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Aim: The purpose of this study is to undertake an integrative literature review in order to determine the prevalence, etiology, and reactivation of oral HSV infection in patients receiving chemotherapy (CT). Methods: The study was carried out in the PubMed/MEDLINE, Embase, Virtual Health Library, and Scopus databases, using the descriptors "Herpes Simplex", "Viral Diseases", "Mouth", and "Antineoplastic Agents". Results: The findings suggest that HSV infection is widespread in this group of patients and can be severe. HSV infection is frequent in CT patients, and treatment should begin as soon as it is feasible, utilizing antivirals to avoid future difficulties, as patients are immunocompromised. Conclusion: It is critical for health professionals to be fully informed on the dangers and treatment choices available, with the most appropriate therapy for each circumstance. Furthermore, more recent research with acceptable methodological rigor is required to better quantify the prevalence of HSV in these patients.
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Interleukin (IL)-33 is an important cytokine in the tumour microenvironment; it is known to promote the growth and metastasis of solid cancers, such as gastric, colorectal, ovarian and breast cancer. Our group demonstrated that the IL-33/ST2 pathway enhances the development of squamous cell carcinoma (SCC). Conversely, other researchers have reported that IL-33 inhibits tumour progression. In addition, the crosstalk between IL-33, cancer cells and immune cells in SCC remains unknown. The aim of this study was to investigate the effect of IL-33 on the biology of head and neck SCC lines and to evaluate the impact of IL-33 neutralisation on the T cell response in a preclinical model of SCC. First, we identified epithelial and peritumoural cells as a major local source of IL-33 in human SCC samples. Next, in vitro experiments demonstrated that the addition of IL-33 significantly increased the proliferative index, motility and invasiveness of SCC-25 cells, and downregulated MYC gene expression in SCC cell lines. Finally, IL-33 blockade significantly delayed SCC growth and led to a marked decrease in the severity of skin lesions. Importantly, anti-IL-33 monoclonal antibody therapy increase the percentage of CD4+IFNγ+ T cells and decreased CD4+ and CD8+ T cells secreting IL-4 in tumour-draining lymph nodes. Together, these data suggest that the IL-33/ST2 pathway may be involved in the crosstalk between the tumour and immune cells by modulating the phenotype of head and neck SCC and T cell activity. IL-33 neutralisation may offer a novel therapeutic strategy for SCC.
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Carcinoma de Células Escamosas , Movimiento Celular , Proliferación Celular , Interleucina-33 , Activación de Linfocitos , Interleucina-33/metabolismo , Humanos , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/metabolismo , Animales , Activación de Linfocitos/inmunología , Invasividad Neoplásica , Ratones , Línea Celular Tumoral , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/patología , Neoplasias de Cabeza y Cuello/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Microambiente Tumoral/inmunología , FemeninoRESUMEN
A resposta imunológica pelo SARS-CoV-2 após protocolos vacinais e infecção natural é pouco compreendida. Comparando indivíduos vacinados com esquema heterólogo que receberam um reforço vacinal (imunidade vacinal) com aqueles que apresentaram episódio leve de COVID-19 (imunidade híbrida) no mesmo período, verificamos níveis semelhantes de anticorpos contra SARS-CoV-2. Em culturas de células mononucleares, o estímulo com o antígeno viral induziu produção de citocinas pró-inflamatórias nos dois grupos, entretanto, os níveis de IL-17 foram menores em indivíduos com imunidade vacinal. Nossos resultados sugerem que o reforço vacinal teve efeitos semelhantes à infecção natural pelo SARS-CoV-2 na resposta imunológica de indivíduos previamente vacinados. (AU)
The immune response generated by SARS-CoV-2 vaccination protocols and natural infection remains incompletely understood. We compared individuals who received a heterologous vaccination scheme with a booster shot (vaccine immunity) to those who experienced a mild COVID-19 episode (hybrid immunity) during the same timeframe. Our findings revealed similar levels of SARS-CoV-2 antibodies in both groups. Stimulation by viral antigen in mononuclear cell cultures induced pro-inflammatory cytokines in both groups, while individuals with vaccine immunity exhibited lower IL-17. These results suggest that a vaccine booster can induce an immune response in previously vaccinated individuals comparable to that elicited by natural SARS-CoV-2 infection. (AU)
