RESUMEN
Nutrition is emerging as a promising therapeutic tool to modulate the immune system in health and disease. We propose that the timing of dietary interventions is probably what determines their success. In this context, we explore recent research that identifies the early phases of dietary intervention as critical time windows for modulating immunity and optimizing cancer therapy. Furthermore, we highlight how the timing of intervention can yield different outcomes. The data suggest that nutrient availability and absorption over a short period can significantly impact mammalian immune and even non-immune landscapes. This, in turn, can lead to changes in mucosal and systemic immunity, potentially exacerbating or ameliorating inflammation, and perhaps influencing tumor cells and their response to cancer therapies.
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Dieta , Neoplasias , Animales , Humanos , Sistema Inmunológico , Neoplasias/terapia , MamíferosRESUMEN
Omnivorous animals, including mice and humans, tend to prefer energy-dense nutrients rich in fat over plant-based diets, especially for short periods of time, but the health consequences of this short-term consumption of energy-dense nutrients are unclear. Here, we show that short-term reiterative switching to 'feast diets', mimicking our social eating behavior, breaches the potential buffering effect of the intestinal microbiota and reorganizes the immunological architecture of mucosa-associated lymphoid tissues. The first dietary switch was sufficient to induce transient mucosal immune depression and suppress systemic immunity, leading to higher susceptibility to Salmonella enterica serovar Typhimurium and Listeria monocytogenes infections. The ability to respond to antigenic challenges with a model antigen was also impaired. These observations could be explained by a reduction of CD4+ T cell metabolic fitness and cytokine production due to impaired mTOR activity in response to reduced microbial provision of fiber metabolites. Reintroducing dietary fiber rewired T cell metabolism and restored mucosal and systemic CD4+ T cell functions and immunity. Finally, dietary intervention with human volunteers confirmed the effect of short-term dietary switches on human CD4+ T cell functionality. Therefore, short-term nutritional changes cause a transient depression of mucosal and systemic immunity, creating a window of opportunity for pathogenic infection.
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Membrana Mucosa , Salmonella typhimurium , Humanos , Ratones , Animales , Linfocitos T , Inmunidad MucosaRESUMEN
A role of CD4+ T cells during the progression from nonalcoholic fatty liver disease (NAFLD) to nonalcoholic steatohepatitis (NASH) has been suggested, but which polarization state of these cells characterizes this progression and the development of fibrosis remain unclear. In addition, a gut-liver axis has been suggested to play a role in NASH, but the role of CD4+ T cells in this axis has just begun to be investigated. Combining single-cell RNA sequencing and multiple-parameter flow cytometry, we provide the first cell atlas to our knowledge focused on liver-infiltrating CD4+ T cells in patients with NAFLD and NASH, showing that NASH is characterized by a population of multicytokine-producing CD4+ T cells. Among these cells, only those with a Th17 polarization state were enriched in patients with advanced fibrosis. In parallel, we observed that Bacteroides appeared to be enriched in the intestine of NASH patients and to correlate with the frequency of multicytokine-producing CD4+ T cells. In short, we deliver a CD4+ T cell atlas of NAFLD and NASH, providing the rationale to target CD4+ T cells with a Th17 polarization state to block fibrosis development. Finally, our data offer an early indication to test whether multicytokine-producing CD4+ T cells are part of the gut-liver axis characterizing NASH.
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Enfermedad del Hígado Graso no Alcohólico , Humanos , Linfocitos T CD4-Positivos , FibrosisRESUMEN
Short Chain Fatty Acids (SCFAs) are produced by the gut microbiota and are present in varying concentrations in the intestinal lumen, in feces but also in the circulatory system. By interacting with different cell types in the body, they have a great impact on host metabolism and their exact quantification is indispensable. Here, we present a derivatization-free method for the gas chromatography mass spectrometry (GC-MS) based quantification of SCFAs in plasma, feces, cecum, liver and adipose tissue. SCFAs were extracted using ethanol and concentrated by alkaline vacuum centrifugation. To allow volatility for separation by GC, samples were acidified with succinic acid. Analytes were detected in selected ion monitoring (SIM) mode and quantified using deuterated internal standards and external calibration curves. Method validation rendered excellent linearity (R2 > 0.99 for most analytes), good recovery rates (95-117%), and good reproducibility (RSD: 1-4.5%). Matrix effects were ruled out in plasma, feces, cecum, liver and fat tissues where most abundant SCFAs were detected and accurately quantified. Finally, applicability of the method was assessed using samples derived from conventionally raised versus germ-free mice or mice treated with antibiotics. Altogether, a reliable, fast, derivatization-free GC-MS method for the quantification of SCFAs in different biological matrices was developed allowing for the study of the (patho)physiological role of SCFAs in metabolic health.
