Celular/imunologia , Linhagem Celular Tumoral , Interleucina-1/genética , Interleucina-1/imunologia , Interleucina-9 , Linfopoese/imunologia , Melanoma Experimental/imunologia , Camundongos , NF-kappa B/genética , NF-kappa B/imunologia , Fenótipo , Subpopulações de Linfócitos T/citologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Auxiliares-Indutores/citologia , Linfócitos T Auxiliares-Indutores/imunologia , Transcriptoma
16.
J Dermatol Sci ; 93(3): 176-185, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30905492

RESUMO

BACKGROUND: Retinoic acid receptor-related orphan receptor gamma t (RORγt) has critical roles in the development, maintenance and function of interleukin (IL)-17-producing cells and is a highly attractive target for the treatment of IL-17-mediated autoimmune disease, particularly psoriasis. On the other hand, RORγt is also critical for controlling apoptosis during thymopoiesis, and genetic RORγt ablation or systematic RORγt inhibition cause progressive thymic aberrations leading to T cell lymphomas. OBJECTIVE: We investigated whether topical administration of our novel RORγt inhibitor, S18-000003 has therapeutic potential for psoriasis with low risk of thymic aberrations. METHODS: We evaluated the effect of topical S18-000003 on psoriasis-like skin inflammation and influence on the thymus in a 12-O-tetradecanoylphorbol-13-acetate-induced K14.Stat3C mouse psoriasis model. RESULTS: S18-000003 markedly inhibited the development of psoriatic skin inflammation via suppression of the IL-17 pathway. In the skin, S18-000003 suppressed all subsets of IL-17-producing cells that we previously identified in this psoriasis model: Th17 cells, Tc17 cells, dermal γδ T cells, TCR- cells that probably included innate lymphoid cells, and CD4-CD8- double-negative αß T cells. Notably, neither reduction of CD4+CD8+ double-positive thymocytes nor dysregulation of cell cycling was observed in S18-000003-treated mice, even at a high dose. CONCLUSION: Our topically administered RORγt inhibitor is a potential therapeutic agent for psoriasis with low risk of thymic lymphoma.


Assuntos
Fármacos Dermatológicos/farmacologia , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/antagonistas & inibidores , Psoríase/tratamento farmacológico , Sulfonas/farmacologia , Administração Cutânea , Animais , Células Cultivadas , Fármacos Dermatológicos/uso terapêutico , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Voluntários Saudáveis , Humanos , Imunidade Inata/efeitos dos fármacos , Interleucina-17/imunologia , Interleucina-17/metabolismo , Leucócitos Mononucleares , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Cultura Primária de Células , Psoríase/diagnóstico , Psoríase/etiologia , Psoríase/patologia , Índice de Gravidade de Doença , Pele/efeitos dos fármacos , Pele/imunologia , Pele/patologia , Sulfonas/uso terapêutico , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Acetato de Tetradecanoilforbol/toxicidade , Resultado do Tratamento
17.
Ann Rheum Dis ; 78(4): 539-550, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30760472

RESUMO

OBJECTIVES: Systemic sclerosis (SSc) is an autoimmune disease characterised by widespread fibrosis, microangiopathy and autoantibodies. Follicular helper T (Tfh) cells CD4+CXCR5+PD-1+ cooperate with B lymphocytes to induce the differentiation of plasmocytes secreting immunoglobulins (Ig). Circulating Tfh (cTfh) cells are increased in several autoimmune diseases. However, there are no data about cTfh cells and their interaction with B cells in SSc. The aim of this study was to perform a quantitative and functional analysis of cTfh cells in SSc. METHODS: Using flow cytometry, we analysed cTfh cells from 50 patients with SSc and 32 healthy controls (HC). In vitro coculture experiments of sorted cTfh and B cells were performed for functional analysis. IgG and IgM production were measured by ELISA. RESULTS: We observed that cTfh cell numbers are increased in patients with SSc compared with HC. Furthermore, the increase in cTfh cells was more potent in patients with severe forms of SSc such as diffuse SSc and in the presence of arterial pulmonary hypertension. cTfh cells from patients with SSc present an activated Tfh phenotype, with high expression of BCL-6, increased capacity to produce IL-21 in comparison with healthy controls. In vitro, cTfh cells from patients with SSc had higher capacity to stimulate the differentiation of CD19+CD27+CD38hi B cells and their secretion of IgG and IgM through the IL-21 pathway than Tfh cells from healthy controls. Blocking IL-21R or using the JAK1/2 inhibitor ruxolitinib reduced the Tfh cells' capacity to stimulate the plasmablasts and decreased the Ig production. CONCLUSIONS: Circulating Tfh cells are increased in SSc and correlate with SSc severity. The IL-21 pathway or JAK1/2 blockade by ruxolitinib could be a promising strategy in the treatment of SSc.