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Vacunas , Citocinas , SARS-CoV-2 , COVID-19 , Inmunidad , AnticuerposRESUMEN
OBJECTIVE: Neutrophils are key effector cells of the innate immune system. They recognize antigens through membrane receptors, which are expressed during their maturation and activation. Neutrophils express FcγRII (CD32), FcγRIII (CD16), and FcγRI (CD64) after being activated by different factors such as cytokines and bacterial products. These receptors are involved with phagocytosis of IgG-opsonized microbes and enhance defense mechanisms. Based on that, our study seeks to compare the expression of FcγRII, FcγRIII, FcγRI, and CD11b on neutrophils from elderly and young subjects and their expression after in vitro activation with cytokines and LPS. METHODOLOGY: Neutrophils were isolated from human peripheral blood and from mice bone marrow by density gradient. After isolation, FCγRs expression was immediately analyzed by flow cytometry or after in vitro stimulation. RESULTS: In freshly isolated cells, the percentage of FcγRIIIb+ and CD11b+ neutrophils were higher in samples from young individuals; FcγRIIIa expression was more prominent on aged neutrophils; FcγRIA expression was similar in all samples analyzed. Exposure to CXCL8 and LPS resulted in a higher percentage of FcγRIa+ neutrophils on elderly individuals' samples but lower when compared with neutrophils from young donors. We observed that LPS caused an increase in FcγRIIa expression on aging human neutrophils. In contrast, FcγRIIIb expression in response to CXCL8 and LPS stimulation was not altered in the four groups. CD11b expression was lower in neutrophils from elderly individuals even in response to LPS and CXCL8. In mice, we observed differences only regarding CD11b expression, which was increased on aged neutrophils. LPS exposure caused an increase in all FcγRs. CONCLUSIONS: Our results suggest that, in humans, the overall pattern of FcγR expression and integrin CD11b are altered during aging and immunosenescence might contribute to age-related infection.
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Neutrófilos , Receptores de IgG , Animales , Recuento de Células , Citometría de Flujo , Ratones , FagocitosisRESUMEN
BACKGROUND: Erythema nodosum leprosum (ENL) is a frequent complication of multibacillary leprosy that can result in significant morbidity, including peripheral nerve damage and physical disability. The identification of possible serum markers could be a valuable tool for the early detection of ENL. AIMS: The purpose of this study was to evaluate selected serum mediators involved in the innate and adaptive immune responses to identify possible immunomarkers for ENL. METHODS: The levels of interleukin-2, interleukin-4, interleukin-6, interleukin-10, interleukin-17, interferon-γ, tumor necrosis factor, nitric oxide and anti-phenolic glycolipid-I antibodies were measured in the sera of leprosy patients with ENL [at the beginning of reaction (M0) and 1 month later (M1)], and then compared with the levels of the same markers in patients with untreated multibacillary leprosy without ENL (controls with leprosy: CTRL) and healthy individuals (healthy controls: CTRH). RESULTS: Significantly higher levels of serum interleukin-6 were observed in M0 than in CTRL. In addition, pairwise comparisons showed higher levels of interleukin-6 in M0 compared to M1. Levels of tumor necrosis factor were higher in M0 than in CTRL, with no significant difference between M0 and M1. There were no differences in the levels of interleukin-2, interleukin-4, interleukin-10, interleukin-17 or interferon-γ between groups. The CTRL group had higher levels of nitric oxide compared to M0 and M1. High levels of anti-phenolic glycolipid-I were observed in M0, M1 and CTRL than in CTRH. LIMITATIONS: Three patients were not assessed at M1, decreasing the number of evaluated patients from 14 to 11. CONCLUSION: High-serum levels of interleukin-6 were observed during ENL, primarily in patients with more severe reactions; levels decreased after specific therapy, suggesting a role for this cytokine in pathogenesis and its utility as an ENL biomarker. Further studies should explore whether interleukin-6 could also be used as a predictive marker for ENL or as a specific target for its treatment.
