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1.
Cancer Immunol Immunother ; 69(2): 315-324, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31915854

RESUMO

There is mounting evidence that the immune system can spontaneously clear malignant lesions before they manifest as overt cancer, albeit this activity has been difficult to demonstrate in humans. The calreticulin (CALR) exon 9 mutations are driver mutations in patients with chronic myeloproliferative neoplasms (MPN), which are chronic blood cancers. The CALR mutations generate a neo-antigen that is recognized by patient T cells, and T cells isolated from a patient with a CALR-mutation can recognize and kill autologous CALR-mutant cells. Surprisingly, healthy individuals display frequent and strong T cell responses to the CALR neo-antigens too. Furthermore, healthy individuals display immune responses to all parts of the mutant CALR epitope, and the CALR neo-epitope specific responses are memory T cell responses. These data suggest that although healthy individuals might acquire a CALR mutation, the mutant cells can be eliminated by the immune system. Additionally, a small fraction of healthy individuals harbor a CALR exon 9 mutation. Four healthy individuals carrying CALR mutations underwent a full medical examination including a bone marrow biopsy after a median follow up of 6.2 years. None of these patients displayed any signs of CALR-mutant MPN. Additionally, all healthy individuals displayed strong CALR neo-epitope specific T cell responses suggesting that these healthy individuals retained their CALR-mutant cells in the editing stage for several years. Thus, we suggest that CALR-mutant MPN could be a disease model of cancer immuno-editing, as we have demonstrated that CALR-mutant MPN displays all three stages described in the theory of cancer immuno-editing.


Assuntos
Suscetibilidade a Doenças , Neoplasias Hematológicas/etiologia , Imunomodulação , Evasão Tumoral , Animais , Antígenos de Neoplasias/imunologia , Biomarcadores Tumorais , Calreticulina/genética , Calreticulina/metabolismo , Transformação Celular Neoplásica , Modelos Animais de Doenças , Epitopos/imunologia , Neoplasias Hematológicas/metabolismo , Humanos , Imunomodulação/genética , Mutação , Evasão Tumoral/genética
2.
Cancer Immunol Immunother ; 69(2): 175-187, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31853576

RESUMO

High grade ovarian serous cancer (HGSC) is a malignant disease with high mortality. Glycosylation plays important roles in tumor invasion and immune evasion, but its effect on the immune microenvironment of HGSC remains unclear. This study examined the association of glycosyltransferase expression with HGSC prognosis and explored the underlying mechanism using clinical specimens and integrated bioinformatic analyses. We identified a cluster of 15 glycogenes associated with reduced overall survival, and GALNT10 was found to be an independent predictor of HGSC prognosis. The high GALNT10 expression was associated with increased regulatory CD4+ T cells infiltration and decreased granzyme B expression in CD8+ T cells. The expression of GALNT10 and its product, Tn antigen, in HGSC specimens was associated with the increased infiltration of M2 macrophages and neutrophils, and the decreased infiltration of CD3+ T cells, NK cells, and B cells. Taken collectively, high GALNT10 expression confers with immunosuppressive microenvironment to promote tumor progression and predicts poor clinical outcomes in HGSC patients.


Assuntos
Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/mortalidade , Expressão Gênica , N-Acetilgalactosaminiltransferases/genética , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Microambiente Tumoral/genética , Biomarcadores Tumorais , Biologia Computacional/métodos , Cistadenocarcinoma Seroso/patologia , Bases de Dados Genéticas , Feminino , Humanos , Imuno-Histoquímica , Imunomodulação/genética , Gradação de Tumores , Neoplasias Ovarianas/patologia , Prognóstico , Estudos Retrospectivos
3.
Semin Oncol ; 46(4-5): 372-379, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31733828

RESUMO

Targeting inhibitory immune checkpoint molecules has dramatically changed treatment paradigms in medical oncology. Understanding the best strategies to unleash a pre-existing immune response or to induce an efficient immune response against tumors has emerged as a research priority. In this work, we focus on a novel target for cancer immunotherapy, the inhibitory receptor T-cell immunoglobulin and mucin domain 3 (TIM3). This narrative review describes TIM3 biology in different (tumor-infiltrating) immune cells, particularly in the immunosuppressive regulatory T cells and dysfunctional/exhausted cytotoxic T lymphocytes, but also in cells that confer innate immunity - natural killer and dendritic cells. We discuss the functional role of TIM3, its expression and its clinical significance in a variety of tumors, and confront the heterogeneous results emerging from different studies, including clinical trials of immunotherapy. Finally, this work summarizes the principal early-phase clinical trials exploring TIM3 blockade and discusses some future perspectives.


