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1.
Khirurgiia (Mosk) ; (9): 80-85, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31532171

RESUMO

This article discusses the need to implement effective methods for monitoring immune status and rehabilitation of patients after kidney transplantation. Induction of immunological tolerance which allows minimizing or even completely canceling supportive immunosuppressive therapy is one of the key tasks in the field of organ transplantation. Regulatory T-cells (TREGs) play an important role in maintaining immunological homeostasis, including limiting kidney transplant rejection, and potentially contribute to the development of immunological tolerance. At the same time, for the introduction of TREG therapy into clinical practice, it is necessary to overcome a number of unsolved problems, such as induction and cultivation of a sufficient number of TREG cells for therapeutic action as well as reducing the risks associated with TREG conversion to effector lymphocytes or an undesirable non-specific immunosuppressive effect. This review examines both the impact of common post-transplant pharmacological immunosuppression approaches on TREGs and the therapeutic potential of TREG cell cultures in prevention of kidney transplant rejection. The questions of ex vivo TREG manufacturing process and possible threats of applying cell technologies in this branch of transplantology were considered.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/métodos , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/prevenção & controle , Transplante de Rim/efeitos adversos , Linfócitos T Reguladores/imunologia , Rejeição de Enxerto/etiologia , Humanos , Tolerância Imunológica/imunologia , Imunossupressão/métodos , Imunossupressores/uso terapêutico , Transplante de Rim/reabilitação , Imunologia de Transplantes/imunologia
2.
Egypt J Immunol ; 26(1): 69-78, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31332997

RESUMO

Hepatocellular carcinoma (HCC) is a primary malignancy of the liver. Tumors can recruit and promote the expansion of regulatory T cells (Tregs) to suppress antitumor immune responses for survival and progression. Furthermore, there is a strong evidence for the potential roles of cytokines in promoting HCC carcinogenesis and progression. We aimed to evaluate the frequency of Treg cells and serum levels of IL6 and IL10 before and after transarterial chemoembolization (TACE). We carried out a cross-sectional study at Assiut University hospitals that included 34 HCC patients and 10 matched apparently healthy controls. Peripheral Treg frequency was evaluated by Flow cytometry. IL6 and IL10 serum levels were evaluated by ELISA before and after TACE. HCC patients had a significantly higher level of IL6 and IL10 when compared to the control group (P=0.0002, P < 0.0001), respectively. However, after treatment, there was an elevation in the levels of IL6 and IL10 followed by a decrease to the baseline levels. Patients with large tumors (≥5 cm) showed higher levels of both IL 6 and IL 10 than those with smaller tumors. Moreover, HCC patients showed a higher frequency of Treg cells in comparison to the controls (P=0.002). No significant correlation was observed between the frequency of Treg cells and IL10 before and after treatment (r=0.38, P=0.30). In conclusion, HCC patients have significantly higher levels of IL 6, IL 10 and a higher percentage of Tregs than control individuals. Treg levels are altered after chemoembolization. IL 6 have a potential in reflecting the patient's condition after treatment, thus, can help in monitoring therapy.


Assuntos
Carcinoma Hepatocelular/imunologia , Quimioembolização Terapêutica , Hepatite C/imunologia , Interleucina-10/sangue , Interleucina-6/sangue , Neoplasias Hepáticas/imunologia , Linfócitos T Reguladores/imunologia , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/virologia , Estudos Transversais , Humanos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/virologia , Resultado do Tratamento
3.
Nat Commun ; 10(1): 2924, 2019 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-31266950

RESUMO

Fas induces apoptosis in activated T cell to maintain immune homeostasis, but the effects of non-apoptotic Fas signaling on T cells remain unclear. Here we show that Fas promotes TH9 cell differentiation by activating NF-κB via Ca2+-dependent PKC-ß activation. In addition, PKC-ß also phosphorylates p38 to inactivate NFAT1 and reduce NFAT1-NF-κB synergy to promote the Fas-induced TH9 transcription program. Fas ligation exacerbates inflammatory bowel disease by increasing TH9 cell differentiation, and promotes antitumor activity in p38 inhibitor-treated TH9 cells. Furthermore, low-dose p38 inhibitor suppresses tumor growth without inducing systemic adverse effects. In patients with tumor, relatively high TH9 cell numbers are associated with good prognosis. Our study thus implicates Fas in CD4+ T cells as a target for inflammatory bowel disease therapy. Furthermore, simultaneous Fas ligation and low-dose p38 inhibition may be an effective approach for TH9 cell induction and cancer therapy.