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Eritema Nudoso/sangre , Interleucina-6/sangre , Lepra/sangre , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Squamous cell carcinoma (SCC) is the second most common skin cancer worldwide and, despite the relatively easy visualization of the tumor in the clinic, a sizeable number of SCC patients are diagnosed at advanced stages with local invasion and distant metastatic lesions. In the last decade, immunotherapy has emerged as the fourth pillar in cancer therapy via the targeting of immune checkpoint molecules such as programmed cell-death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). FDA-approved monoclonal antibodies directed against these immune targets have provide survival benefit in a growing list of cancer types. Currently, there are two immunotherapy drugs available for cutaneous SCC: cemiplimab and pembrolizumab; both monoclonal antibodies (mAb) that block PD-1 thereby promoting T-cell activation and/or function. However, the success rate of these checkpoint inhibitors currently remains around 50%, which means that half of the patients with advanced SCC experience no benefit from this treatment. This review will highlight the mechanisms by which the immune checkpoint molecules regulate the tumor microenvironment (TME), as well as the ongoing clinical trials that are employing single or combinatory therapeutic approaches for SCC immunotherapy. We also discuss the regulation of additional pathways that might promote superior therapeutic efficacy, and consequently provide increased survival for those patients that do not benefit from the current checkpoint inhibitor therapies.
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Abstract Objective Neutrophils are key effector cells of the innate immune system. They recognize antigens through membrane receptors, which are expressed during their maturation and activation. Neutrophils express FcγRII (CD32), FcγRIII (CD16), and FcγRI (CD64) after being activated by different factors such as cytokines and bacterial products. These receptors are involved with phagocytosis of IgG-opsonized microbes and enhance defense mechanisms. Based on that, our study seeks to compare the expression of FcγRII, FcγRIII, FcγRI, and CD11b on neutrophils from elderly and young subjects and their expression after in vitro activation with cytokines and LPS. Methodology Neutrophils were isolated from human peripheral blood and from mice bone marrow by density gradient. After isolation, FCγRs expression was immediately analyzed by flow cytometry or after in vitro stimulation. Results In freshly isolated cells, the percentage of FcγRIIIb+ and CD11b+ neutrophils were higher in samples from young individuals; FcγRIIIa expression was more prominent on aged neutrophils; FcγRIA expression was similar in all samples analyzed. Exposure to CXCL8 and LPS resulted in a higher percentage of FcγRIa+ neutrophils on elderly individuals' samples but lower when compared with neutrophils from young donors. We observed that LPS caused an increase in FcγRIIa expression on aging human neutrophils. In contrast, FcγRIIIb expression in response to CXCL8 and LPS stimulation was not altered in the four groups. CD11b expression was lower in neutrophils from elderly individuals even in response to LPS and CXCL8. In mice, we observed differences only regarding CD11b expression, which was increased on aged neutrophils. LPS exposure caused an increase in all FcγRs. Conclusions Our results suggest that, in humans, the overall pattern of FcγR expression and integrin CD11b are altered during aging and immunosenescence might contribute to age-related infection.
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Animales , Ratones , Receptores de IgG , Neutrófilos , Fagocitosis , Recuento de Células , Citometría de FlujoRESUMEN
BACKGROUND AND OBJECTIVE: Several studies have demonstrated that mast cells are equipped with versatile tools to combat and kill bacteria. Additionally, mast cells produce and secrete a variety of mediators, which either regulate the host's immune system or directly attack bacteria. In this study, the intracellular microbicidal capacity of mast cells against Aggregatibacter actinomycetemcomitans was evaluated. METHODS: Murine mast cells were challenged in vitro with A actinomycetemcomitans for 3, 5, 10, and 24 hours. Subsequently, the colony-forming units were counted. Additionally, the production and release of nitric oxide and hydrogen peroxide were analyzed by DAF-FM diacetate, the Griess reaction, and the Amplex Red kit, respectively. Cell death was evaluated using FITC Annexin V and propidium iodide staining. RESULTS: Mast cells are able to efficiently eliminate periodontopathogen, with best results after 10 hours of intracellular challenge. The production/release of nitric oxide-and to a lesser extent of hydrogen peroxide-by mast cells was in agreement with its microbicidal capacity. Ninety percent of the mast cells maintained their cellular viability even after 24 hours of bacterial challenge. CONCLUSIONS: This is-to the best of our knowledge-the first report to describe the intracellular microbicidal activity of mast cells against A actinomycetemcomitans, concerning the production and release of potentially bactericidal substances. Further, the low number of cell deaths confirms that the decreased number of colony-forming units was due to the higher antimicrobial activity of mast cells. The results highlight the importance of these cells in the defense mechanisms of biofilm-induced periodontal disease.