RESUMEN
Isolation of cells from organs and tissues represents a challenge for many researchers. Cell yield, purity, and cell death are common problems associated with it, which greatly affect experimental results in terms of reproducibility and biological observations. Here, we describe state-of-the-art protocols of how to isolate CD4+ T cells from both human and murine organs and tissues, reducing at minimum cell death, while increasing at the same time cell yield and purity.
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Separación Celular , Citometría de Flujo , Tejido Linfoide/citología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Biomarcadores/metabolismo , Supervivencia Celular , Enzimas/metabolismo , Humanos , Separación Inmunomagnética , Ratones Endogámicos C57BL , Fenotipo , Proyectos de Investigación , Linfocitos T Colaboradores-Inductores/metabolismo , Flujo de TrabajoRESUMEN
CD4+ T helper (TH) cells are key mediators of immunity, and according to their effector functions, they can be divided into different subsets, namely, TH1, TH2, TH17, and TH22. In order to maintain systemic homeostasis and peripheral tolerance, CD4+ TH cells are counterbalanced by CD4+ T cells with regulatory properties, namely, Foxp3+ regulatory T cells (Foxp3+TREG) and TR1 cells. Here, we describe how to in vitro differentiate murine naïve CD4+ T cells toward helper (TH1, TH2, TH17, and TH22) and regulatory (Foxp3+TREG and TR1) cells.
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Diferenciación Celular , Plasticidad de la Célula , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Reguladores/inmunología , Animales , Anticuerpos/farmacología , Biomarcadores/metabolismo , Diferenciación Celular/efectos de los fármacos , Plasticidad de la Célula/efectos de los fármacos , Células Cultivadas , Técnicas de Cocultivo , Citocinas/farmacología , Citometría de Flujo , Separación Inmunomagnética , Ratones Endogámicos C57BL , Fenotipo , Proyectos de Investigación , Linfocitos T Colaboradores-Inductores/efectos de los fármacos , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Reguladores/efectos de los fármacos , Linfocitos T Reguladores/metabolismo , Flujo de TrabajoRESUMEN
The molecular basis of the persistence of experienced T lymphocytes, also known as "memory T lymphocytes," is still enigmatic. We are beginning to understand their considerable heterogeneity and topographic compartmentalization into memory T cells circulating through the body and those residing in a particular tissue. In some tissues, like murine spleen, subpopulations of memory T cells proliferating in the absence of antigen (homeostatic proliferation) have been described. Other populations are maintained resting in terms of transcription, mobility, and proliferation in dedicated survival niches organized by stromal cells. The survival of these memory T cells is conditional on being in such a niche, where they can persist for a lifetime. Circulating memory T lymphocytes of distinct immune responses slowly decline in numbers over time. The rules governing their entry into and exit from blood, as well as their lifestyle outside of the blood and their relation to resident memory T cells are poorly understood. Homeostasis of circulating, proliferating, and resting memory T cells is obviously controlled by different rheostats: tissue-exit and tissue-entry signals for circulating and proliferation-inducing signals for proliferating memory T cells. For tissue-resident, resting memory T cells, it is the availability of their survival niche. Apparently, this mechanism (i.e., the link between memory T cell and stromal cell) is so robust that it provides efficient T-cell memory over a lifetime in tissues such as the bone marrow.