Assuntos
Diferenciação Celular , Doenças Inflamatórias Intestinais/imunologia , Transdução de Sinais , Linfócitos T Reguladores/citologia , Receptor fas/imunologia , Animais , Citocinas/genética , Citocinas/imunologia , Feminino , Humanos , Doenças Inflamatórias Intestinais/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Camundongos Nus , NF-kappa B/genética , NF-kappa B/imunologia , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/imunologia , Neoplasias/genética , Neoplasias/imunologia , Neoplasias/terapia , Proteína Quinase C beta/genética , Proteína Quinase C beta/imunologia , Linfócitos T Reguladores/imunologia , Receptor fas/genética , Proteínas Quinases p38 Ativadas por Mitógeno/genética , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia
4.
Rev Soc Bras Med Trop ; 52: e20190101, 2019 Jul 18.
Artigo em Inglês | MEDLINE | ID: mdl-31340370

RESUMO

INTRODUCTION: Tropical spastic paraparesis/HTLV-1 associated myelopathy (TSP/HAM) is a disease caused by human T-cell lymphotropic virus type 1 (HTLV-I) that mainly infects CD4 T cells-for example, those of the CD4+CD25hiFOXP3+ [Treg] phenotype-where it inhibits forkhead box protein P3 (FOXP3) expression and promotes interferon-γ (IFN-γ) expression. However, the role it exerts on regulatory B cells (CD19+CD24hiCD38hi; Breg) is unknown. METHODS: The frequencies of Treg and Breg cells was evaluated and the Th1 profiles were assessed in TSP/HAM patients and healthy control subjects. RESULTS: Low percentages of Breg cells and high production of IFN-γ were observed in patients compared to those in healthy control subjects. CONCLUSIONS: The low percentage of Breg cells in patients and the increase in the frequency of Th1 cells suggest an imbalance in the control of the inflammatory response that contributes to the immunopathogenesis of TSP/HAM.


Assuntos
Linfócitos B Reguladores/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Interferon gama/imunologia , Paraparesia Espástica Tropical/imunologia , Linfócitos T Reguladores/imunologia , Adolescente , Linfócitos B Reguladores/virologia , Linfócitos T CD4-Positivos/virologia , Linfócitos T CD8-Positivos/virologia , Feminino , Humanos , Masculino , Paraparesia Espástica Tropical/virologia , Linfócitos T Reguladores/virologia , Carga Viral
5.
J Agric Food Chem ; 67(33): 9382-9389, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31361959

RESUMO

Early stage exposure of foodborne substances, such as brightening agent titanium dioxide nanoparticles (TiO2 NPs), can cause long-term effects in adulthood. We aimed to explore the potential adverse effect of long-term dietary intake of TiO2 NPs. After feeding for 2-3 months from weaning, TiO2 NPs-exposed mice showed lower body weight and induced intestinal inflammation. However, this phenomenon was not observed in gut microbiota-removed mice. TiO2 NPs exposure rarely affected the diversity of microbial communities, but significantly decreased the abundance of several probiotic taxa including Bifidobacterium and Lactobacillus. Additionally, TiO2 NPs aggravated DSS-induced chronic colitis and immune response in vivo, and reduced the population of CD4+T cells, regulatory T cells, and macrophages in mesenteric lymph nodes. Therefore, dietary TiO2 NPs could interfere with the balance of immune system and dynamic of gut microbiome, which may result in low-grade intestinal inflammation and aggravated immunological response to external stimulus, thus introducing potential health risk.


Assuntos
Intestinos/efeitos dos fármacos , Intestinos/imunologia , Nanopartículas/metabolismo , Nanopartículas/toxicidade , Titânio/metabolismo , Titânio/toxicidade , Animais , Bactérias/classificação , Bactérias/efeitos dos fármacos , Bactérias/genética , Bactérias/isolamento & purificação , Peso Corporal/efeitos dos fármacos , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Feminino , Microbioma Gastrointestinal/efeitos dos fármacos , Intestinos/microbiologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Camundongos , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia , Fatores de Tempo
6.
Exp Parasitol ; 204: 107725, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31306646

RESUMO

Characterisation of the cellular immune response to schistosomiasis is well established for Schistosoma mansoni but a comprehensive description of T cell-mediated immune responses against S. japonicum infection is lacking. Accordingly, 20 CBA mice were infected with cercariae of S. japonicum and the immune response at different time points was determined. Mouse spleen and liver lymphocytes were isolated from the mice and stimulated with schistosomal adult worm antigen preparation (SWAP) and schistosomal soluble egg antigen (SEA). There was a relatively higher Th1 immune response to SWAP compared to SEA at the early phase of infection (up to week 5 post challenge). However, a Th2 immune response directed against SEA was dominant at week 6 post-infection, a time point when the highest IgG response against both SWAP and, especially, SEA was generated. The regulatory immune response was highest at the early phase of the immune response (up to week 5 post challenge) followed by a rapid decline at week 6-post infection. Before egg-laying, S. japonicum induced a regulatory T cell immune response which may limit the early Th1-mediated immune response that is believed to be protective in murine schistosomiasis. Following egg laying, the immune response was polarized to a Th2 immune response mainly directed against the eggs and this may contribute to parasite survival.


