RESUMO
Mucosa-associated invariant T (MAIT) cells are MR1-restricted, innate-like T lymphocytes with tremendous antibacterial and immunomodulatory functions. Additionally, MAIT cells sense and respond to viral infections in an MR1-independent fashion. However, whether they can be directly targeted in immunization strategies against viral pathogens is unclear. We addressed this question in multiple wild-type and genetically altered but clinically relevant mouse strains using several vaccine platforms against influenza viruses, poxviruses and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). We demonstrate that 5-(2-oxopropylideneamino)-6-D-ribitylaminouracil (5-OP-RU), a riboflavin-based MR1 ligand of bacterial origin, can synergize with viral vaccines to expand MAIT cells in multiple tissues, reprogram them towards a pro-inflammatory MAIT1 phenotype, license them to bolster virus-specific CD8+ T cell responses, and potentiate heterosubtypic anti-influenza protection. Repeated 5-OP-RU administration did not render MAIT cells anergic, thus allowing for its inclusion in prime-boost immunization protocols. Mechanistically, tissue MAIT cell accumulation was due to their robust proliferation, as opposed to altered migratory behavior, and required viral vaccine replication competency and Toll-like receptor 3 and type I interferon receptor signaling. The observed phenomenon was reproducible in female and male mice, and in both young and old animals. It could also be recapitulated in a human cell culture system in which peripheral blood mononuclear cells were exposed to replicating virions and 5-OP-RU. In conclusion, although viruses and virus-based vaccines are devoid of the riboflavin biosynthesis machinery that supplies MR1 ligands, targeting MR1 enhances the efficacy of vaccine-elicited antiviral immunity. We propose 5-OP-RU as a non-classic but potent and versatile vaccine adjuvant against respiratory viruses.
Assuntos
COVID-19 , Células T Invariantes Associadas à Mucosa , Vacinas , Feminino , Masculino , Humanos , Camundongos , Animais , Eficácia de Vacinas , Leucócitos Mononucleares , COVID-19/metabolismo , SARS-CoV-2 , Riboflavina/metabolismo , Antígenos de Histocompatibilidade Classe I , Antígenos de Histocompatibilidade MenorRESUMO
Strategies to modify the gut microbiome in cancer patients using fecal microbiota transplantation (FMT) have gained momentum as a therapeutic intervention. However, how FMT impacts innate-like, antimicrobial T lymphocytes is unclear. In this study, we assessed peripheral blood (PB) mucosa-associated invariant T (MAIT) cell frequencies and functions in patients with metastatic renal cell carcinoma (mRCC) before and seven days after they received FMT as part of a clinical trial. We found comparable MAIT cell frequencies in healthy controls and mRCC patients. In contrast, γδ T cells exhibited a numerical decline in mRCC, which was partially reversed by FMT. We also found a significant increase in the PB CD4+ MAIT cell compartment of mRCC patients with or without FMT. Paired sample analyses revealed CD69 upregulation on MAIT cells accompanied by decreased PD-1 levels post-FMT. These changes were unique to MAIT cells as non-MAIT T lymphocytes showed either no trend or a trend in the opposite direction. Importantly, FMT did not render MAIT cells exhausted as also judged by their stable expression of TIM-3, LAG-3, BTLA, CTLA-4, TIGIT and VISTA. These findings were corroborated in functional assays in which MAIT cells were stimulated with MR1 ligands or with a combination of IL-12 and IL-18 to produce inflammatory cytokines and granzyme B. Indeed, when stimulated ex vivo with IL-12 and IL-18, MAIT cells mounted a more rigorous TNF-α response post-FMT. In conclusion, FMT improves MAIT cell functions, which should serve patients well in subsequent microbial challenges in the face of cancer-elicited immunosuppression. Trial Registration: https://clinicaltrials.gov/ Identifier: NCT04163289 (registration date: November 14, 2019).