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Aggregatibacter actinomycetemcomitans , Mastocitos , Enfermedades Periodontales , Animales , Biopelículas , Ratones , Óxido Nítrico , Enfermedades Periodontales/microbiologíaRESUMEN
The release of the prototypic DAMP High Mobility Group Box 1 (HMGB1) into extracellular environment and its binding to the Receptor for Advanced Glycation End Products (RAGE) has been described to trigger sterile inflammation and regulate healing outcome. However, their role on host response to Ti-based biomaterials and in the subsequent osseointegration remains unexplored. In this study, HMGB1 and RAGE inhibition in the Ti-mediated osseointegration were investigated in C57Bl/6 mice. C57Bl/6 mice received a Ti-device implantation (Ti-screw in the edentulous alveolar crest and a Ti-disc in the subcutaneous tissue) and were evaluated by microscopic (microCT [bone] and histology [bone and subcutaneous]) and molecular methods (ELISA, PCR array) during 3, 7, 14, and 21 days. Mice were divided into 4 groups: Control (no treatment); GZA (IP injection of Glycyrrhizic Acid for HMGB1 inhibition, 4 mg/Kg/day); RAP (IP injection of RAGE Antagonistic Peptide, 4 mg/Kg/day), and vehicle controls (1.5% DMSO solution for GZA and 0.9% saline solution for RAP); treatments were given at all experimental time points, starting 1 day before surgeries. HMGB1 was detected in the Ti-implantation sites, adsorbed to the screws/discs. In Control and vehicle groups, osseointegration was characterized by a slight inflammatory response at early time points, followed by a gradual bone apposition and matrix maturation at late time points. The inhibition of HMGB1 or RAGE impaired the osseointegration, affecting the dynamics of mineralized and organic bone matrix, and resulting in a foreign body reaction, with persistence of macrophages, necrotic bone, and foreign body giant cells until later time points. While Control samples were characterized by a balance between M1 and M2-type response in bone and subcutaneous sites of implantation, and also MSC markers, the inhibition of HMGB1 or RAGE caused a higher expression M1 markers and pro-inflammatory cytokines, as well chemokines and receptors for macrophage migration until later time points. In conclusion, HMGB1 and RAGE have a marked role in the osseointegration, evidenced by their influence on host inflammatory immune response, which includes macrophages migration and M1/M2 response, MSC markers expression, which collectively modulate bone matrix deposition and osseointegration outcome.
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Antígenos de Neoplasias/metabolismo , Artroplastia/métodos , Materiales Biocompatibles/metabolismo , Proteínas HMGB/metabolismo , Inflamación/inmunología , Macrófagos/inmunología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Titanio/metabolismo , Animales , Materiales Biocompatibles/química , Biomarcadores/metabolismo , Matriz Ósea/efectos de los fármacos , Movimiento Celular , Ácido Glicirrínico/administración & dosificación , Proteínas HMGB/antagonistas & inhibidores , Humanos , Inmunomodulación , Ratones , Ratones Endogámicos C57BL , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Oseointegración , Péptidos/administración & dosificación , Titanio/químicaRESUMEN
TBX21-1993T/C (rs4794067) polymorphism increases the transcriptional activity of the Tbx21, essential for interferon gamma (IFNg) transcription, but its functional impact on development Th1- response in vivo remains unclear, as well its potential influence over inflammatory osteolytic conditions, such as periapical lesions. Therefore, this study comprises a case-control and functional investigation of Tbx21 genetic variations impact on Th1 response in vivo and in vitro, and its impact on periapical lesions risk and outcome, performed with a population of healthy controls (H; N = 283) and patients presenting periapical lesions (L; N = 188) or deep caries (DC; N = 152). TBX21-1993T/C genotyping demonstrated that the polymorphic allele C, as well TC/TC+CC genotypes, was significantly less frequent in the L patients compared to H and DC groups. Additionally, gene expression analysis demonstrates that T-cell-specific T-box transcription factor (Tbet) and IFNg transcripts levels were downregulated whereas IL-17 levels were upregulated in the TBX21-1993 C carriers (TC/TC+CC) in comparison with the TT group. Also, while TT and TC+CC genotypes are equally prevalent in the lesions presenting low IFN/IL17 ratio, a significant decrease in polymorphic TC+CC genotypes was observed in lesions presenting intermediate and high IFN/IL17 ratio. In vitro experiments confirmed the predisposition to Th1 polarization associated with TBX21-1993, since PBMC CD4 T cells from T allele carriers produce higher IFNg levels upon CD3/CD28 stimulation than the C group, in both standard/neutral and Th1-polarizing culture conditions. In conclusion, the TBX21-1993 T allele and TC/CC genotypes predispose to Th1-type immune response development in vitro, influence immune response polarization in vivo, and consequently account for the risk for apical periodontitis development.