Assuntos
Imunidade Celular , Schistosoma japonicum/imunologia , Esquistossomose Japônica/imunologia , Linfócitos T/imunologia , Animais , Antígenos de Helmintos/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Interleucina-17/imunologia , Interleucina-17/metabolismo , Fígado/citologia , Fígado/imunologia , Fígado/parasitologia , Linfócitos/imunologia , Camundongos , Camundongos Endogâmicos CBA , Óvulo/imunologia , Contagem de Ovos de Parasitas , Receptores de Antígenos de Linfócitos T gama-delta/imunologia , Caramujos/parasitologia , Baço/citologia , Baço/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th2/imunologia
7.
Cancer Sci ; 110(9): 2783-2793, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31325403

RESUMO

Oral cancer, a subtype of head and neck cancer, is characterized by increased infiltrating regulatory T cells (Treg); however, the pathological significance of the increase in Tregs in disease prognosis and progression and their underlying mechanism remain unestablished. C-C motif chemokine ligand 22 (CCL22) has been implicated in the recruitment of Tregs. We used RT-qPCR to determine CCL22 mRNA expression in clinical specimens and cultured cells. Loss-of-function and gain-of-function studies were carried out to analyze the effects of CCL22 modulations on cell proliferation, migration, invasion, and tumorigenesis and the mechanism involved in the deregulation of CCL22. In oral cancer specimens, CCL22 mRNA was upregulated. The increase was not only associated with reduced disease-free survival but also strongly correlated with an increase in FOXP3 mRNA, a master regulator of Treg development and functions. Silencing CCL22 expression reduced cell proliferation, migration, and invasion, whereas ectopic overexpression showed opposite effects. Manipulation of CCL22 expression in cancer cells altered tumorigenesis in both immune-compromised and -competent mice, supporting both autonomous and non-autonomous actions of CCL22. Release of interleukin 1ß (IL-1ß) from cancer-associated fibroblasts (CAF) induces CCL22 mRNA expression in oral cancer cells by activating transcription factor nuclear factor kappa B (NF-κB). Our data support a model in which CAF-derived IL-1ß, CCL22, and its receptor CCR4 foster a protumor environment by promoting cell transformation and Treg infiltration. Intervention of the IL-1ß-CCL22-CCR4 signaling axis may offer a novel therapeutic strategy for oral cancer treatment.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Quimiocina CCL22/metabolismo , Interleucina-1beta/metabolismo , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Animais , Fibroblastos Associados a Câncer/imunologia , Linhagem Celular Tumoral , Movimento Celular/imunologia , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/patologia , Quimiocina CCL22/genética , Intervalo Livre de Doença , Feminino , Seguimentos , Fatores de Transcrição Forkhead/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Interleucina-1beta/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Mucosa Bucal/patologia , Mucosa Bucal/cirurgia , Neoplasias Bucais/imunologia , Neoplasias Bucais/mortalidade , Neoplasias Bucais/cirurgia , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/patologia , Prognóstico , RNA Interferente Pequeno/metabolismo , Receptores CCR4/metabolismo , Transdução de Sinais/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Análise de Sobrevida , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Cancer Immunol Immunother ; 68(8): 1223-1233, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31201473

RESUMO

Plasmacytoid dendritic cells (pDCs) are present in various primary and metastatic human neoplasms; however, their clinical significance in hepatocellular carcinoma (HCC) is unclear. In this study, we investigated the distribution, prognostic value, and potential function of pDCs in HCC patients undergoing curative resection. We performed immunohistochemical analyses of whole tumor sections from 224 patients to assess the expression of BDCA2, CD3, CD4, CD8, Foxp3, granzyme B, IL-17, and CD34. The findings were validated using tissue microarrays from another two independent cohorts totaling 841 HCC patients undergoing curative resection. Our results demonstrated that high numbers of BDCA2+ pDCs within tumors correlated with high alpha-fetoprotein levels, greater vascular invasion, advanced tumor-node-metastasis stage, shorter overall survival, and a higher recurrence rate. However, patient outcomes were not associated with pDCs in peritumoral stromal or nontumor tissues. Furthermore, an increase in intratumoral pDCs was associated with increased intratumoral infiltration of Foxp3+ regulatory T cells and IL-17-producing cells and correlated with tumor vascular density. Univariate and multivariate analyses revealed that the presence of intratumoral pDCs alone or in combination with regulatory T and/or IL-17-producing cells was an independent predictor of time to recurrence and overall survival. In conclusion, our study demonstrated that intratumoral infiltration by pDCs is a novel indicator for poor prognosis in patients with HCC, possibly through the induction of an immune tolerogenic and inflammatory tumor microenvironment comprising regulatory T and IL-17-producing cells. An assessment of the combination of these cells represents a superior predictor of patient outcome.