Assuntos
Carcinoma de Células Renais , Neoplasias Renais , Células T Invariantes Associadas à Mucosa , Humanos , Interleucina-18/metabolismo , Carcinoma de Células Renais/terapia , Carcinoma de Células Renais/metabolismo , Células T Invariantes Associadas à Mucosa/metabolismo , Transplante de Microbiota Fecal , Neoplasias Renais/terapia , Neoplasias Renais/metabolismo , Interleucina-12/metabolismoRESUMO
Mucosa-associated invariant T (MAIT) cells are evolutionarily conserved, innate-like T lymphocytes with enormous immunomodulatory potentials. Due to their strategic localization, their invariant T cell receptor (iTCR) specificity for major histocompatibility complex-related protein 1 (MR1) ligands of commensal and pathogenic bacterial origin, and their sensitivity to infection-elicited cytokines, MAIT cells are best known for their antimicrobial characteristics. However, they are thought to also play important parts in the contexts of cancer, autoimmunity, vaccine-induced immunity, and tissue repair. While cognate MR1 ligands and cytokine cues govern MAIT cell maturation, polarization, and peripheral activation, other signal transduction pathways, including those mediated by costimulatory interactions, regulate MAIT cell responses. Activated MAIT cells exhibit cytolytic activities and secrete potent inflammatory cytokines of their own, thus transregulating the biological behaviors of several other cell types, including dendritic cells, macrophages, natural killer cells, conventional T cells, and B cells, with significant implications in health and disease. Therefore, an in-depth understanding of how costimulatory pathways control MAIT cell responses may introduce new targets for optimized MR1/MAIT cell-based interventions. Herein, we compare and contrast MAIT cells and mainstream T cells for their expression of classic costimulatory molecules belonging to the immunoglobulin superfamily and the tumor necrosis factor (TNF)/TNF receptor superfamily, based not only on the available literature but also on our transcriptomic analyses. We discuss how these molecules participate in MAIT cells' development and activities. Finally, we introduce several pressing questions vis-à-vis MAIT cell costimulation and offer new directions for future research in this area.
Assuntos
Células T Invariantes Associadas à Mucosa , Ligantes , Citocinas/metabolismo , Células Matadoras Naturais , Expressão Gênica , Antígenos de Histocompatibilidade Classe I , Antígenos de Histocompatibilidade Menor/genéticaRESUMO
The Wilms' tumor suppressor Wt1 is involved in multiple developmental processes and adult tissue homeostasis. The first phenotypes recognized in Wt1 knockout mice were developmental cardiac and kidney defects. Wt1 expression in the heart has been described in epicardial, endothelial, smooth muscle cells, and fibroblasts. Expression of Wt1 in cardiomyocytes has been suggested but remained a controversial issue, as well as the role of Wt1 in cardiomyocyte development and regeneration after injury. We determined cardiac Wt1 expression during embryonic development, in the adult, and after cardiac injury by quantitative RT-PCR and immunohistochemistry. As in vitro model, phenotypic cardiomyocyte differentiation, i.e., the appearance of rhythmically beating clones from mouse embryonic stem cells (mESCs) and associated changes in gene expression were analyzed. We detected Wt1 in cardiomyocytes from embryonic day (E10.5), the first time point investigated, until adult age. Cardiac Wt1 mRNA levels decreased during embryonic development. In the adult, Wt1 was reactivated in cardiomyocytes 48 h and 3 weeks following myocardial infarction. Wt1 mRNA levels were increased in differentiating mESCs. Overexpression of Wt1(-KTS) and Wt1(+KTS) isoforms in ES cells reduced the fraction of phenotypically cardiomyocyte differentiated clones, which was preceded by a temporary increase in c-kit expression in Wt1(-KTS) transfected ES cell clones and induction of some cardiomyocyte markers. Taken together, Wt1 shows a dynamic expression pattern during cardiomyocyte differentiation and overexpression in ES cells reduces their phenotypical cardiomyocyte differentiation.
Assuntos
Diferenciação Celular , Células-Tronco Embrionárias Murinas/citologia , Infarto do Miocárdio/patologia , Miócitos Cardíacos/citologia , Proteínas WT1/metabolismo , Animais , Feminino , Camundongos , Células-Tronco Embrionárias Murinas/metabolismo , Infarto do Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Proteínas WT1/genéticaRESUMO
Skin can acquire cadmium (Cd) by oral route, but there is paucity of data concerning cutaneous effects of this metal. Cd acquired by oral route can affect skin wound healing, but the effect of Cd on other activities involved in skin homeostasis, including skin immunity, are not explored. Using the rat model of 30-day oral administration of Cd (5â¯ppm and 50â¯ppm) in drinking water, basic aspects of immune-relevant activity of epidermal cells were examined. Dose-dependent Cd deposition in the the skin was observed (0.035⯱â¯0.02⯵g/g and 0.127⯱â¯0.04⯵g/g at 5â¯ppm and 50â¯ppm, respectively, compared to 0.012⯱â¯0.009⯵g/g at 0â¯ppm of Cd). This resulted in skin inflammation (oxidative stress at both Cd doses and dose-dependent structural changes in the skin and the presence/activation of innate immunity cells). At low Cd dose inflammatory response (nitric oxide and IL-1ß) was observed. Other inflammatory cytokines (IL-6 and TNF) response occurred at 50â¯ppm, which was increased further following skin sensitization with contact allergen dinitro-chlorobenzene (DNCB). Epidermal cells exposed to both Cd doses enhanced concanavalin A (ConA)-stimulated lymphocyte production of IL-17. This study showed for the first time the effect of the metal which gained access to the skin via gut on immune reactivity of epidermal cells. Presented data might be relevant for the link between dietary Cd and the risk of skin pathologies.