Assuntos
Regulação Neoplásica da Expressão Gênica , Receptor Celular 2 do Vírus da Hepatite A/genética , Neoplasias/genética , Animais , Biomarcadores Tumorais , Ensaios Clínicos como Assunto , Receptor Celular 2 do Vírus da Hepatite A/antagonistas & inibidores , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Humanos , Imunomodulação/efeitos dos fármacos , Imunomodulação/genética , Imunomodulação/imunologia , Terapia de Alvo Molecular , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Resultado do Tratamento
4.
DNA Cell Biol ; 38(11): 1170-1177, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31502877

RESUMO

Host response to viral infection is a highly regulated process involving engagement of various host factors, cytokines, chemokines, and stimulatory signals that pave the way for an antiviral immune response. The response is manifested in terms of viral sequestration, phagocytosis, and inhibition of genome replication, and, finally, if required, lymphocyte-mediated clearance of virally infected cells. During this process, cross-talk between viral and host factors can shape disease outcomes and immunopathology. Bone marrow stromal antigen 2 (BST-2), also know as tetherin, is induced by type I interferon produced in response to viral infections, as well as in certain cancers. BST-2 has been shown to be a host restriction factor of virus multiplication through its ability to physically tether budding virions and restrict viral spread. However, BST-2 has other roles in the host antiviral response. This review focuses on the diverse functions of BST-2 and its downstream signaling pathways in regulating host immune responses.


Assuntos
Antígenos CD/fisiologia , Imunomodulação/genética , Vírion/imunologia , Vírion/metabolismo , Imunidade Adaptativa/genética , Animais , Antígenos CD/genética , Proteínas Ligadas por GPI/genética , Proteínas Ligadas por GPI/fisiologia , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunomodulação/imunologia , Viroses/genética , Viroses/imunologia
5.
Genome Med ; 11(1): 43, 2019 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-31340855

RESUMO

Immune checkpoint blockade therapy can elicit robust and durable responses in a variety of cancer types. While many patients do not respond, recent reports highlight a distinct group of patients whose tumors undergo rapid growth, leading to progressive disease and poor outcome. In this perspective, we synthesize and summarize some important issues surrounding hyperprogression, defining characteristics, prognostic implications, and controversies.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Antineoplásicos Imunológicos/farmacologia , Progressão da Doença , Humanos , Imunomodulação/efeitos dos fármacos , Imunomodulação/genética , Terapia de Alvo Molecular , Neoplasias/etiologia , Fatores de Risco , Subpopulações de Linfócitos T/efeitos dos fármacos , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Resultado do Tratamento
6.
Biomed Res Int ; 2019: 2045915, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31312654

RESUMO

Purpose: To elucidate the microRNAs existent in exosomes derived from stored red blood cell (RBC) unit and their potential function. Materials and Methods: Exosomes were isolated from the supernatant derived from stored RBC units by sequential centrifugation. Isolated exosomes were characterized by TEM (transmission electron microscopy), western blotting, and DLS (dynamic light scattering). MicroRNA (miRNA) microarray was performed to detect the expression of miRNAs in 3 exosome samples. Results revealed miRNAs that were simultaneously expressed in the 3 exosome samples and were previously reported to exist in mature RBCs. Functions and potential pathways of some detected miRNAs were illustrated by bioinformatic analysis. Validation of the top 3 abundant miRNAs was carried out by qRT-PCR (quantitative reverse transcription-polymerase chain reaction). Results: TEM and DLS revealed the mean size of the exosomes (RBC-derived) as 64.08 nm. These exosomes exhibited higher abundance of short RNA than the long RNA. 78 miRNAs were simultaneously detected in 3 exosome samples and mature RBCs. Several biological processes might be impacted by these miRNAs, through their target gene(s) enriched in a particular signalling pathway. The top 3 (abundant) miRNAs detected were as follows: miR-125b-5p, miR-4454, and miR-451a. qRT-PCR revealed higher abundance of miR-451a than others. Only miR-4454 and miR-451a abundance tended to increase with increasing storage time. Conclusion: Exosomes derived from stored RBC units possessed multiple miRNAs and, hence, could serve various functions. The function of exosomes (RBC-derived) might be implemented partly by the predominantly enriched miR-451a.