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Memoria Inmunológica , Células T de Memoria/fisiología , Animales , Supervivencia Celular , Homeostasis , HumanosRESUMEN
Hyperinflammation contributes to lung injury and subsequent acute respiratory distress syndrome (ARDS) with high mortality in patients with severe coronavirus disease 2019 (COVID-19). To understand the underlying mechanisms involved in lung pathology, we investigated the role of the lung-specific immune response. We profiled immune cells in bronchoalveolar lavage fluid and blood collected from COVID-19 patients with severe disease and bacterial pneumonia patients not associated with viral infection. By tracking T cell clones across tissues, we identified clonally expanded tissue-resident memory-like Th17 cells (Trm17 cells) in the lungs even after viral clearance. These Trm17 cells were characterized by a a potentially pathogenic cytokine expression profile of IL17A and CSF2 (GM-CSF). Interactome analysis suggests that Trm17 cells can interact with lung macrophages and cytotoxic CD8+ T cells, which have been associated with disease severity and lung damage. High IL-17A and GM-CSF protein levels in the serum of COVID-19 patients were associated with a more severe clinical course. Collectively, our study suggests that pulmonary Trm17 cells are one potential orchestrator of the hyperinflammation in severe COVID-19.
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COVID-19/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Memoria Inmunológica , Pulmón/inmunología , Células Th17/metabolismo , Líquido del Lavado Bronquioalveolar/citología , Líquido del Lavado Bronquioalveolar/inmunología , COVID-19/complicaciones , COVID-19/patología , Células Clonales , Humanos , Inflamación/etiología , Inflamación/inmunología , Pulmón/patología , Células Mieloides , Neumonía Bacteriana/inmunología , Células Th17/inmunologíaRESUMEN
The persistence of long-lived memory plasma cells in the bone marrow depends on survival factors available in the bone marrow, which are provided in niches organized by stromal cells. Using an ex vivo system in which we supply the known survival signals, direct cell contact to stromal cells, and the soluble cytokine a proliferation-inducing ligand (APRIL), we have elucidated the critical signaling pathways required for the survival of long-lived plasma cells. Integrin-mediated contact of bone marrow plasma cells with stromal cells activates the phosphatidylinositol 3-kinase (PI3K) signaling pathway, leading to critical inactivation of Forkhead-Box-Protein O1/3 (FoxO1/3) and preventing the activation of mitochondrial stress-associated effector caspases 3 and 7. Accordingly, inhibition of PI3K signaling in vivo ablates bone marrow plasma cells. APRIL signaling, by the nuclear factor κB (NF-κB) pathway, blocks activation of the endoplasmic-reticulum-stress-associated initiator caspase 12. Thus, stromal-cell-contact-induced PI3K and APRIL-induced NF-κB signaling provide the necessary and complementary signals to maintain bone marrow memory plasma cells.
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Estrés del Retículo Endoplásmico , Memoria Inmunológica , Mitocondrias/metabolismo , FN-kappa B/metabolismo , Fosfatidilinositol 3-Quinasa/metabolismo , Células Plasmáticas/citología , Células Plasmáticas/inmunología , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo , Animales , Células de la Médula Ósea/metabolismo , Caspasas/metabolismo , Muerte Celular , Supervivencia Celular , Regulación hacia Abajo , Proteína Forkhead Box O1/metabolismo , Proteína Forkhead Box O3/metabolismo , Factores Reguladores del Interferón/metabolismo , Ratones Endogámicos C57BL , Transducción de Señal , Células del Estroma/metabolismoRESUMEN
At present, it is not clear how memory B lymphocytes are maintained over time, and whether only as circulating cells or also residing in particular tissues. Here we describe distinct populations of isotype-switched memory B lymphocytes (Bsm) of murine spleen and bone marrow, identified according to individual transcriptional signature and B cell receptor repertoire. A population of marginal zone-like cells is located exclusively in the spleen, while a population of quiescent Bsm is found only in the bone marrow. Three further resident populations, present in spleen and bone marrow, represent transitional and follicular B cells and B1 cells, respectively. A population representing 10-20% of spleen and bone marrow memory B cells is the only one qualifying as circulating. In the bone marrow, all cells individually dock onto VCAM1+ stromal cells and, reminiscent of resident memory T and plasma cells, are void of activation, proliferation and mobility.