Assuntos
Cádmio/administração & dosagem , Pele/efeitos dos fármacos , Administração Oral , Animais , Citocinas/imunologia , Imunidade Inata/efeitos dos fármacos , Masculino , Óxido Nítrico/imunologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Pele/imunologiaRESUMO
PURPOSE: Warfarin (WF) is an anticoagulant which also affects physiological processes other than hemostasis. Our previous investigations showed the effect of WF which gained access to the organism via skin on resting peripheral blood granulocytes. Based on these data, the aim of the present study was to examine whether WF could modulate the inflammatory processes as well. To this aim the effect of WF on the inflammatory response induced by subcutaneous sponge implantation in rats was examined. MATERIALS AND METHODS: Warfarin-soaked polyvinyl sponges (WF-sponges) were implanted subcutaneously and cell infiltration into sponges, the levels of nitric oxide (NO) and inflammatory cytokines tumor necrosis factor (TNF) and interleukin-6 (IL-6) production by sponge cells were measured as parameters of inflammation. T cell infiltration and cytokine interferon-γ (IFN-γ), interleukin-17 (IL-17) and interleukin-10 (IL-10) were measured at day 7 post implantation. RESULTS: Warfarin exerted both stimulatory and suppressive effects depending on the parameter examined. Flow cytometry of cells recovered from sponges showed higher numbers of granulocytes (HIS48+ cells) at days 1 and 3 post implantation and CD11b+ cells at day 1 compared to control sponges. Cells from WF-sponges had an increased NO production (Griess reaction) at days 1 and 7. In contrast, lower levels of TNF (measured by ELISA) production by cells recovered from WF-soaked sponges were found in the early (day one) phase of reaction with unchanged levels at other time points. While IL-6 production by cells recovered from WF-soaked sponges was decreased at day 1, it was increased at day 7. Higher T cell numbers were noted in WF sponges at day 7 post implantation, and recovered cells produced more IFN-γ and IL-17, while IL-10 production remained unchanged. CONCLUSIONS: Warfarin affects some of the parameters of inflammatory reaction induced by subcutaneous polyvinyl sponge implantation. Differential (both stimulatory as well as inhibitory) effects of WF on inflammatory response to sponge implants might affect the course and/or duration of this reaction.
Assuntos
Inflamação/imunologia , Polivinil/administração & dosagem , Varfarina/administração & dosagem , Animais , Anticoagulantes/administração & dosagem , Anticoagulantes/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Citocinas/imunologia , Inflamação/metabolismo , Contagem de Leucócitos , Masculino , Óxido Nítrico/metabolismo , Peroxidase/metabolismo , Polivinil/farmacologia , Ratos , Pele/efeitos dos fármacos , Pele/imunologia , Pele/metabolismo , Varfarina/farmacologiaRESUMO
CONTEXT: Skin is the target of both acute and chronic exposure to warfarin, coumarin anticoagulant. Single exposure of rat skin to this agent induces early (24 h following epicutaneous administration) local response which might be part of inflammatory/reparatory homeostatic program or introduction to pathological events in exposed skin. OBJECTIVE: To examine time-dependent changes in skin of rats exposed to epicutaneously applied warfarin. MATERIALS AND METHODS: The effect of low (10 µg) and high (100 µg) doses of warfarin on histologically evident changes of epidermis (epidermal thickness) and dermis (numbers of mesenchymal cells and dermal capillaries), skin cell proliferative activity (Ki67(+) and PCNA(+) cells) and apoptotic (TUNEL(+)) and necrotic (ultra structural appearance) cells was examined one, three and seven days after the application. RESULTS: Both warfarin doses affected the majority of skin cell activity, but with differential time-course of skin epidermal and dermal cells state/activity. The occurrence of necrotic/apoptotic epidermal and dermal cells was noted the first day after the application and the activities which point to tissue reparation/remodeling were observed seven days after skin exposure to this agent. DISCUSSION: The observed pattern of changes (early evidence of cell/tissue injury which was later followed by signs of cell activity characteristic for tissue reparation/remodeling) implied warfarin-induced toxicity in skin cells as stimulus for subsequent activities relevant for tissue homeostasis. CONCLUSION: The data presented provide new and additional information concerning skin responses to warfarin that gains access to this tissue.