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Predisposición Genética a la Enfermedad , Enfermedades Periapicales/genética , Polimorfismo de Nucleótido Simple/genética , Proteínas de Dominio T Box/genética , Células TH1/metabolismo , Células Th17/metabolismo , Adolescente , Adulto , Linfocitos T CD4-Positivos/inmunología , Femenino , Regulación de la Expresión Génica , Humanos , Interferón gamma/metabolismo , Masculino , Persona de Mediana Edad , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de Riesgo , Adulto JovenRESUMEN
OBJECTIVE: This study aimed to examine programmed death protein 1 (PD-1) and programmed death lig-and 1 (PD-L1) expression on leukocytes from chronic apical periodontitis, and to determine the levels of cytokines in the apical periodontitis lesions. METHODS: Leukocytes from healthy gingival tissue (n=16) and chronic apical periodontitis (n=10) were eval-uated using flow cytometry. The PD-1 and PDL-1 expressions were evaluated using flow cytometry. The cy-tokine levels were evaluated by enzyme-linked immunosorbent assay. Data were analyzed using one-way ANOVA. The statistical significance level was set at P<0.05. RESULTS: Results showed that the apical periodontitis lesions are more infiltrated by PD-1+ and PDL1+ lym-phocytes than the control samples. In addition, the PDL-1 expression was detected on macrophages in the apical periodontitis lesions, and was significantly higher compared to leukocytes from healthy gingival tis-sue. The IFN-γ, TGF-ß, IL-10, and TNF-α levels were significantly higher in the apical periodontitis lesions com-pared to control samples. CONCLUSION: The PD-1, PD-L1, and CTLA-4 molecules are evident in apical periodontitis, and can be an impor-tant immune checkpoint in chronic periapical periodontitis.
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Squamous cell carcinoma (SCC) is the second most common form of skin cancer and the mechanism(s) involved in the progression of this tumor are unknown. Increases in the expression of IL-33/ST2 axis components have been demonstrated to contribute to neoplastic transformation in several tumor models and interleukin-33 is correlated with poor prognosis of patients with squamous cell carcinoma of the tongue. Based on these observations, we sought to determine the role of the IL-33/ST2 pathway during the development of SCC. Our findings show that ST2-deficiency led to a marked decrease in the severity of skin lesions, suggesting that ST2 signaling contributed to tumor development. An analysis of tumor lesions in wild-type and ST2KO mice revealed that a lack of ST2 was associated with specific and significant reductions in the numbers of CD4+ T cells, CD8+ T cells, dendritic cells, and macrophages. In addition, NK cells that were isolated from ST2KO mice exhibited higher cytotoxic activity than cells isolated from wild-type mice. Notably, ST2 deficiency resulted in lower IFN-γ, TNF-α, IL-10, and IL-17 production in tumor samples. Our findings indicate that the IL-33/ST2 pathway contributes to the development of SCC by affecting leukocyte migration to tumor microenvironment and impairing NK cytotoxic activity.