Assuntos
Exossomos/genética , MicroRNAs/genética , Transfusão de Sangue/tendências , Biologia Computacional , Difusão Dinâmica da Luz , Eritrócitos/imunologia , Eritrócitos/metabolismo , Exossomos/ultraestrutura , Regulação da Expressão Gênica/genética , Regulação da Expressão Gênica/imunologia , Humanos , Imunomodulação/genética , MicroRNAs/classificação , Microscopia Eletrônica de Transmissão
7.
Int J Mol Sci ; 20(15)2019 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-31357555

RESUMO

Glycoprotein A repetition predominant (GARP), a specific surface molecule of activated regulatory T cells, has been demonstrated to significantly contribute to tolerance in humans by induction of peripheral Treg and regulatory M2-macrophages and by inhibition of (tumorantigen-specific) T effector cells. Previous work identified GARP on Treg, and also GARP on the surface of several malignant tumors, as well as in a soluble form being shedded from their surface, contributing to tumor immune escape. Preliminary results also showed GARP expression on brain metastases of malignant melanoma. On the basis of these findings, we investigated whether GARP is also expressed on primary brain tumors. We showed GARP expression on glioblastoma (GB) cell lines and primary GB tissue, as well as on low-grade glioma, suggesting an important influence on the tumor micromilieu and the regulation of immune responses also in primary cerebral tumors. This was supported by the finding that GB cells led to a reduced, in part GARP-dependent effector T cell function (reduced proliferation and reduced cytokine secretion) in coculture experiments. Interestingly, GARP was localized not only on the cell surface but also in the cytoplasmatic, as well as nuclear compartments in tumor cells. Our findings reveal that GARP, as an immunoregulatory molecule, is located on, as well as in, tumor cells of GB and low-grade glioma, inhibiting effector T cell function, and thus contributing to the immunosuppressive tumor microenvironment of primary brain tumors. As GARP is expressed on activated Treg, as well as on brain tumors, it may be an interesting target for new immunotherapeutic approaches using antibody-based strategies as this indication.


Assuntos
Glioblastoma/etiologia , Glioblastoma/metabolismo , Imunomodulação , Proteínas de Membrana/metabolismo , Microambiente Tumoral , Idoso , Idoso de 80 Anos ou mais , Biomarcadores , Terapia Combinada , Feminino , Regulação Neoplásica da Expressão Gênica , Glioblastoma/diagnóstico , Glioblastoma/terapia , Humanos , Imuno-Histoquímica , Imunomodulação/genética , Imagem por Ressonância Magnética , Masculino , Proteínas de Membrana/genética , Pessoa de Meia-Idade , Gradação de Tumores , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Microambiente Tumoral/genética
8.
Int J Mol Sci ; 20(11)2019 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-31151139

RESUMO

Here, we investigate the role of RelB in the regulation of genes which were identified to be induced in an aryl hydrocarbon receptor (AhR)-dependent manner and critically involved in regulation of immune responses. We analyzed the expression of genes of the AhR gene battery, cytokines, and immune regulatory enzymes in bone marrow-derived macrophages (BMM) and thymus of B6 wildtype (wt) mice and RelB knockout (RelB-/-) mice after treatment with various AhR ligands. The 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced expression of indoleamine 2,3-dioxygenase 1 (IDO1) and IDO2 was significantly repressed in thymus of RelB-/- mice but not in BMM derived from RelB-/- mice. Interestingly, the induced and basal expression of the cytokines interleukin (IL)-17A, IL-22, and CCL20 required the functional expression of RelB. The RelB-dependent expression of CCL20 was induced by the AhR ligands TCDD and 6-formylindolo[3,2-b]carbazole (FICZ), whereas indole-3-carbinol (I3C) suppressed CCL20 in lipopolysaccharide (LPS)-activated wt BMM. The LPS-induced expression of IL-6 and IL-10 was enhanced by TCDD and FICZ, whereas I3C significantly suppressed these cytokines in BMM. The exposure to FICZ led to higher increases of IL-17A and IL-22 mRNA compared to the effect of TCDD or I3C in thymus of wt mice. On the other hand, TCDD was the strongest inducer of CYP1A1, AhR Repressor (AhRR), and IDO2. In summary, these findings provide evidence for the important role of RelB in the transcriptional regulation of cytokines and enzymes induced by AhR ligands.


Assuntos
Receptores de Hidrocarboneto Arílico/metabolismo , Fator de Transcrição RelB/metabolismo , Animais , Citocinas/genética , Citocinas/metabolismo , Expressão Gênica , Regulação da Expressão Gênica , Imunomodulação/genética , Ligantes , Macrófagos/metabolismo , Masculino , Camundongos , Camundongos Knockout , Ligação Proteica , Receptores de Hidrocarboneto Arílico/genética , Timo/imunologia , Timo/metabolismo , Fator de Transcrição RelB/genética
9.
Breast Cancer Res Treat ; 177(2): 335-343, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31222709