Assuntos
Anticoagulantes/toxicidade , Rodenticidas/toxicidade , Pele/efeitos dos fármacos , Varfarina/toxicidade , Administração Cutânea , Animais , Apoptose/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Antígeno Ki-67/metabolismo , Masculino , Necrose/induzido quimicamente , Necrose/patologia , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Pele/metabolismo , Pele/patologia , Pele/ultraestruturaRESUMO
CONTEXT: Dermal toxicity of coumarin anticoagulant rodenticides, such as warfarin, represents potential risk for workers handling these agents and for individuals applying easily available rodenticides in their households as well. OBJECTIVE: In this study, proinflammatory effects of repeated epicutaneous administration of warfarin in rats were explored by examining inflammatory cytokine skin responses. MATERIALS AND METHODS: Ex vivo production of IL-1ß, IL-6, TNF-α and IL-17 by skin explants and by epidermal cells isolated by enzyme (dispase/trypsin) digestion from skin repeatedly (once a day, three consecutive days) exposed to 10 µg of warfarin was measured 24 h and 72 h following the last warfarin application by ELISAs for respective rat cytokines. RESULTS: Warfarin treatment resulted in histological changes, but skin or epidermal cell viability were not compromised, judging by MTT reduction assay. Both skin and epidermal cells responded to administration of this agent by production of all examined inflammatory cytokines (skin explants by TNF-α and IL-17; epidermal cells by IL-1ß and TNF-α) except IL-6. DISCUSSION: Along with histomorphological changes, cytokines indicate functional consequences in treated skin. IL-1ß production, that precede production of TNF-α, might be responsible for production of the latter cytokine. Sustained production of IL-1ß suggests persistence of epidermal cell stimulation or existence of some amplification mechanisms. Requirements for T cells seem to exist concerning epidermal cell IL-17 production. CONCLUSION: Presented data provide additional new information concerning proinflammatory effects of warfarin.
Assuntos
Anticoagulantes/farmacologia , Citocinas/biossíntese , Mediadores da Inflamação/metabolismo , Rodenticidas/farmacologia , Pele/efeitos dos fármacos , Animais , Masculino , Ratos , Pele/citologia , Pele/metabolismoRESUMO
OBJECTIVE: To evaluate immunologic mechanisms underlying Aspergillus fumigatus pulmonary infections in immunocompetent Dark Agouti (DA) and Albino Oxford (AO) rats recognized as being susceptible to some inflammatory diseases in different manners. METHODS: Lung fungal burden (quantitative colony forming units, CFU, assay), leukocyte infiltration (histology, cell composition) and their function (phagocytosis, oxidative activity, CD11b adhesion molecule expression) and cytokine interferon-γ (IFN-γ) and interleukin-17 and -4 (IL-17 and IL-4) lung content were evaluated following infection (intratracheally, 1x10(7) conidia). RESULTS: Slower reduction of fungal burden was observed in AO rats in comparison with that in DA rats, which was coincided with less intense histologically evident lung cell infiltration and leukocyte recovery as well as lower level of most of the their activities including intracellular myeloperoxidase activity, the capacity of nitroblue tetrazolium salt reduction and CD11b adhesion molecule expression (except for phagocytosis of conidia) in these rats. Differential patterns of changes in proinflammatory cytokine levels (unchanged levels of IFN-γ and transient increase of IL-17 in AO rats vs continuous increase of both cytokines in DA rats) and unchanged levels of IL-4 were observed. CONCLUSION: Genetically-based differences in the pattern of antifungal lung leukocyte activities and cytokine milieu, associated with differential efficiency of fungal elimination might be useful in the future use of rat models in studies of pulmonary aspergillosis.