Assuntos
Carcinoma Hepatocelular/diagnóstico , Células Dendríticas/imunologia , Interleucina-17/metabolismo , Neoplasias Hepáticas/diagnóstico , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/mortalidade , Progressão da Doença , Feminino , Seguimentos , Fatores de Transcrição Forkhead/metabolismo , Hepatectomia , Humanos , Lectinas Tipo C/metabolismo , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/mortalidade , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Metástase Neoplásica , Prognóstico , Receptores Imunológicos/metabolismo , Análise de Sobrevida , alfa-Fetoproteínas/metabolismo
9.
Cancer Sci ; 110(8): 2348-2356, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31222843

RESUMO

Immune checkpoint blockade (ICB) therapy has achieved remarkable clinical benefit in non-small-cell lung cancer (NSCLC), but our understanding of biomarkers that predict the response to ICB remain obscure. Here we integrated somatic mutational profile and clinicopathologic information from 113 NSCLC patients treated by ICB (CTLA-4/PD-1). High tumor mutation burden (TMB) and neoantigen burden were identified significantly associated with improved efficacy in NSCLC immunotherapy. Furthermore, we identified apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) mutational signature was markedly associated with responding of ICB therapy (log-rank test, P = .001; odds ratio (OR), 0.18 [95% CI, 0.06-0.50], P < .001). The association with progression-free survival remained statistically significant after controlling for age, sex, histological type, smoking, PD-L1 expression, hypermutation, smoking signature and mismatch repair (MMR) (HR, 0.30 [95% CI, 0.12-0.75], P = .010). Combined high TMB with APOBEC signature preferably predict immunotherapy responders in NSCLC cohort. The CIBERSORT algorithm revealed that high APOBEC mutational activity samples were associated with increased infiltration of CD4 memory activated T cells, CD8+ T cells and natural killer (NK) cells, but reduced infiltration of regulatory T cells. Besides, individual genes mutation of IFNGR1 or VTCN1 were only found in responders; however, the PTEN mutation was only found in non-responders (Fisher's exact test, all P < .05). These findings may be applicable for guiding immunotherapy for patients with NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/imunologia , Imunidade/genética , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/imunologia , Mutação/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Imunidade/imunologia , Memória Imunológica/genética , Células Matadoras Naturais/imunologia , Masculino , Pessoa de Meia-Idade , Mutação/imunologia , Intervalo Livre de Progressão , Linfócitos T Reguladores/imunologia , Carga Tumoral/genética , Carga Tumoral/imunologia
10.
Scand J Immunol ; 90(3): e12799, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31211854

RESUMO

Pemphigus vulgaris (PV) is an autoimmune disease characterized by the production of IgG autoantibodies owing to an imbalance in the Th1/Th2 and Th17/Tregs cell pathways. The role of gut microbiota in the development of immune system and autoimmune diseases has been unraveled in the last two decades. However, data pertaining to gut microbiota of PV patients is largely lacking. We aimed to compare the gut microbiota of PV patients and healthy controls and assessed potential correlation with circulating cytokines of Th1/Th2/Th17 cell. Faecal bacterial diversity was analysed in 18 PV patients and 14 age- and gender-matched healthy individuals using hypervariable tag sequencing of the V3-V4 region of the 16S rRNA gene. Plasma levels of 20 inflammatory cytokines were assessed using the Luminex screening system. As a result, we identified 10 differentially abundant taxa between patients and controls. At the genera level, Lachnospiracea_incertae_sedis and Coprococcus decreased, while Granulicatella, Flavonifractor enriched in PV. Plasma levels of C5a, interleukin (IL)-2R, IL-6, IL-8, IL-7, IL-1ß, IL17A, IL-5 and IL-21 were significantly increased in PV Flavonifractor exhibited a positive correlation with C5a, IL-6, IL-8, IL-7, IL-1ß, IL17A and IL-21. Lachnospiracea_incertae_sedis and Coprococcus showed a negative correlation with IL-17A. Our results are consistent with the hypothesis that PV patients have gut microbial dysbiosis which might contribute to the immune disorder and the development of PV.


Assuntos
Doenças Autoimunes/imunologia , Citocinas/imunologia , Microbioma Gastrointestinal/imunologia , Inflamação/imunologia , Pênfigo/imunologia , Plasma/imunologia , Adulto , Autoanticorpos/imunologia , Doenças Autoimunes/microbiologia , Fezes/microbiologia , Feminino , Humanos , Inflamação/microbiologia , Masculino , Pessoa de Meia-Idade , Pênfigo/microbiologia , Plasma/microbiologia , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/microbiologia , Células Th1/imunologia , Células Th1/microbiologia , Células Th17/imunologia , Células Th17/microbiologia , Células Th2/imunologia , Células Th2/microbiologia
11.
Ann Hematol ; 98(8): 1845-1854, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31154474