RESUMO

PURPOSE: Breast cancer (BC) is a heterogeneous disorder, with variable response to systemic chemotherapy. Likewise, BC shows highly complex immune activation patterns, only in part reflecting classical histopathological subtyping. Schlafen-11 (SLFN11) is a nuclear protein we independently described as causal factor of sensitivity to DNA damaging agents (DDA) in cancer cell line models. SLFN11 has been reported as a predictive biomarker for DDA and PARP inhibitors in human neoplasms. SLFN11 has been implicated in several immune processes such as thymocyte maturation and antiviral response through the activation of interferon signaling pathway, suggesting its potential relevance as a link between immunity and cancer. In the present work, we investigated the transcriptional landscape of SLFN11, its potential prognostic value, and the clinico-pathological associations with its variability in BC. METHODS: We assessed SLFN11 determinants in a gene expression meta-set of 5061 breast cancer patients annotated with clinical data and multigene signatures. RESULTS: We found that 537 transcripts are highly correlated with SLFN11, identifying "immune response", "lymphocyte activation", and "T cell activation" as top Gene Ontology processes. We established a strong association of SLFN11 with stromal signatures of basal-like phenotype and response to chemotherapy in estrogen receptor negative (ER-) BC. We identified a distinct subgroup of patients, characterized by high SLFN11 levels, ER- status, basal-like phenotype, immune activation, and younger age. Finally, we observed an independent positive predictive role for SLFN11 in BC. CONCLUSIONS: Our findings are suggestive of a relevant role for SLFN11 in BC and its immune and molecular variability.


Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Regulação Neoplásica da Expressão Gênica , Imunidade/genética , Neoplasia de Células Basais/genética , Neoplasia de Células Basais/imunologia , Proteínas Nucleares/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Biologia Computacional/métodos , Progressão da Doença , Feminino , Perfilação da Expressão Gênica , Ontologia Genética , Humanos , Imunomodulação/genética , Neoplasia de Células Basais/mortalidade , Neoplasia de Células Basais/patologia , Fenótipo , Prognóstico
10.
BMC Vet Res ; 15(1): 214, 2019 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-31238913

RESUMO

BACKGROUND: Per- and polyfluoroalkyl substances (PFASs) are environmentally persistent and bioaccumulative chemicals. Immunomodulation is among the most concerning of toxic effects linked with PFAS exposure in mammalian models. However, no studies had yet shown this to be true in birds. Thus, we designed and conducted the first study to determine if PFASs could cause immunomodulation in birds. Secondly, we wanted to determine the effects on an avian host when exposed not only to immunomodulating chemicals, but also to a viral challenge. The aim, to determine if PFAS mediated immunmodulation functionally affects a pathogen challenge for a host. As innate immune system signalling pathways initiate crucial responses against a pathogen challenge, and are lesser studied than their adaptive counterparts, we focused on these pathways. To provide the first information on this, an in vitro experiment was designed and performed using chicken embryo fibroblasts exposed to perfluorooctane sulfonate (PFOS) (22 ppm) and immune markers characterised before and after being infected with gallid herpesvirus-2 (GaHV-2). RESULTS: The expression of two pro-inflammatory cytokines, namely interleukin 8 (IL-8) and tumor necrosis factor alpha (TNF-α), the nuclear factor 'kappa-light-chain-enhancer' of activated B-cells (NF-κB), and the anti-inflammatory cytokine interleukin 4 (IL-4) were investigated in various scenarios. These results showed that exposure to PFOS decreased immune gene expression in chicken fibroblasts from 36 h post-exposure. Next, it was shown that this decrease could be mitigated by infection with gallid herpesvirus-2, which increased gene expression back to the baseline/control levels. CONCLUSIONS: Not only is this the first study to provide the expected evidence that PFOS has immunomodulatory potential in birds, it also provides unexpected data that virus infections can mitigate this negative effect. Thereby, further research, including in vivo and in situ studies, on the impact of PFOS on host-virus interactions is now warranted, as it has been overlooked and might contribute to our understanding of recent disease outbreaks in wildlife. The mechanisms by which gallid herpesvirus mitigates immunomodulation were beyond the scope of this study, but are now of interest for future study.


Assuntos
Ácidos Alcanossulfônicos/toxicidade , Fluorcarbonetos/toxicidade , Herpesvirus Galináceo 2/imunologia , Imunomodulação/efeitos dos fármacos , Doença de Marek/imunologia , Viroses/veterinária , Ácidos Alcanossulfônicos/imunologia , Animais , Linhagem Celular , Embrião de Galinha , DNA Complementar , Fibroblastos/efeitos dos fármacos , Fluorcarbonetos/imunologia , Expressão Gênica/efeitos dos fármacos , Imunomodulação/genética , Mediadores da Inflamação/metabolismo , RNA Viral/isolamento & purificação , Reação em Cadeia da Polimerase em Tempo Real/veterinária , Transdução de Sinais/efeitos dos fármacos , Viroses/imunologia
11.
Immunogenetics ; 71(5-6): 407-420, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31037384