Assuntos
Aspergillus fumigatus/imunologia , Pulmão/imunologia , Aspergilose Pulmonar/imunologia , Animais , Citocinas/metabolismo , Pulmão/metabolismo , Pulmão/microbiologia , Pulmão/patologia , Masculino , RatosRESUMO
Recombinant vesicular stomatitis virus (rVSV) vaccines expressing spike proteins of Wuhan, Beta, and/or Delta variants of SARS-CoV-2 were generated and tested for induction of antibody and T cell immune responses following intramuscular delivery to mice. rVSV-Wuhan and rVSV-Delta vaccines and an rVSV-Trivalent (mixed rVSV-Wuhan, -Beta, -Delta) vaccine elicited potent neutralizing antibodies (nAbs) against live SARS-CoV-2 Wuhan (USAWA1), Beta (B.1.351), Delta (B.1.617.2), and Omicron (B.1.1.529) viruses. Prime-boost vaccination with rVSV-Beta was less effective in this capacity. Heterologous boosting of rVSV-Wuhan with rVSV-Delta induced strong nAb responses against Delta and Omicron viruses, with the rVSV-Trivalent vaccine consistently effective in inducing nAbs against all the SARS-CoV-2 variants tested. All vaccines, including rVSV-Beta, elicited a spike-specific immunodominant CD8+ T cell response. Collectively, rVSV vaccines targeting SARS-CoV-2 variants of concern may be considered in the global fight against COVID-19.
RESUMO
Fecal microbiota transplantation (FMT) represents a potential strategy to overcome resistance to immune checkpoint inhibitors in patients with refractory melanoma; however, the role of FMT in first-line treatment settings has not been evaluated. We conducted a multicenter phase I trial combining healthy donor FMT with the PD-1 inhibitors nivolumab or pembrolizumab in 20 previously untreated patients with advanced melanoma. The primary end point was safety. No grade 3 adverse events were reported from FMT alone. Five patients (25%) experienced grade 3 immune-related adverse events from combination therapy. Key secondary end points were objective response rate, changes in gut microbiome composition and systemic immune and metabolomics analyses. The objective response rate was 65% (13 of 20), including four (20%) complete responses. Longitudinal microbiome profiling revealed that all patients engrafted strains from their respective donors; however, the acquired similarity between donor and patient microbiomes only increased over time in responders. Responders experienced an enrichment of immunogenic and a loss of deleterious bacteria following FMT. Avatar mouse models confirmed the role of healthy donor feces in increasing anti-PD-1 efficacy. Our results show that FMT from healthy donors is safe in the first-line setting and warrants further investigation in combination with immune checkpoint inhibitors. ClinicalTrials.gov identifier NCT03772899 .
Assuntos
Transplante de Microbiota Fecal , Melanoma , Animais , Camundongos , Transplante de Microbiota Fecal/métodos , Inibidores de Checkpoint Imunológico , Fezes/microbiologia , Melanoma/terapia , Imunoterapia , Resultado do TratamentoRESUMO
Cadmium (Cd) is a toxic heavy metal that when absorbed into the body causes nephrotoxicity and effects in other tissues.Anatomical barrier tissues are tissues that prevent the entry of pathogens and include skin, mucus membranes and the immune system. The adverse effects of Cd-induced immune cell's activity are the most extensively studied in the kidneys and the liver. There are though fewer data relating the effect of this metal on the other tissues, particularly in those in which cells of the immune system form local circuits of tissue defense, maintaining immune-mediated homeostasis. In this work, data on the direct and indirect effects of Cd on anatomical barrier tissue of inner and outer body surfaces (the lungs, gut, reproductive organs, and skin) were summarized.
Assuntos
Cádmio/toxicidade , Homeostase/efeitos dos fármacos , Sistema Imunitário/efeitos dos fármacos , Imunidade Celular/efeitos dos fármacos , Animais , Intoxicação por Cádmio/imunologia , HumanosRESUMO
Cadmium (Cd) represents a unique hazard because of the long biological half-life in humans (20-30 years). This metal accumulates in organs causing a continuum of responses, with organ disease/failure as extreme outcome. Some of the cellular and molecular alterations in target tissues can be related to immune-modulating potential of Cd. This metal may cause adverse responses in which components of the immune system function as both mediators and effectors of Cd tissue toxicity, which, in combination with Cd-induced alterations in homeostatic reparative activities may contribute to tissue dysfunction. In this work, current knowledge concerning inflammatory/autoimmune disease manifestations found to be related with cadmium exposure are summarized. Along with epidemiological evidence, animal and in vitro data are presented, with focus on cellular and molecular immune mechanisms potentially relevant for the disease susceptibility, disease promotion, or facilitating development of pre-existing pathologies.