Assuntos
Interleucinas/imunologia , Plasmócitos/patologia , Pirazóis/farmacologia , Escleroderma Sistêmico/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos B/imunologia , Estudos de Casos e Controles , Diferenciação Celular/efeitos dos fármacos , Diferenciação Celular/imunologia , Células Cultivadas , Técnicas de Cocultura , Feminino , Humanos , Imunofenotipagem , Interleucinas/antagonistas & inibidores , Janus Quinases/antagonistas & inibidores , Ativação Linfocitária/efeitos dos fármacos , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/sangue , Estudos Prospectivos , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos
18.
Molecules ; 24(4)2019 Feb 19.
Artigo em Inglês | MEDLINE | ID: mdl-30791382

RESUMO

The proteolytic digest of milk casein, known as casein phosphopeptide (CPP-III), exhibits diverse biological activities, including calcium absorption and antioxidant activities. We hypothesized that the additional phosphorylation of this peptide can enhance its immunomodulatory activity such as suppression of allergy-associated cytokine and antigen-specific immune response. This study was conducted to assess whether oral intake of additionally phosphorylated CPP-III (P-CPP) attenuates ovalbumin (OVA)-induced IgE-mediated allergic reactions because of the additional phosphate groups. Female BALB/c mice were intraperitoneally sensitized with OVA twice at intervals of 14 days and then orally fed native CPP-III (N-CPP), P-CPP, and dephosphorylated CPP-III (D-CPP) for 6 weeks. Next, the mice were orally challenged with 50 mg of OVA. Oral administration of P-CPP suppressed total and specific IgE levels in the serum. Mice fed P-CPP exhibited low levels of OVA-specific IgG1 and increased OVA-specific IgG2a. P-CPP also suppressed IL-4 production, while D-CPP showed similar a level compared to that of the control. Further, P-CPP increased the population of the T follicular helper (Tfh) cell in the spleen. These results suggest that additional phosphorylation of CPP can enhance the attenuation of allergen-specific IgE-modulated allergic reactions in a murine food allergy model.


Assuntos
Antialérgicos/farmacologia , Caseínas/química , Leite/química , Ovalbumina/imunologia , Fosfopeptídeos/farmacologia , Animais , Antialérgicos/administração & dosagem , Antialérgicos/química , Temperatura Corporal , Imunomodulação/efeitos dos fármacos , Camundongos , Fosfopeptídeos/administração & dosagem , Fosfopeptídeos/química , Fosforilação , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/metabolismo , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo
19.
J Immunol ; 202(5): 1373-1382, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30683697

RESUMO

Abatacept is a CTLA-4-Ig fusion protein that binds to the costimulatory ligands CD80 and CD86 and blocks their interaction with the CD28 and CTLA-4 receptors expressed by T cells, therefore inhibiting T cell activation and function. Abatacept has shown clinical efficacy in treating some autoimmune diseases but has failed to show clinical benefit in other autoimmune conditions. The reasons for these disparate results are not clear and warrant further investigation of abatacept's mode of action. Longitudinal specimens from the Immune Tolerance Network's A Cooperative Clinical Study of Abatacept in Multiple Sclerosis trial were used to examine the effects of abatacept treatment on the frequency and transcriptional profile of specific T cell populations in peripheral blood. We found that the relative abundance of CD4+ T follicular helper (Tfh) cells and regulatory T cells was selectively decreased in participants following abatacept treatment. Within both cell types, abatacept reduced the proportion of activated cells expressing CD38 and ICOS and was associated with decreased expression of genes that regulate cell-cycle and chromatin dynamics during cell proliferation, thereby linking changes in costimulatory signaling to impaired activation, proliferation, and decreased abundance. All cellular and molecular changes were reversed following termination of abatacept treatment. These data expand upon the mechanism of action of abatacept reported in other autoimmune diseases and identify new transcriptional targets of CD28-mediated costimulatory signaling in human regulatory T and Tfh cells, further informing on its potential use in diseases associated with dysregulated Tfh activity.