RESUMO

Primary immune thrombocytopenia is an autoimmune disease, characterized with decreased platelet and increased risk of bleeding. Recent studies have shown the reduction and dysfunction of regulatory T (Treg) cells in ITP patients. CD39 is highly expressed on the surface of Treg cells. It degrades ATP to AMP and CD73 dephosphorylates AMP into adenosine. Then adenosine binds with adenosine receptor and suppresses immune response by activating Treg cells and inhibiting the release of inflammatory cytokines from effector T (Teff) cells. Adenosine receptor has several subtypes and adenosine A2A receptor (A2AR) plays a crucial role especially within lymphocytes. The CD39+ Treg cells and the expression of A2AR showed abnormality in some autoimmune disease. But knowledge of CD39+ Treg cells and A2AR which are crucial in the adenosine immunosuppressive pathway is still limited in ITP. Thirty-one adult patients with newly diagnosed ITP were enrolled in this study. CD39 and A2AR expression was measured by flow cytometry and RT-PCR. The function of CD39 was reflected by the change of ATP concentration detected by CellTiter-Glo Luminescent Cell Viability Assay. CD39 expression within CD4+CD25+ Treg cells in ITP patients was decreased compared to normal controls. After high-dose dexamethasone therapy, response (R) group showed increased CD39 expression within Treg cells while non-response (NR) group did not show any difference in contrast to those before treatment. The expression of A2AR in CD4+CD25- Teff and CD4+CD25+ Treg cells was both lower in ITP patients than that of normal controls. After therapy, CD4+CD25- Teff cells had higher A2AR expression while CD4+CD25+ Treg cells did not show any difference in comparison to that before treatment. The enzymatic activity of CD39 was damaged in ITP patients and improved after high-dose dexamethasone therapy. In ITP, there was not only numerical decrease but also impaired enzymatic activity in CD39+ Treg cells. After high-dose dexamethasone treatment, these two defects could be reversed. Our results also suggested that ITP patients had reduced A2AR expression in both CD4+CD25+ Treg cells and CD4+CD25- Teff cells. CD4+CD25- Teff cells had increased A2AR expression after treatment.


Assuntos
Apirase/genética , Dexametasona/uso terapêutico , Imunossupressores/uso terapêutico , Púrpura Trombocitopênica Idiopática/tratamento farmacológico , Receptor A2A de Adenosina/genética , Linfócitos T Reguladores/efeitos dos fármacos , Adenosina/imunologia , Adenosina/metabolismo , Trifosfato de Adenosina/imunologia , Trifosfato de Adenosina/metabolismo , Adulto , Idoso , Apirase/imunologia , Estudos de Casos e Controles , Feminino , Expressão Gênica , Humanos , Imunofenotipagem , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Púrpura Trombocitopênica Idiopática/enzimologia , Púrpura Trombocitopênica Idiopática/genética , Púrpura Trombocitopênica Idiopática/imunologia , Receptor A2A de Adenosina/imunologia , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/enzimologia , Linfócitos T Citotóxicos/imunologia , Linfócitos T Reguladores/enzimologia , Linfócitos T Reguladores/imunologia
12.
Vet Immunol Immunopathol ; 212: 38-42, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31213250

RESUMO

Food allergen-specific sublingual immunotherapy (FA-SLIT) is a novel, safe and effective approach in dogs with adverse food reactions (AFR) to reduce their clinical symptoms. However, little is known about the specific immune components which mediate this reduction in clinical symptoms. In humans, regulatory T cells seem to play an important role in this desensitisation process. Here, we investigated changes in peripheral T cell responses of dogs with AFR upon FA-SLIT. Five dogs received a dose escalation of FA-SLIT over a six-month period. An oral food challenge was performed at the beginning and end of the study to assess the efficacy of the FA-SLIT. Using in vitro allergen-recall assays, we assessed the proliferation of T cell subsets before and at the end of the treatment. FA-SLIT significantly increased the percentage of proliferating CD4-CD8- double-negative (DN) T cells, while the percentage of allergen-specific CD4-CD8+ and CD4+CD8+ double-positive (DP) T cells decreased upon treatment. These findings indicate that sublingual immunotherapy in dogs activates DN T cells, which might be important for the desensitisation of dogs with adverse food reactions. However, further research is needed to corroborate these findings and to further elucidate the mechanism of action of FA-SLIT in dogs with AFR.


Assuntos
Hipersensibilidade Alimentar/imunologia , Hipersensibilidade Alimentar/terapia , Imunoterapia Sublingual , Linfócitos T Reguladores/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Dessensibilização Imunológica/métodos , Cães , Imunoglobulina E/sangue , Imunoglobulina E/imunologia , Interleucina-10/imunologia , Ativação Linfocitária
13.
Cancer Immunol Immunother ; 68(8): 1273-1286, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31243491

RESUMO

Therapeutic cancer vaccines have met limited clinical success. In the setting of cancer, the immune system is either tolerized and/or has a limited tumor-specific T cell repertoire. In this study, we explore whether intratumoral (IT) vaccination with an HPV vaccine can elicit quantitative and qualitative differences in immune response as compared to intramuscular (IM) vaccination to overcome immune resistance in established tumors. We report that IT administration of an HPV-16 E7 peptide vaccine formulated with polyinosinic-polycytidylic acid [poly(I:C)] generated an enhanced antitumor effect relative to IM delivery. The elicited anti-tumor effect with IT vaccination was consistent among the vaccinated groups and across various C57BL/6 substrains. IT vaccination resulted in an increased frequency of PD-1hi TILs, which represented both vaccine-targeted and non-vaccine-targeted tumor-specific CD8+ T cells. Overall, the CD8+/Treg ratio was increased within the tumor microenvironment using IT vaccination. We also assessed transcriptional changes in several immune-related genes in the tumor microenvironment of the various treated groups, and our data suggest that IT vaccination leads to upregulation of a broad complement of immunomodulatory genes, including upregulation of interferon gamma (IFNγ) and antigen presentation and processing machine (APM) components. IT vaccine delivery is superior to traditional IM vaccination routes with the potential to improve tumor immunogenicity, which has potential clinical application in the setting of accessible lesions such as head and neck squamous cell carcinomas (HNSCCs).