Assuntos
Doenças Autoimunes , Cádmio/toxicidade , Imunomodulação , Animais , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/imunologia , Humanos , Inflamação/induzido quimicamente , Inflamação/imunologiaRESUMO
Cadmium (Cd) has been listed as one of the most toxic substances affecting numerous tissues/organs, including the immune system. Due to variations in studies examining Cd effects on the immune system (exposure regime, experimental systems, immune endpoint measured), data on Cd immunotoxicity in humans and experimental animals are inconsistent. However, it is clear that Cd can affect cells of the immune system and can modulate some immune responses. Due to the complex nature of the immune system and its activities which are determined by multiple interactions, the underlying mechanisms involved in the immunotoxicity of this metal are still vague. Here, the current knowledge regarding the interaction of Cd with cells of the immune system, which may affect immune responses as well as potential mechanisms of consequent biological effects of such activities, is reviewed. Tissue injury caused by Cd-induced effects on innate cell activities depicts components of the immune system as mediators/effectors of Cd tissue toxicity. Cd-induced immune alterations, which may compromise host defense against pathogenic microorganisms and homeostatic reparative activities, stress this metal as an important health hazard.
Assuntos
Cádmio/toxicidade , Poluentes Ambientais/toxicidade , Sistema Imunitário/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Animais , HumanosRESUMO
Poly(DL-lactide-co-ε-caprolactone)/poly(acrylic acid) implantable composite reservoirs for cationic drugs are synthesized by sequentially applying photoirradiation and liquid phase inversion. The chemical composition and microstructure of reservoirs are characterized with Fourier transform infrared spectroscopy-attenuated total reflection (FTIR-ATR) and scanning electron microscopy (SEM), respectively. Drug loading and release properties are investigated using methylene blue as the drug model. Biocompatibility of reservoirs is examined through a series of in vitro tests and an in vivo experiment of subcutaneous implantation in Dark Agouti rats. Reservoirs show good ion-exchange capacity, high water content, and fast reversible swelling with retained geometry. Results of drug loading and release reveal excellent loading efficiency and diffusion-controlled release during 2 weeks. Biocompatibility tests in vitro demonstrate the lack of implant proinflammatory potential and hindered adhesion of L929 cells on the implant surface. Implants exhibit low acute toxicity and elicit a normal acute foreign body reaction that reaches the early stages of fibrous capsule formation after 7 days.
Assuntos
Resinas Acrílicas/farmacologia , Portadores de Fármacos/farmacologia , Implantes de Medicamento/farmacologia , Poliésteres/farmacologia , Resinas Acrílicas/química , Animais , Materiais Biocompatíveis/química , Materiais Biocompatíveis/farmacologia , Adesão Celular/efeitos dos fármacos , Linhagem Celular , Portadores de Fármacos/química , Implantes de Medicamento/química , Liberação Controlada de Fármacos , Hidrogéis/química , Hidrogéis/farmacologia , Masculino , Camundongos , Poliésteres/química , RatosRESUMO
OBJECTIVE: The aim of this study is to investigate the effects of oral cadmium (Cd) ingestion on the pulmonary immune response. METHODS: Determination of Cd content in lungs and histopathological evaluation of the tissue was performed in rats following 30-day oral Cd administration (5 and 50 mg/L). Antioxidant enzyme defense (superoxide dismutase and catalase), cell infiltration, and production of tumor necrosis factor (TNF) and interferon (IFN)-γ, as well as the activity of myeloperoxidase (MPO), nitric oxide (NO), and various cytokines [interleukin (IL)-1ß, IL-6, IL-10, and IL-17] were investigated. RESULTS: Cd caused tissue damage and cell infiltration in the lungs, and this damage was more pronounced at higher doses. Cd deposition resulted in lung inflammation characterized by a dose-dependent IL-1ß increase in lung homogenates, increased TNF levels at both doses, and IL-6 stimulation at low doses with inhibition observed at higher doses. Cd exerted differential effects on lung leukocytes isolated by enzyme digestion, and these effects were characterized by a lack of change in the production of reactive oxygen and nitrogen species, an inhibition of IL-1ß and TNF, and stimulation of MPO and IFN-γ. The higher capacity of Cd-exposed lung cells to respond to the opportunistic pathogen Staphylococcus epidermidis was demonstrated in vitro. CONCLUSION: The potential of ingested Cd to exert both proinflammatory and immunosuppressive effects on pulmonary tissue inflammation and immune reactivity highlights the complex immunomodulatory actions of this metal.