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BACKGROUND: The granulation tissue present in surgically-created early healing sockets has been considered as a possible source of osteoprogenitor cells for periodontal regeneration, as demonstrated in animal studies. However, the in vitro osteogenic properties of tissue removed from human surgically-created early healing alveolar defects (SC-EHAD) remains to be established, being that the aim of this study. METHODS: Surgical defects were created in the edentulous ridge of two systemically healthy adults. The healing tissue present in these defects was removed 21 days later for the establishment of primary culture. The in vitro characteristics of the cultured cells were determined by Armelin method, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, immunohistochemistry, alkaline phosphatase (ALP) activity, mineralization assay, and flow cytometry for detection of stem cells/osteoprogenitor cell markers. RESULTS: Cells were able to adhere to the plastic and assumed spindle-shaped morphology at earlier passages, changing to a cuboidal one with increasing passages. Differences in the proliferation rate were observed with increasing passages, suggesting osteogenic differentiation. ALP and mineralization activities were detected in conventional and osteogenic medium. Fresh samples of SC-EHAD tissue exhibited CD34- and CD45- phenotypes. Cells at later passages (14th) exhibited CD34- , CD45- , CD105- , CD166- , and collagen type I+ phenotype. CONCLUSION: Tissue removed from SC-EHAD is a possible source of progenitor cells.
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Células Madre Mesenquimatosas , Osteogénesis , Adulto , Animales , Diferenciación Celular , Células Cultivadas , Humanos , Células Madre , Cicatrización de HeridasRESUMEN
Recent evidence indicates that nonprofessional immune cells such as epithelial cells, endothelial cells, and fibroblasts also contribute to innate immunity via secretion of cytokines. Fibroblasts are the principal type of cell found in the periodontal connective tissues and they are involved in the immune response during periodontal disease. The role of fibroblasts in the recognition of pathogens via Toll-like receptors (TLRs) has been established; however, few studies have been conducted concerning the involvement of innate immune receptors in the recognition of Candida albicans by gingival fibroblast. In the current study, we investigate the functional activity of TLR2, cluster of differentiation 14 (CD14), and myeloid differentiation primary response gene 88 (MyD88) molecules in the recognition of C. albicans by gingival fibroblast. First, we identified that gingival fibroblasts expressed TLR2, TLR3, and TLR4. Our results showed that TLR agonists had no effect on these receptors' expression by TLR2, MyD88, and CD14-deficient cells. Notably, C. albicans and a synthetic triacylated lipoprotein (Pam3CSK4) induced a remarkable increase of TLR3 expression on MyD88-deficient gingival fibroblasts. TLR4 expression levels were lower than TLR2 and TLR3 levels and remained unchanged after TLR agonist stimulation. Gingival fibroblasts presented morphological similarities; however, TLR2 deficiency on these cells leads to a lower proliferative response, whereas the deficiency on CD14 expression resulted in lower levels of type I collagen by these cells. In addition, the recognition of C. albicans by gingival fibroblasts had an effect on the secretion of cytokines and it was dependent on a specific recognition molecule. Specifically, tumor necrosis factor-α (TNF-α) production after the recognition of C. albicans was dependent on MyD88, CD14, and TLR2 molecules, whereas the production of interleukin-1ß (IL-1ß) and IL-13 was dependent on TLR2. These findings are the first to describe a role of gingival fibroblast in the recognition of C. albicans and the pathways involved in this process. An understanding of these pathways may lead to alternative treatments for patients with periodontal disease.