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Linfocitos B/inmunología , Células de la Médula Ósea/inmunología , Cambio de Clase de Inmunoglobulina , Memoria Inmunológica , Bazo/inmunología , Adyuvantes Inmunológicos/farmacología , Animales , Animales Salvajes/inmunología , Linfocitos B/citología , Linfocitos B/efectos de los fármacos , Células de la Médula Ósea/citología , Ciclo Celular , Proliferación Celular/genética , Regulación de la Expresión Génica/inmunología , Ratones Endogámicos C57BL , Ratones Transgénicos , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/inmunología , Bazo/citología , Células del Estroma/citología , Molécula 1 de Adhesión Celular Vascular/metabolismoRESUMEN
It is a matter of current debate whether the bone marrow is a hub for circulating memory T lymphocytes and/or the home of resident memory T lymphocytes. Here we demonstrate for CD69+ murine CD8+ , and CD69+ murine and human CD4+ memory T lymphocytes of the bone marrow, making up between 30 and 60% of bone marrow memory T lymphocytes, that they express the gene expression signature of tissue-resident memory T lymphocytes. This suggests that a substantial proportion of bone marrow memory T lymphocytes are resident. It adds to previous evidence that bone marrow memory T cells are resting in terms of mobility and proliferation, and maintain exclusive long-term memory to distinct, systemic antigens.
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Células de la Médula Ósea/inmunología , Memoria Inmunológica/inmunología , Bazo/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/inmunología , Humanos , Lectinas Tipo C/inmunología , Ratones , Bazo/citología , Transcriptoma/inmunologíaRESUMEN
It is well accepted that Th17 cells are a highly plastic cell subset that can be easily directed toward the Th1 phenotype in vitro and also in vivo during inflammation. However, there is an ongoing debate regarding the reverse plasticity (conversion from Th1 to Th17). We show here that ectopic ROR-γt expression can restore or initiate IL-17 expression by non-classic or classic Th1 cells, respectively, while common pro-Th17 cytokine cocktails are ineffective. This stability of the Th1 phenotype is at least partially due to the presence of a molecular machinery governed by the transcription factor Eomes, which promotes IFN-γ secretion while inhibiting the expression of ROR-γt and IL-17. By using a mouse model of T cell-dependent colitis we demonstrate that Eomes controls non-classic Th1 cell development also in vivo and promotes their pathogenic potential. Eomes expression associates to a highly inflammatory phenotype also in patients with juvenile idiopathic arthritis. Indeed, it favors the acquisition of a cytotoxic signature, and promotes the development of IFN-γ+ GM-CSF+ cells that have been described to be pathogenic in chronic inflammatory disorders.
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Artritis Juvenil/inmunología , Inflamación/inmunología , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Proteínas de Dominio T Box/metabolismo , Subgrupos de Linfocitos T/inmunología , Células TH1/inmunología , Células Th17/inmunología , Animales , Diferenciación Celular , Plasticidad de la Célula , Células Cultivadas , Humanos , Interferón gamma/metabolismo , Interleucina-17/metabolismo , Ratones , Ratones Noqueados , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Proteínas de Dominio T Box/genéticaRESUMEN
The bone marrow maintains memory CD4 T cells, which provide memory to systemic antigens. Here we demonstrate that memory CD4 T cells are reactivated by antigen in the bone marrow. In a secondary immune response, antigen-specific T cells of the bone marrow mobilize and aggregate in immune clusters together with MHC class II-expressing cells, mostly B lymphocytes. They proliferate vigorously and express effector cytokines, but they do not develop into follicular T-helper cells. Neither do the B lymphocytes develop into germinal center B cells in the bone marrow. Within 10 days, the immune clusters disappear again. Within 30 days, the expanded antigen-specific memory CD4 T cells return to memory niches and are maintained again individually as resting cells. Thus, in secondary immune responses in the bone marrow T-cell memory is amplified, while in germinal center reactions of secondary lymphoid organs humoral memory is adapted by affinity maturation.
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Médula Ósea/inmunología , Linfocitos T CD4-Positivos/inmunología , Memoria Inmunológica , Animales , Linfocitos B/inmunología , Médula Ósea/efectos de los fármacos , Linfocitos T CD4-Positivos/citología , Movimiento Celular , Proliferación Celular , Clorhidrato de Fingolimod/inmunología , Clorhidrato de Fingolimod/farmacología , Regulación de la Expresión Génica/inmunología , Inmunización Secundaria , Inmunosupresores/farmacología , Activación de Linfocitos , Masculino , Ratones Endogámicos C57BL , Receptores CXCR5/genética , Receptores CXCR5/inmunología , Bazo/citología , Bazo/inmunologíaRESUMEN
Conflicting evidence has been provided as to whether induction of intestinal inflammation by adoptive transfer of naïve T cells into Rag-/- mice requires expression of the transcription factor T-bet by the T cells. Here, we formally show that the intestinal microbiota composition of the Rag-/- recipient determines whether or not T-bet-deficient Th cells can induce colitis and we have resolved the differences of the two microbiomes, permissive or non-permissive to T-bet-independent colitis. Our data highlight the dominance of the microbiota over particular T cell differentiation programs in the pathogenesis of chronic intestinal inflammation.