RESUMO

Major histocompatibility complex (MHC) class II-associated invariant chain is a chaperone responsible for targeting the MHC class II dimer to the endocytic pathway, thus enabling the loading of exogenous antigens onto the MHC class II receptor. In the current study, in vivo and in vitro methods were used to investigate the regulation of the rainbow trout invariant chain proteins S25-7 and INVX, upon immune system activation. Whole rainbow trout and the macrophage/monocyte-like cell line RTS11 were treated with PMA at concentrations shown to induce IL-1ß transcripts and homotypic aggregation of RTS11. S25-7 transcript levels remained unchanged in the gill, spleen, and liver and were found to be significantly decreased in head kidney beginning 24 h post-stimulation. Meanwhile, INVX transcript levels remained unchanged in all tissues studied. Both S25-7 and INVX proteins were produced in gill and spleen tissues but their expression was unaffected by immune system stimulation. Surprisingly, neither INVX nor S25-7 protein was detected in the secondary immune organ, the head kidney. Analysis of RTS11 cultures demonstrated that both INVX and S25-7 transcript levels significantly increased at 96 h and 120 h following PMA stimulation before returning to control levels at 168 h. Meanwhile, at the protein level in RTS11, S25-7 remained unchanged while INVX had a significant decrease at 168 h post-stimulation. These results indicate that neither INVX nor S25-7 is upregulated upon immune system activation; thus, teleosts have evolved a system of immune regulation that is different than that found in mammals.


Assuntos
Antígenos de Diferenciação de Linfócitos B/genética , Antígenos de Diferenciação de Linfócitos B/imunologia , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Imunomodulação/genética , Oncorhynchus mykiss/genética , Oncorhynchus mykiss/imunologia , Imunidade Adaptativa , Animais , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Imunização , Macrófagos/imunologia , Macrófagos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Especificidade de Órgãos/genética , Especificidade de Órgãos/imunologia , Isoformas de Proteínas , Transcriptoma
12.
Biomed Res Int ; 2019: 2323540, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31119156

RESUMO

Bifidobacterium animalis subsp. lactis IPLA 20020 and Lactobacillus gasseri IPLA 20212, two strains isolated from human samples, were evaluated for safety and influence over the intestinal microbiota and cytokine production by the intestinal tissue of adult BALB/c mice. Mice were divided into four groups receiving during 8 days PBS or a suspension of each strain, prepared fresh or lyophilized (bifidobacteria), at an amount of 4x108 viable cells/day. This dose could be comparable to the probiotic intake of a human adult who consumed about 100-200 mL of functional fermented milk per day, considering the usual level of probiotics in commercial products. No microbial translocation to liver or alterations in food intake, weight, and behavior were observed in treated mice. Intestinal content of secretory immunoglobulin A (s-IgA) was not affected, discarding any adverse effect on the mucosa-associated immunity. The profile of intestinal proinflammatory/regulatory cytokines after intervention evidenced that the microbial strain administered and its cellular state (fresh or lyophilized) as well as the host tissue analyzed (small or large intestine) influenced the immune response and suggests a moderate shift towards a T helper 1 profile (Th1) in the large intestine after the administration of both strains. Changes on relative levels of some intestinal microbial groups were evidenced after intervention. It is noteworthy that butyrate was positively associated with a balanced pro-Th1 immune response. Therefore, B. animalis subsp. lactis IPLA20020 and L. gasseri IPLA 20212 could be considered potential probiotic candidates to be included in functional foods for balancing the intestinal immune response.


Assuntos
Bifidobacterium/imunologia , Microbioma Gastrointestinal/imunologia , Imunidade nas Mucosas/imunologia , Lactobacillus/imunologia , Animais , Bifidobacterium/crescimento & desenvolvimento , Fermentação , Humanos , Imunomodulação/genética , Mucosa Intestinal/imunologia , Mucosa Intestinal/microbiologia , Intestinos/imunologia , Intestinos/microbiologia , Lactobacillus/crescimento & desenvolvimento , Camundongos , Probióticos , Células Th1/imunologia , Células Th1/microbiologia
13.
Chemosphere ; 226: 439-446, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30951938