Assuntos
Cádmio/toxicidade , Pulmão/efeitos dos fármacos , Administração Oral , Animais , Cádmio/administração & dosagem , Leucócitos/metabolismo , Pulmão/imunologia , Pulmão/patologia , Masculino , Ratos , Staphylococcus epidermidis , Testes de Toxicidade SubcrônicaRESUMO
Warfarin is the world's most widely used anticoagulant drug. Its anticoagulant activity is based on the inhibition of the vitamin K-dependent (VKD) step in the complete synthesis of a number of blood coagulation factors that are required for normal blood coagulation. Warfarin also affects synthesis of VKD proteins not related to haemostasis including those involved in bone growth and vascular calcification. Antithrombotic activity of warfarin is considered responsible for some aspects of its anti-tumour activity of warfarin. Some aspects of activities against tumours seem not to be related to haemostasis and included effects of warfarin on non-haemostatic VKD proteins as well as those not related to VKD proteins. Inflammatory/immunomodulatory effects of warfarin indicate much broader potential of action of this drug both in physiological and pathological processes. This review provides an overview of the published data dealing with the effects of warfarin on biological processes other than haemostasis.
Assuntos
Anticoagulantes/farmacologia , Varfarina/farmacologia , Animais , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Antitrombinas/farmacologia , Hemostasia/efeitos dos fármacos , Humanos , Fatores Imunológicos/farmacologia , Osteocalcina/antagonistas & inibidores , Calcificação Vascular , Vitamina K/antagonistas & inibidoresRESUMO
Warfarin is an anticoagulant used in prevention/prophylaxis of thromboembolism. Besides the effects on coagulation, non-hemorrhagic reactions have also been documented. Although cutaneous reactions were reported in some patients, the impact on skin immunity was not explored. In the present paper, the effect of 30-day oral warfarin intake on skin cytokine responses in rats was analyzed. Increased release of inflammatory cytokines (TNF, IL-1ß and IL-10) was noted by skin explants from rats which received warfarin, but without effect on IL-6. No impact on epidermal cell cytokine secretion was seen, except a tendency of an increase of IL-6 response to stimulation with microbial product lipopolysaccharide (LPS). Topical application of contact allergen dinitrochlorobenzene (DNCB) resulted in slight (numerical solely) increase of TNF release by skin explants of warfarin-treated animals, while epidermal cells responded by increased secretion of all four cytokines examined. The data presented provide new information on the potential of oral warfarin to modulate skin innate immune activity.
Assuntos
Anticoagulantes/farmacologia , Citocinas/imunologia , Pele/efeitos dos fármacos , Varfarina/farmacologia , Administração Oral , Alérgenos/farmacologia , Animais , Dinitroclorobenzeno/farmacologia , Masculino , Ratos , Pele/imunologia , Pele/patologiaRESUMO
Occupational/accidental exposure data have showed hemorrhage as a result of transdermal exposure to warfarin, however, other effects are not known. In the present study, the impact of epicutaneous application of 10 µg or 100 µg of warfarin (three times, once a day) on peripheral blood polymorphonuclear (PMN) and mononuclear cells (PBMC) was examined in rats. Both doses resulted in prolongation of prothrombin time and changes in hematologic parameters. Increases in PMN intracellular myeloperoxidase (MPO) activity were seen at higher warfarin dose and both doses resulted in higher percentages of granular CD11b(+) cells. In contrast, a decrease in PMN TNF and IL-6 production (ELISA) and gene expression (RT-PCR) was observed. Epicutaneous application of warfarin resulted in decreased numbers of PBMC, higher numbers of mononuclear CD11b(+) cells, but without effect on PMBC cytokine production. The data obtained showed differential effects of transdermal exposure to warfarin depending on leukocyte type and activity.