Assuntos
Abatacepte/farmacologia , Imunossupressores/farmacologia , Esclerose Múltipla/tratamento farmacológico , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Linfócitos T Reguladores/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Método Duplo-Cego , Humanos , Esclerose Múltipla/imunologia , Esclerose Múltipla/patologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Auxiliares-Indutores/patologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/patologia
20.
Arthritis Rheumatol ; 71(1): 50-62, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30009417

RESUMO

OBJECTIVE: The production of class-switched high-affinity autoantibodies derived from organized germinal centers (GCs) is a hallmark of many autoimmune inflammatory diseases, including rheumatoid arthritis (RA). TANK-binding kinase 1 (TBK-1) is a serine/threonine kinase involved in the maturation of GC follicular helper T (Tfh) cells downstream of inducible costimulator signaling. We undertook this study to assess the therapeutic potential of TBK-1 inhibition using the small-molecule inhibitor WEHI-112 in antibody-dependent models of inflammatory arthritis. METHODS: Using the models of collagen-induced arthritis (CIA), antigen-induced arthritis (AIA), and K/BxN serum-transfer-induced arthritis (STIA), we determined the effectiveness of WEHI-112 at inhibiting clinical and histologic features of arthritis in C57BL/6 and DBA/1 mice. We used immunohistochemistry to characterize GC populations during CIA development, and we used enzyme-linked immunosorbent assays to determine levels of Ig autoantibodies in WEHI-112-treated mice compared to vehicle-treated mice. RESULTS: WEHI-112, a tool compound that is semiselective for TBK-1 but that also has activity against IKKε and JAK2, abolished TBK-1-dependent activation of interferon (IFN) regulatory factor 3 and inhibited type I IFN responses in vitro. In vivo, treatment with WEHI-112 selectively abrogated clinical and histologic features of established, antibody-dependent CIA, but had minimal effects on an antibody-independent model of AIA or on K/BxN STIA. In keeping with these findings, WEHI-112 reduced arthritogenic type II collagen-specific IgG1 and IgG2b antibody production. Furthermore, WEHI-112 altered the GC Tfh cell phenotype and GC B cell function in CIA. CONCLUSION: We report that TBK-1 inhibition using WEHI-112 abrogated antibody-dependent CIA. As WEHI-112 failed to inhibit non-antibody-driven joint inflammation, we conclude that the major effect of this compound was most likely the targeting of TBK-1-mediated mechanisms in the GC reaction. This approach may have therapeutic potential in RA and in other GC-associated autoantibody-driven inflammatory diseases.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Autoanticorpos/efeitos dos fármacos , Centro Germinativo/efeitos dos fármacos , Inibidores de Proteínas Quinases/farmacologia , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Linfócitos T Auxiliares-Indutores/efeitos dos fármacos , Animais , Autoanticorpos/imunologia , Azetidinas/farmacologia , Colágeno Tipo II , Ciclobutanos/farmacologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , Adjuvante de Freund , Centro Germinativo/imunologia , Imuno-Histoquímica , Fatores Imunológicos , Técnicas In Vitro , Fator Regulador 3 de Interferon/efeitos dos fármacos , Fator Regulador 3 de Interferon/imunologia , Interferon Tipo I/efeitos dos fármacos , Interferon Tipo I/imunologia , Inibidores de Janus Quinases/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Morfolinas/farmacologia , Soroalbumina Bovina , Sulfonamidas/farmacologia , Linfócitos T Auxiliares-Indutores/imunologia
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