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Colitis/inmunología , Colitis/microbiología , Microbioma Gastrointestinal/inmunología , Proteínas de Dominio T Box/genética , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/trasplante , Traslado Adoptivo/métodos , Animales , Diferenciación Celular/inmunología , Colitis/genética , Colitis/patología , Modelos Animales de Enfermedad , Proteínas de Homeodominio/genética , Inflamación/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Subgrupos de Linfocitos T/inmunologíaRESUMEN
In T lymphocytes, expression of miR-148a is induced by T-bet and Twist1, and is specific for pro-inflammatory Th1 cells. In these cells, miR-148a inhibits the expression of the pro-apoptotic protein Bim and promotes their survival. Here we use sequence-specific cholesterol-modified oligonucleotides against miR-148a (antagomir-148a) for the selective elimination of pro-inflammatory Th1 cells in vivo. In the murine model of transfer colitis, antagomir-148a treatment reduced the number of pro-inflammatory Th1 cells in the colon of colitic mice by 50% and inhibited miR-148a expression by 71% in the remaining Th1 cells. Expression of Bim protein in colonic Th1 cells was increased. Antagomir-148a-mediated reduction of Th1 cells resulted in a significant amelioration of colitis. The effect of antagomir-148a was selective for chronic inflammation. Antigen-specific memory Th cells that were generated by an acute immune reaction to nitrophenylacetyl-coupled chicken gamma globulin (NP-CGG) were not affected by treatment with antagomir-148a, both during the effector and the memory phase. In addition, antibody titers to NP-CGG were not altered. Thus, antagomir-148a might qualify as an effective drug to selectively deplete pro-inflammatory Th1 cells of chronic inflammation without affecting the protective immunological memory.
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Antagomirs/genética , Colitis/inmunología , Colon/inmunología , Inflamación/inmunología , MicroARNs/genética , Células TH1/fisiología , Animales , Diferenciación Celular , Células Cultivadas , Modelos Animales de Enfermedad , Humanos , Ratones , Ratones Endogámicos C57BL , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo , Proteína 1 Relacionada con Twist/genética , Proteína 1 Relacionada con Twist/metabolismoRESUMEN
Dietary habits have a profound impact on intestinal homeostasis and in general on human health. In Western countries, high intake of calories derived from fried products, butter and processed meat is favored over dietary regimens rich in fruits and vegetables. This type of diet is usually referred to as Western-type diet (WTD) and it has been associated with several metabolic and chronic inflammatory conditions of the gastrointestinal tract. In this review, we describe how WTD promotes intestinal and extra-intestinal inflammation and alters mucosal immunity acting on CD4+ T cells in a microbiota-dependent or -independent fashion, ultimately leading to higher susceptibility to infectious and autoimmune diseases. Moreover, summarizing recent findings, we propose how dietary supplementation with fiber and vitamins could be used as a tool to modulate CD4+ T cell phenotype and function, ameliorating inflammation and restoring mucosal homeostasis.
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Conducta Alimentaria , Inmunidad Mucosa/inmunología , Intestinos/inmunología , Animales , Ingestión de Alimentos , Enterocolitis/etiología , Enterocolitis/metabolismo , Enterocolitis/patología , Microbioma Gastrointestinal , Humanos , Sistema Inmunológico/inmunología , Sistema Inmunológico/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
It is current belief that numbers of CD8+ memory T lymphocytes in the memory phase of an immune response are maintained by homeostatic proliferation. Here, we compare the proliferation of CD8+ memory T lymphocytes, generated by natural infections and by intentional immunization, in spleen and bone marrow (BM). Fifty percent of CD8+ memory T lymphocytes in the spleen are eliminated by cyclophosphamide within 14 days, indicating that numbers of at least 50% of splenic CD8+ memory T lymphocytes are maintained by proliferation. The numbers of CD8+ memory T lymphocytes in the BM, however, were not affected by cyclophosphamide. This stability was independent of circulating CD8+ memory T cells, blocked by FTY720, showing that BM is a privileged site for the maintenance of memory T lymphocytes, as resident cells, resting in terms of proliferation.