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeça e Pescoço/terapia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Experimentais/imunologia , Proteínas E7 de Papillomavirus/imunologia , Vacinas contra Papillomavirus/imunologia , Linfócitos T Reguladores/imunologia , Animais , Apresentação do Antígeno/genética , Vacinas Anticâncer/imunologia , Carcinoma de Células Escamosas/imunologia , Células Cultivadas , Citotoxicidade Imunológica , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Imunidade Celular/genética , Injeções Intramusculares , Interferon gama/genética , Ativação Linfocitária , Camundongos , Camundongos Endogâmicos C57BL , Poli I-C/imunologia , Receptor de Morte Celular Programada 1/metabolismo , Vacinação
14.
Parasitol Res ; 118(7): 2287-2293, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31168702

RESUMO

Schistosomiasis is a devastating disease caused by Schistosoma infection. Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) has emerged as a candidate vaccine component against Schistosoma japonicum, but only confers partial protection. Cytotoxic T lymphocyte antigen-4 (CTLA-4) regulates T cell activation and shows negative effects on vaccine-induced immune protection; however, its potential influence on the protective effects of a GAPDH vaccine against S. japonicum and the underlying mechanism remain unclear. In this study, we established a mouse model of S. japonicum infection, and the mice were randomly divided into uninfected, infected control, anti-CTLA-4 monoclonal antibody (anti-CTLA-4 mAb), GAPDH, and GAPDH combined with anti-CTLA-4 mAb groups to compare the protective effects against infection and the consequent tissue damage. The worm reduction rate in the GAPDH-treated infected mice was 26.58%, which increased to 54.61% when combined with anti-CTLA-4 mAb. The frequency of regulatory T cells (Tregs) was significantly higher in the anti-CTLA-4 mAb group and was lower in the GAPDH group. However, both anti-CTLA-4 mAb and GAPDH elevated the levels of the cytokines IFN-γ, IL-2, IL-4, and IL-5 in the spleens of infected mice, and their combination further enhanced cytokine production. The diameter of egg granuloma in the anti-CTLA-4 mAb group and combined treatment group increased significantly compared to that of the other groups. These results suggest that anti-CTLA-4 mAb can be used as an adjuvant to enhance the immune protection of the GAPDH vaccine via inducing the Th1 immune response, although this comes at the cost of enhanced body injury.


Assuntos
Antígenos de Helmintos/imunologia , Antígeno CTLA-4/imunologia , Gliceraldeído-3-Fosfato Desidrogenases/imunologia , Schistosoma japonicum/imunologia , Esquistossomose Japônica/imunologia , Vacinas/imunologia , Animais , Anticorpos Monoclonais/imunologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Camundongos , Camundongos Endogâmicos BALB C , Esquistossomose Japônica/parasitologia , Esquistossomose Japônica/prevenção & controle , Baço/imunologia , Linfócitos T Reguladores/imunologia
15.
Int J Nanomedicine ; 14: 2383-2395, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31040663

RESUMO

Background: The inflammatory basis of diabetes mellitus directed the researchers' attention to the immune system for better management and prevention of complications. Metoclopramide (MCA; the only US Food and Drug Administration-approved for gastroparesis) has the ability to restore immune function through increasing prolactin secretion. This study aimed to test the effect of BSA/MCA nanoparticles (NPs) on modulating immune response. Methods: BSA/MCA NPs were fabricated by desolvation and evaluated in vitro via measuring loading efficiency, particle size, and surface charge. The selected formula was further evaluated via differential scanning calorimetry and release behavior. Then, NPs were injected into rats (25 mg MCA/kg/week) for 3 weeks to be evaluated histopathologically and immunologically via measuring proinflammatory cytokines, such as IL1ß, IL6, and TNFα, in addition to measuring regulatory T-cell frequency. Results: MCA was successfully loaded on BSA, achieving high encapsulation efficiency reaching 63±2%, particles size of 120-130 nm with good polydispersity, and a negative surface charge indicating that entire positively charged drug was encapsulated inside NPs. Differential scanning calorimetry thermography of selected NPs showed an obvious interaction between components and cross-linking of BSA molecules using glutaraldehyde, resulting in sustained release of MCA (around 50% within 3 days). MCA NPs significantly restored the immune response via decreasing proinflammatory cytokines and increasing regulatory T-cell frequency when compared to control and free MCA (drug not loaded in NPs)-treated groups. Histopathological examination of this MCA NPs-treated group did not show the characteristic lesions of diabetes, and apoptosis nearly disappeared. Conclusion: BSA/MCA NPs could be considered a new modality for treatment of gastro-paresis, in addition to management of diabetes itself and preventing its complications via an MCA-immunomodulatory effect.