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Candida albicans/metabolismo , Fibroblastos/microbiología , Encía/microbiología , Receptores de Lipopolisacáridos/metabolismo , Factor 88 de Diferenciación Mieloide/metabolismo , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 4/metabolismo , Actinas/metabolismo , Animales , Células Cultivadas , Colágeno/metabolismo , Citocinas/metabolismo , Fibroblastos/metabolismo , Inmunidad Innata , Mediadores de Inflamación/metabolismo , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
Squamous cell carcinoma (SCC) is one of the most common human cancers worldwide. Recent studies show that regulatory T cells (Treg) have a critical role in the modulation of an antitumor immune response, and consequently the SCC development. Because the accumulation of Tregs at the tumor site is, in part, due to selective recruitment through CCR5- and CCR5-associated chemokines, we investigated the role of CCR5 in the SCC development. Our findings showed that CCR5-deficient mice (CCR5KO) were efficient in controlling papilloma's incidence when compared with wild-type mice. Analysis of tumor lesions in wild-type (WT) and CCR5KO mice revealed that lack of CCR5 lead to significant reduction in frequency of Tregs and increased of CD4 T cells into the tumors. Moreover, the adoptive transfer of naturally occurring Tregs CD4+CD25+CCR5+, CD4+CD25-CCR5+ or CD8+CCR5+ conventional T cells to CCR5KO mice resulted in an increased papilloma incidence. Interestingly, adoptive transfer of WT CD4+CD25+CCR5+ cells to CCR5KO mice induced more undifferentiated SCC lesions, characterized by higher infiltration of macrophages and dendritic cells. In this study, we also demonstrated that Treg migration to the tumor microenvironment is mediated by CCR5, and these cells are promoting tumor growth via inhibition of antitumor cells such as cytotoxic CD8+ T cells. Our findings reinforce the therapeutic potential of CCR5 inhibition for cancer treatment, and indicate an attractive approach for SCC treatment. Mol Cancer Ther; 16(12); 2871-80. ©2017 AACR.
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Carcinoma de Células Escamosas/inmunología , Receptores CCR5/inmunología , Neoplasias Cutáneas/inmunología , Linfocitos T Reguladores/inmunología , Animales , Carcinoma de Células Escamosas/patología , Humanos , Ratones , Neoplasias Cutáneas/patología , Microambiente TumoralRESUMEN
Leprosy remains a health problem in several countries. Current management of patients with leprosy is complex and requires multidrug therapy. Nonetheless, antibiotic treatment is insufficient to prevent nerve disabilities and control Mycobacterium leprae. Successful infectious disease treatment demands an understanding of the host immune response against a pathogen. Immune-based therapy is an effective treatment option for malignancies and infectious diseases. A promising therapeutic approach to improve the clinical outcome of malignancies is the blockade of immune checkpoints. Immune checkpoints refer to a wide range of inhibitory or regulatory pathways that are critical for maintaining self-tolerance and modulating the immune response. Programmed cell-death protein-1 (PD-1), programmed cell death ligand-1 (PD-L1), cytotoxic T-lymphocyte-associated protein 4, and lymphocyte-activation gene-3 are the most important immune checkpoint molecules. Several pathogens, including M. leprae, are supposed to utilize these mechanisms to evade the host immune response. Regulatory T cells and expression of co-inhibitory molecules on lymphocytes induce specific T-cell anergy/exhaustion, leading to disseminated and progressive disease. From this perspective, we outline how the co-inhibitory molecules PD-1, PD-L1, and Th1/Th17 versus Th2/Treg cells are balanced, how antigen-presenting cell maturation acts at different levels to inhibit T cells and modulate the development of leprosy, and how new interventions interfere with leprosy development.
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OBJECTIVE: In this study, we evaluated whether budlein A modulates the activation of innate and adaptive immune cells such as neutrophils and lymphocytes. MATERIAL AND METHODS: Our research group has investigated several plant species and several compounds have been isolated, identified, and their medical potential evaluated. Budlein A is a SL isolated from the species Aldama buddlejiformis and A. robusta (Asteraceae) and shows anti-inflammatory and anti-nociceptive activities. Advances in understanding how plant-derived substances modulate the activation of innate and adaptive immune cells have led to the development of new therapies for human diseases. RESULTS: Budlein A inhibited MPO activity, IL-6, CXCL8, IL-10, and IL-12 production and induces neutrophil apoptosis. In contrast, budlein A inhibited lymphocyte proliferation and IL-2, IL-10, TGF-ß, and IFN-γ production, but it did not lead to cell death. CONCLUSIONS: Collectively, our results indicate that budlein A shows distinct immunomodulatory effects on immune cells.