RESUMO

Cylindrospermopsin (CYN), a cyanobacterial toxin, is an important water pollutant with broad biological activity. It has been known mainly from tropical areas, but the area of occurrence of its producers is spreading to temperate climates. It can be found in high concentrations in the environment as well as in purified drinking waters. The aim of the study is to bring a basic information on the ability of CYN to interfere with mammalian innate immunity cells and thus increase the understanding of the immunomodulatory potency of CYN. This study investigated whether immune cells can be a target of CYN either alone or in combination with a model immunomodulatory agent, lipopolysaccharide (LPS). We examined the effects on cellular viability and inflammation signaling of CYN on murine macrophage-like RAW 264.7 cells. Macrophages were treated either with pure toxin (1 µM) or together with a known stimulator of immunologically active cells, bacterial or cyanobacterial LPS. CYN has had a significant effect on production on pro-inflammatory mediator tumor necrosis factor α (TNF-α) which correlates with its effect on reactive oxygen species (ROS) production. We found that CYN potentiated the effect of bacterial and cyanobacterial LPS that was documented by activation of inflammatory signaling pathways including mitogen-activated protein kinase p38 as well as consequent expression of inducible nitric oxide synthase (iNOS) and increased production of pro-inflammatory mediators such as nitric oxide (NO), TNF-α, interleukin-6 (IL-6). Our study brings one of the first information that contributes to the elucidation of immunomodulatory role of CYN in macrophages under normal and pro-inflammatory conditions.


Assuntos
Toxinas Bacterianas/imunologia , Imunidade Inata/imunologia , Imunomodulação/genética , Macrófagos/efeitos dos fármacos , Toxinas Marinhas/imunologia , Microcistinas/imunologia , Uracila/análogos & derivados , Animais , Camundongos , Transdução de Sinais , Uracila/imunologia
14.
EBioMedicine ; 43: 159-170, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30987862

RESUMO

BACKGROUND: Dysregulation of immune checkpoint molecules leads to immune evasion in human tumours but has become a viable target for tumour therapy. Here, we examined expression of Herpes virus entry mediator (HVEM), an immune checkpoint molecule, in human glioblastoma (GBM) to assess its potential as a molecular target for treatment. METHODS: Molecular and clinical data from publicly available genomic databases containing WHO grade II-IV human glioma cases (n = 1866) were analyzed. Immunohistochemistry was applied to assess HVEM protein levels in primary tumour sections. Statistical analysis was performed using Matlab and R language. FINDINGS: HVEM was found to be elevated in aggressive gliomas, particularly in the mesenchymal and isocitrate dehydrogenase (IDH) wild-type molecular subtypes of GBM. HVEMhigh tumours tended to be associated with amplification of EGFR and loss of PTEN, while HVEMlow tumours harbored mutations in IDH1 (93%). HVEM exhibited potential as a prognostic marker based on Cox regression and nomogram models. HVEM displayed intra-tumour heterogeneity and was more highly expressed in peri-necrotic and microvascular regions. Gene ontology and pathway analysis revealed enrichment of HVEM in multiple immune regulatory processes, such as suppression of T cell mediated immunity in GBM. Finally, in cell lineage analysis, HVEM was found to be tightly associated with several infiltrating immune and stromal cell types which localized to the tumour microenvironment. INTERPRETATION: Our data highlights the importance of HVEM in the development of GBM and as a potential molecular target in combination with current immune checkpoint blockades for treatment of GBM.


Assuntos
Biomarcadores Tumorais , Regulação Neoplásica da Expressão Gênica , Glioblastoma/genética , Glioblastoma/mortalidade , Membro 14 de Receptores do Fator de Necrose Tumoral/genética , Progressão da Doença , Heterogeneidade Genética , Variação Genética , Genômica/métodos , Glioblastoma/imunologia , Glioblastoma/patologia , Humanos , Imuno-Histoquímica , Imunomodulação/genética , Estimativa de Kaplan-Meier , Gradação de Tumores , Prognóstico , Células Estromais/metabolismo , Linfócitos T/imunologia , Linfócitos T/metabolismo , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
15.
Molecules ; 24(6)2019 Mar 22.
Artigo em Inglês | MEDLINE | ID: mdl-30909396

RESUMO

Background: The damage to intestinal barrier function plays an important role in the development of obesity and associated diseases. Soy isoflavones are effective natural active components for controlling obesity and reducing the level of blood lipid. Here, we explored whether these effects of soy isoflavones were associated with the intestinal barrier function. Methods and Results: The obese rat models were established by high fat diet feeding. Then, those obese rats were supplemented with soy isoflavones at different doses for 4 weeks. Our results showed that obesity induced the expressions of pro-inflammatory cytokines, decreased the anti-inflammatory cytokine (IL-10) expression, elevated intestinal permeability, altered gut microbiota and exacerbated oxidative damages in colon. The administration of soy isoflavones reversed these changes in obese rats, presenting as the improvement of intestinal immune function and permeability, attenuation of oxidative damage, increase in the fraction of beneficial bacteria producing short-chain fatty acids and short-chain fatty acid production, and reduction in harmful bacteria. Furthermore, soy isoflavones blocked the expressions of TLR4 and NF-κB in the colons of the obese rats. Conclusions: Soy isoflavones could improve obesity through the attenuation of intestinal oxidative stress, recovery of immune and mucosal barrier, as well as re-balance of intestinal gut microbiota.