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Células de la Médula Ósea/inmunología , Linfocitos T CD8-positivos/inmunología , Proliferación Celular , Bazo/inmunología , Animales , Linfocitos T CD8-positivos/citología , Memoria Inmunológica/inmunología , Ratones , Ratones Endogámicos C57BLRESUMEN
INTRODUCTION: Despite the broad spectrum of antirheumatic drugs, RA is still not well controlled in up to 30-50 % of patients. Inhibition of JAK kinases by means of the pan-JAK inhibitor tofacitinib has demonstrated to be effective even in difficult-to-treat patients. Here, we discuss whether the efficacy of JAK inhibition can be improved by simultaneously inhibiting SYK kinase, since both kinases mediate complementary and non-redundant pathways in RA. METHODS: Efficacy of dual JAK + SYK inhibition with selective small molecule inhibitors was evaluated in chronic G6PI-induced arthritis, a non-self-remitting and destructive arthritis model in mice. Clinical and histopathological scores, as well as cytokine and anti-G6PI antibody production were assessed in both preventive and curative protocols. Potential immunotoxicity was also evaluated in G6PI-induced arthritis and in a 28-day TDAR model, by analysing the effects of JAK + SYK inhibition on hematological parameters, lymphoid organs, leukocyte subsets and cell function. RESULTS: Simultaneous JAK + SYK inhibition completely prevented mice from developing arthritis. This therapeutic strategy was also very effective in ameliorating already established arthritis. Dual kinase inhibition immediately resulted in greatly decreased clinical and histopathological scores and led to disease remission in over 70 % of the animals. In contrast, single JAK inhibition and anti-TNF therapy (etanercept) were able to stop disease progression but not to revert it. Dual kinase inhibition decreased Treg and NK cell counts to the same extent as single JAK inhibition but overall cytotoxicity remained intact. Interestingly, treatment discontinuation rapidly reversed such immune cell reduction without compromising clinical efficacy, suggesting long-lasting curative effects. Dual kinase inhibition reduced the Th1/Th17 cytokine cascade and the differentiation and function of joint cells, in particular osteoclasts and fibroblast-like synoviocytes. CONCLUSIONS: Concurrent JAK + SYK inhibition resulted in higher efficacy than single kinase inhibition and TNF blockade in a chronic and severe arthritis model. Thus, blockade of multiple immune signals with dual JAK + SYK inhibition represents a reasonable therapeutic strategy for RA, in particular in patients with inadequate responses to current treatments. Our data supports the multiplicity of events underlying this heterogeneous and complex disease.
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Antirreumáticos/administración & dosificación , Artritis Experimental/patología , Artritis Reumatoide/patología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Quinasas Janus/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Animales , Artritis Experimental/inmunología , Artritis Reumatoide/inmunología , Ciclohexilaminas/administración & dosificación , Modelos Animales de Enfermedad , Quimioterapia Combinada/métodos , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Inmunofenotipificación , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Piperidinas/administración & dosificación , Pirimidinas/administración & dosificación , Pirroles/administración & dosificación , Quinasa SykRESUMEN
NK cells are the main cells of the innate immune system that produce IFN-γ, and they express this cytokine at early stages of maturation in response to cytokine stimulation. Conversely, acquisition of IFN-γ-competence in CD4(+) T helper cells requires a differentiation process from naïve toward type 1 (Th1) cells, which is associated with epigenetic remodeling at the IFNG locus. In the present study, we show that the ability of NK cells to produce IFN-γ in response to activating receptor (actR) engagement is gradually acquired during terminal differentiation and is accompanied by progressively higher NF-κB activation in response to actR triggering. Moreover, during the differentiation process NK cells gradually display increasing expression of IFNG and TBX21 (encoding T-bet) transcripts and demethylation at the IFNG promoter. This study provides new insights in the molecular mechanisms underlying NK-cell ability to express IFN-γ upon actR engagement. Thus, we propose that in order to efficiently produce IFN-γ in response to infected or transformed cells, NK cells gain Th1-like features, such as higher IFN-γ competence and epigenetic remodeling of the IFNG promoter, during their terminal differentiation.