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Antiinflamatorios/farmacología , Lactonas/farmacología , Neutrófilos/efectos de los fármacos , Sesquiterpenos/farmacología , Linfocitos T/efectos de los fármacos , Adulto , Análisis de Varianza , Apoptosis/efectos de los fármacos , Asteraceae/química , Proliferación Celular/efectos de los fármacos , Células Cultivadas , Ensayo de Inmunoadsorción Enzimática , Femenino , Citometría de Flujo , Humanos , Interleucina-8/análisis , Interleucina-8/efectos de los fármacos , Interleucinas/análisis , Masculino , Persona de Mediana Edad , Peroxidasa/análisis , Peroxidasa/efectos de los fármacos , Reproducibilidad de los Resultados , Factores de Crecimiento Transformadores/análisis , Factores de Crecimiento Transformadores/efectos de los fármacosRESUMEN
ABSTRACT Sesquiterpene lactones (SLs) are the active constituents of a variety of medicinal plants used in traditional medicine for the treatment of inflammatory diseases and other ailments. Objective In this study, we evaluated whether budlein A modulates the activation of innate and adaptive immune cells such as neutrophils and lymphocytes. Material and Methods Our research group has investigated several plant species and several compounds have been isolated, identified, and their medical potential evaluated. Budlein A is a SL isolated from the species Aldama buddlejiformis and A. robusta (Asteraceae) and shows anti-inflammatory and anti-nociceptive activities. Advances in understanding how plant-derived substances modulate the activation of innate and adaptive immune cells have led to the development of new therapies for human diseases. Results Budlein A inhibited MPO activity, IL-6, CXCL8, IL-10, and IL-12 production and induces neutrophil apoptosis. In contrast, budlein A inhibited lymphocyte proliferation and IL-2, IL-10, TGF-β, and IFN-γ production, but it did not lead to cell death. Conclusions Collectively, our results indicate that budlein A shows distinct immunomodulatory effects on immune cells.
Asunto(s)
Humanos , Masculino , Femenino , Adulto , Persona de Mediana Edad , Sesquiterpenos/farmacología , Linfocitos T/efectos de los fármacos , Lactonas/farmacología , Antiinflamatorios/farmacología , Neutrófilos/efectos de los fármacos , Ensayo de Inmunoadsorción Enzimática , Factores de Crecimiento Transformadores/análisis , Factores de Crecimiento Transformadores/efectos de los fármacos , Células Cultivadas , Reproducibilidad de los Resultados , Análisis de Varianza , Interleucina-8/análisis , Interleucina-8/efectos de los fármacos , Interleucinas/análisis , Apoptosis/efectos de los fármacos , Peroxidasa/análisis , Peroxidasa/efectos de los fármacos , Asteraceae/química , Proliferación Celular/efectos de los fármacos , Citometría de FlujoRESUMEN
The aim of this study was to evaluate the mechanism involved in the stem cell factor (SCF)-induced production of fibroblast growth factor-2 (FGF-2), transforming growth factor-ß1 (TGF-ß1), and chemokine (C-C motif) ligand 3 (CCL3) in tracheal smooth muscle cells (tSMCs) and the signaling pathway involved in the process. tSMC primary cultures were stimulated with SCF and evaluated at 24 h. Cells treated with specific antibodies did not show any immunolabeling for cytokeratin or fibroblast activation protein, but were positive for α-smooth muscle actin, indicating the purity of the primary cell line. Western blot analysis showed constitutive phosphorylation of c-Kit, as well as increased total protein and phosphorylated c-Kit levels in tSMCs after SCF stimulation. Flow cytometry analysis also showed an increase in cell-surface c-Kit expression in the presence of SCF. SCF induced TGF-ß mRNA expression in tSMCs, as well as the production of TGF-ß1, CCL3, and FGF-2. Pretreatment with anti-CCL3 antibody blocked TGF-ß1 expression and partially inhibited FGF-2 production. On the other hand, anti-c-Kit antibody blocked TGF-ß1 expression and FGF-2 production. Thus, TGF-ß1 and FGF-2 production were mediated by CCL3 production through c-Kit. Pretreatment with mitogen-activated protein kinase kinase 1, p38, and Jun N-terminal kinase inhibitors showed that the effects mediated by SCF were involved with the modulation of mitogen-activated protein kinase (MAPK) pathways. Development of inhibitors targeting CCL3 through MAPK activation could thus be an attractive strategy to inhibit tSMC activation during asthma.