Assuntos
Colo/efeitos dos fármacos , Colo/imunologia , Dieta Hiperlipídica/efeitos adversos , Imunomodulação/efeitos dos fármacos , Isoflavonas/farmacologia , Obesidade/etiologia , Animais , Biodiversidade , Biomarcadores , Peso Corporal/efeitos dos fármacos , Colo/metabolismo , Citocinas/genética , Citocinas/metabolismo , Suplementos Nutricionais , Modelos Animais de Doenças , Microbioma Gastrointestinal/efeitos dos fármacos , Expressão Gênica , Regulação da Expressão Gênica , Imunomodulação/genética , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Isoflavonas/química , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , NF-kappa B/metabolismo , Obesidade/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais , Ratos , Transdução de Sinais , Soja/química , Receptor 4 Toll-Like/metabolismo
16.
Fish Shellfish Immunol ; 89: 35-42, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30890430

RESUMO

C-type lectin has received widespread attention in animal immunomodulation functions since it was discovered, but it is still limited in crustaceans. The present study is to explore effects of one recombinant C-type lectin (LvLec protein) on haemocyte immune response in Litopenaeus vannamei (L. vannamei). The methods of keeping haemocyte immune activity were optimised by the Key Laboratory of Mariculture. The experiment was divided into four groups: control group, recombinant protein group (LvLec protein, 1.0 mg mL-1), Lipopolysaccharide group (LPS, 1.0 mg mL-1), and LPS combine with LvLec protein group (LPS + LvLec protein, 1.0 mg mL-1 + 1.0 mg mL-1), while each group processes 0, 3, 6, 9, 12, and 24 h respectively. The results showed that the haemocyte count reduced, while the exocytosis PO activity, hemagglutinating activity and phagocytic activity promoted, and the concentration of cGMP and PKA increased after LvLec protein treatment. However, the levels of antibacterial activity and bacteriolytic activity as well as the concentrations of cAMP and PKG did not change significantly after treating with LvLec protein, LPS or LPS + LvLec protein. Therefore, these results suggest that LvLec protein can stimulate the exocytosis PO activity through cGMP-PKA pathway to affect the phagocytic activity and hemagglutinating activity of L. vannamei haemocytes in vitro.


Assuntos
Hemócitos/imunologia , Imunidade Inata/genética , Lectinas Tipo C/genética , Lectinas Tipo C/imunologia , Penaeidae/genética , Penaeidae/imunologia , Animais , Proteínas de Artrópodes/genética , Proteínas de Artrópodes/imunologia , Catecol Oxidase/genética , Catecol Oxidase/metabolismo , Precursores Enzimáticos/genética , Precursores Enzimáticos/metabolismo , Hemócitos/enzimologia , Imunomodulação/genética , Lipopolissacarídeos/fisiologia , Penaeidae/enzimologia , Fagocitose/imunologia , Proteínas Recombinantes/genética , Proteínas Recombinantes/imunologia
17.
Iran J Immunol ; 16(1): 62-70, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30864556

RESUMO

BACKGROUND: Ulcerative colitis (UC) and Crohn's disease (CD) are the two forms of inflammatory bowel disease (IBD). Adaptive immune responses involving helper T cells play an important role in developing IBDs. Programmed death (PD)-1 and its ligands namely PD-L1 and PD-L2 are negative costimulatory molecules that control T cell motility and formation of an immune synapse between T cells and antigen-presenting cells (APCs). OBJECTIVE: To investigate the role of PD-L1 and PD-L2 in patients with UC to clarify the mechanism of IBD development. METHODS: Biopsy specimens were obtained from 50 UC patients and 45 sex- and age-matched control subjects. Total RNA was extracted from all samples and applied for cDNA synthesis. Relative expression of PD-L1 and PD-L2 mRNA was determined using Taqman qRT-PCR. RESULTS: Relative gene expression levels of both PD-L1 and PD-L2 were higher in UC patients than the control groups (p<0.05 and p<0.01, respectively). Furthermore, both PD-L1 and PD-L2 expressions were positively correlated in all study subjects (r=0.339, p<0.001). However, among the groups with disease severity, the relative gene expression levels of PD-L1 and PD-L2 showed no significant difference. CONCLUSIONS: During IBD, the occurrence of PD-L1 and PD-L2 up-regulation may modulate the chronic inflammation of colonic mucosa.