Assuntos
Citocinas/metabolismo , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/imunologia , Fatores Imunológicos/farmacologia , Mediadores da Inflamação/metabolismo , Metoclopramida/farmacologia , Nanopartículas/química , Linfócitos T Reguladores/imunologia , Animais , Apoptose/efeitos dos fármacos , Varredura Diferencial de Calorimetria , Citocinas/sangue , Diabetes Mellitus Experimental/patologia , Modelos Animais de Doenças , Portadores de Fármacos/química , Liberação Controlada de Fármacos , Masculino , Nanopartículas/ultraestrutura , Tamanho da Partícula , Ratos Wistar , Soroalbumina Bovina/química , Eletricidade Estática , Linfócitos T Reguladores/efeitos dos fármacos
16.
Nat Commun ; 10(1): 2352, 2019 05 28.
Artigo em Inglês | MEDLINE | ID: mdl-31138793

RESUMO

Regulatory T cells (Tregs) have crucial functions in the inhibition of immune responses. Their development and suppressive functions are controlled by the T cell receptor (TCR), but the TCR signaling mechanisms that mediate these effects remain ill-defined. Here we show that CARD11-BCL10-MALT1 (CBM) signaling mediates TCR-induced NF-κB activation in Tregs and controls the conversion of resting Tregs to effector Tregs under homeostatic conditions. However, in inflammatory milieus, cytokines can bypass the CBM requirement for this differentiation step. By contrast, CBM signaling, in a MALT1 protease-dependent manner, is essential for mediating the suppressive function of Tregs. In malignant melanoma models, acute genetic blockade of BCL10 signaling selectively in Tregs or pharmacological MALT1 inhibition enhances anti-tumor immune responses. Together, our data uncover a segregation of Treg differentiation and suppressive function at the CBM complex level, and provide a rationale to explore MALT1 inhibitors for cancer immunotherapy.


Assuntos
Proteína 10 de Linfoma CCL de Células B/imunologia , Proteínas Adaptadoras de Sinalização CARD/imunologia , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Animais , Proteína 10 de Linfoma CCL de Células B/metabolismo , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Diferenciação Celular , Citocinas/imunologia , Melanoma Experimental , Camundongos , Proteína de Translocação 1 do Linfoma de Tecido Linfoide Associado à Mucosa/metabolismo , NF-kappa B/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo
17.
Nat Commun ; 10(1): 2011, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31043609

RESUMO

TET enzymes oxidize 5-methylcytosine to 5-hydroxymethylcytosine and other oxidized methylcytosines in DNA. Here we examine the role of TET proteins in regulatory T (Treg) cells. Tet2/3fl/flFoxp3Cre mice lacking Tet2 and Tet3 in Treg cells develop inflammatory disease, and Treg cells from these mice show altered expression of Treg signature genes and upregulation of genes involved in cell cycle, DNA damage and cancer. In littermate mice with severe inflammation, both CD4+Foxp3+ and CD4+Foxp3- cells show strong skewing towards Tfh/Th17 phenotypes. Wild-type Treg cells in mixed bone marrow chimeras and in Tet2/3fl/flFoxp3WT/Cre heterozygous female mice are unable to rescue the aberrant properties of Tet2/3fl/flFoxp3Cre Treg cells. Treg cells from Tet2/3fl/flFoxp3Cre mice tend to lose Foxp3 expression, and transfer of total CD4+ T cells isolated from Tet2/3fl/flFoxp3Cre mice could elicit inflammatory disease in fully immunocompetent mice. Together, these data indicate that Tet2 and Tet3 are guardians of Treg cell stability and immune homeostasis.


Assuntos
Proteínas de Ligação a DNA/metabolismo , Inflamação/imunologia , Proteínas Proto-Oncogênicas/metabolismo , Linfócitos T Reguladores/imunologia , Transferência Adotiva , Animais , Transplante de Medula Óssea , Colite , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/imunologia , Modelos Animais de Doenças , Feminino , Humanos , Inflamação/genética , Inflamação/patologia , Masculino , Camundongos , Camundongos Knockout , Proteínas Proto-Oncogênicas/genética , Proteínas Proto-Oncogênicas/imunologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/transplante , Quimeras de Transplante
18.
Nat Commun ; 10(1): 2220, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101805

RESUMO

Both medullary thymic epithelial cells (mTEC) and dendritic cells (DC) present tissue-restricted antigens (TRA) to thymocytes to induce central tolerance, but the relative contributions of these antigen-presenting cell (APC) subsets remain unresolved. Here we developed a two-photon microscopy approach to observe thymocytes interacting with intact APCs presenting TRAs. We find that mTECs and DCs cooperate extensively to induce tolerance, with their relative contributions regulated by the cellular form of the TRA and the class of major histocompatibility complex (MHC) on which antigen is presented. Even when TRA expression is restricted to mTECs, DCs still present self-antigens at least as frequently as mTECs. Notably, the DC subset cDC2 efficiently acquires secreted mTEC-derived TRAs for cross-presentation on MHC-I. By directly imaging interactions between thymocytes and APCs, while monitoring intracellular signaling, this study reveals that distinct DC subsets and AIRE+ mTECs contribute substantially to presentation of diverse self-antigens for establishing central tolerance.