Assuntos
Antígeno B7-H1/genética , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Expressão Gênica , Imunomodulação/genética , Proteína 2 Ligante de Morte Celular Programada 1/genética , Adolescente , Adulto , Estudos de Casos e Controles , Criança , Colite Ulcerativa/diagnóstico , Feminino , Regulação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Adulto Jovem
18.
Front Immunol ; 10: 15, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30761124

RESUMO

Persistent and excessive cytokine production is a hallmark of autoimmune diseases and may play a role in disease pathogenesis and amplification. Therefore, cytokine neutralization is a useful therapeutic strategy to treat immune-mediated conditions. MicroRNAs (miRNAs) are small non-coding RNA molecules that regulate gene expression in diverse biological processes. Altered miRNA levels are observed in most autoimmune diseases and are recognized to influence autoimmunity through different mechanisms. Here, we review the impact of altered miRNA levels on the expression of cytokines that play a relevant pathogenic role in autoimmunity, namely primary pro-inflammatory cytokines, the IL-17/IL-23 axis, type I interferons and IL-10. Regulation can be either "direct" on the target cytokine, or "indirect," meaning that one given miRNA post-transcriptionally regulates the expression of a protein that in turn influences the level of the cytokine. In addition, miRNAs associated with extracellular vesicles can regulate cytokine production in neighboring cells, either post-transcriptionally or via the stimulation of innate immune RNA-sensors, such as Toll-like receptors. Because of their tremendous potential as physiological and pathological regulators, miRNAs are in the limelight as promising future biopharmaceuticals. Thus, these studies may lead in the near future to the design and testing of therapeutic miRNAs as next generation drugs to target pathogenic cytokines in autoimmunity.


Assuntos
Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Autoimunidade/genética , Citocinas/genética , Regulação da Expressão Gênica , MicroRNAs/genética , Interferência de RNA , Animais , Doenças Autoimunes/metabolismo , Doenças Autoimunes/terapia , Biomarcadores , Citocinas/metabolismo , Humanos , Imunomodulação/genética , Terapia de Alvo Molecular , Transdução de Sinais
19.
Biosci Rep ; 39(1)2019 01 31.
Artigo em Inglês | MEDLINE | ID: mdl-30610158

RESUMO

The regenerative and immunomodulatory characteristics of mesenchymal stem cells (MSCs) make them attractive in the treatment of many diseases. Although they have shown promising preclinical studies of immunomodulation and paracrine effects in inflammatory airway disorders and other lung diseases, there are still challenges that have to be overcome before MSCs can be safely, effectively, and routinely applied in the clinical setting. A good understanding of the roles and mechanisms of the MSC immunomodulatory effects will benefit the application of MSC-based clinical therapy. In this review, we summarize the promises and challenges of the preclinical and clinical trials of MSC therapies, aiming to better understand the role that MSCs play in attempt to treat inflammatory airway disorders.


Assuntos
Terapia Baseada em Transplante de Células e Tecidos/tendências , Imunomodulação/genética , Inflamação/terapia , Transplante de Células-Tronco Mesenquimais/tendências , Humanos , Inflamação/genética , Inflamação/patologia , Células-Tronco Mesenquimais/citologia
20.
Genes Chromosomes Cancer ; 58(8): 578-588, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-30664300

RESUMO

Characterization of tumors utilizing next-generation sequencing methods, including assessment of the number of somatic mutations (tumor mutational burden [TMB]), is currently at the forefront of the field of personalized medicine. Recent clinical studies have associated high TMB with improved patient response rates and survival benefit from immune checkpoint inhibitors; hence, TMB is emerging as a biomarker of response for these immunotherapy agents. However, variability in current methods for TMB estimation and reporting is evident, demonstrating a need for standardization and harmonization of TMB assessment methodology across assays and centers. Two uniquely placed organizations, Friends of Cancer Research (Friends) and the Quality Assurance Initiative Pathology (QuIP), have collaborated to coordinate efforts for international multistakeholder initiatives to address this need. Friends and QuIP, who have partnered with several academic centers, pharmaceutical organizations, and diagnostic companies, have adopted complementary, multidisciplinary approaches toward the goal of proposing evidence-based recommendations for achieving consistent TMB estimation and reporting in clinical samples across assays and centers. Many factors influence TMB assessment, including preanalytical factors, choice of assay, and methods of reporting. Preliminary analyses highlight the importance of targeted gene panel size and composition, and bioinformatic parameters for reliable TMB estimation. Herein, Friends and QuIP propose recommendations toward consistent TMB estimation and reporting methods in clinical samples across assays and centers. These recommendations should be followed to minimize variability in TMB estimation and reporting, which will ensure reliable and reproducible identification of patients who are likely to benefit from immune checkpoint inhibitors.


Assuntos
Biomarcadores Tumorais , Mutação , Neoplasias/genética , Animais , Tomada de Decisão Clínica , Estudos Clínicos como Assunto , Gerenciamento Clínico , Humanos , Imunomodulação/genética , Imunoterapia , Terapia de Alvo Molecular , Neoplasias/diagnóstico , Neoplasias/imunologia , Neoplasias/terapia , Resultado do Tratamento
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