Assuntos
Tolerância Central/imunologia , Células Dendríticas/imunologia , Timócitos/imunologia , Timo/imunologia , Animais , Apresentação do Antígeno/imunologia , Autoantígenos/imunologia , Autoantígenos/metabolismo , Transplante de Medula Óssea , Separação Celular/métodos , Células Dendríticas/metabolismo , Células Epiteliais/imunologia , Feminino , Citometria de Fluxo/métodos , Microscopia Intravital/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Linfócitos T Reguladores/imunologia , Timócitos/metabolismo , Timo/citologia , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Quimeras de Transplante/imunologia
19.
Transplant Proc ; 51(4): 1234-1238, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31101204

RESUMO

BACKGROUND: New-onset diabetes mellitus after transplant (NODAT) is a well-known complication of renal transplant that severely affects graft and patient survival. It is necessary to explore further risk factors and reveal the underlying pathomechanism. METHODS: Renal transplants performed between January 2010 and June 2018 were involved. Exclusion criteria were the recipient age younger than 18 years, follow-up period less than 6 months, and patients with diabetes at the time of transplant. Only primary kidney transplants were involved in our study, which totaled 223 cases. Besides donor and recipient demographic data, the type of immunosuppression, the average fasting glucose level, and T-subset profiles were compared. RESULTS: Of 223 cases there were 33 patients (14.8%) with NODAT (17 female; mean age, 54.2 [SD, 10.3] years; mean body mass index [calculated as weight in kilograms divided by height in meters squared], 27.8 [SD, 5.1]; mean follow-up, 43.3 [SD, 25.5] months). The control group consisted of 190 patients. The average fasting blood glucose level was higher in the NODAT group vs the control group (P < .001). The average fasting blood glucose level above diabetic threshold (≥7 mmol/L) was in association with a 6-fold higher risk of NODAT (odds ratio, 5.86; 95% CI, 2.46-13.97; P < .001). Absolute value of CD4+CD25brightCD127dim regulatory T cells was lower in the NODAT group at the first month after transplant (P = .048) Immunosuppressive protocol and survival data did not differ. CONCLUSIONS: Intensive management of the carbohydrate excursions during the early post-transplant period may decrease the incidence of NODAT. Further investigations will be required to decide whether the reduced CD4+CD25brightCD127dim/regulatory T-cell count contributes the development of NODAT.


Assuntos
Diabetes Mellitus/imunologia , Transplante de Rim/efeitos adversos , Linfócitos T Reguladores/imunologia , Adulto , Diabetes Mellitus/epidemiologia , Diabetes Mellitus/etiologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Fatores de Risco
20.
Nat Commun ; 10(1): 2150, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089130

RESUMO

Peptide-major histocompatibility complex class II (pMHCII)-based nanomedicines displaying tissue-specific autoantigenic epitopes can blunt specific autoimmune conditions by re-programming cognate antigen-experienced CD4+ T-cells into disease-suppressing T-regulatory type 1 (TR1) cells. Here, we show that single pMHCII-based nanomedicines displaying epitopes from mitochondrial, endoplasmic reticulum or cytoplasmic antigens associated with primary biliary cholangitis (PBC) or autoimmune hepatitis (AIH) can broadly blunt PBC, AIH and Primary Sclerosing Cholangitis in various murine models in an organ- rather than disease-specific manner, without suppressing general or local immunity against infection or metastatic tumors. Therapeutic activity is associated with cognate TR1 cell formation and expansion, TR1 cell recruitment to the liver and draining lymph nodes, local B-regulatory cell formation and profound suppression of the pro-inflammatory capacity of liver and liver-proximal myeloid dendritic cells and Kupffer cells. Thus, autoreactivity against liver-enriched autoantigens in liver autoimmunity is not disease-specific and can be harnessed to treat various liver autoimmune diseases broadly.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Antígenos de Histocompatibilidade Classe II/imunologia , Hepatopatias/tratamento farmacológico , Nanopartículas/administração & dosagem , Peptídeos/administração & dosagem , Idoso , Animais , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Linhagem Celular , Modelos Animais de Doenças , Epitopos/imunologia , Feminino , Antígenos de Histocompatibilidade Classe II/química , Humanos , Fígado/efeitos dos fármacos , Fígado/imunologia , Hepatopatias/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Nanomedicina/métodos , Nanopartículas/química , Peptídeos/química , Peptídeos/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia
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