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CD4+ TH cells develop into subsets that are specialized in the secretion of particular cytokines to mediate restricted types of inflammation and immune responses. Among the subsets that promote development of allergic inflammatory responses, IL-9-producing TH9 cells are regulated by a number of transcription factors. We have previously shown that the E26 transformation-specific (Ets) family members PU.1 and Ets translocation variant 5 (ETV5) function in parallel to regulate IL-9. In this study we identified a third member of the Ets family of transcription factors, Ets-related gene (ERG), that mediates IL-9 production in TH9 cells in the absence of PU.1 and ETV5. Chromatin immunoprecipitation assays revealed that ERG interaction at the Il9 promoter region is restricted to the TH9 lineage and is sustained during murine TH9 polarization. Knockdown or knockout of ERG during murine or human TH9 polarization in vitro led to a decrease in IL-9 production in TH9 cells. Deletion of ERG in vivo had modest effects on IL-9 production in vitro or in vivo. However, in the absence of PU.1 and ETV5, ERG was required for residual IL-9 production in vitro and for IL-9 production by lung-derived CD4 T cells in a mouse model of chronic allergic airway disease. Thus, ERG contributes to IL-9 regulation in TH9 cells.
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Alveolitis Alérgica Extrínseca , Asma , Hipersensibilidad , Neumonía , Animales , Humanos , Ratones , Linfocitos T CD4-Positivos , Diferenciación Celular , Interleucina-9 , Neumonía/metabolismo , Linfocitos T Colaboradores-Inductores , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Regulador Transcripcional ERG/metabolismoAsunto(s)
Colitis/etiología , Mucosa Intestinal/inmunología , Proteínas Proto-Oncogénicas/fisiología , Receptores de Interleucina-9/fisiología , Transducción de Señal/fisiología , Subgrupos de Linfocitos T/fisiología , Linfocitos T Colaboradores-Inductores/inmunología , Transactivadores/fisiología , Animales , HumanosRESUMEN
OBJECTIVE: Determine the contribution of joint and skin improvements to health-related quality of life (HRQoL) in patients with psoriatic arthritis (PsA). METHODS: SPIRIT-P1 and SPIRIT-P2 are phase 3 trials investigating ixekizumab, an interleukin-17A antagonist, in the treatment of patients with active PsA. Patients were randomised to ixekizumab or placebo. Outcomes included the Disease Activity Index for Psoriatic Arthritis (DAPSA), the Psoriasis Area and Severity Index (PASI), the European Quality of Life-Five Dimensions (EQ-5D) Visual Analogue Score (VAS), the 36-Item Short-Form Health Survey (SF-36) and the Work Productivity and Activity Impairment (WPAI) Questionnaire. The contribution of joint and skin improvements to HRQoL was modelled using a smoothing spline method and depicted with response surface graphics. RESULTS: In this integrated analysis, 402 patients with PsA had baseline psoriasis of ≥3% of body surface area. We applied response surface modelling to this patient data set to investigate the relationship between DAPSA, PASI and HRQoL improvements at week 24. The greatest improvement in EQ-5D VAS was associated with the largest per cent improvements in both DAPSA and PASI together, rather than DAPSA or PASI alone. Similar observations were made in domains of SF-36 and WPAI. CONCLUSION: Optimal improvements in patients' HRQoL were dependent on successful treatment of both joint and skin symptoms.
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Anticuerpos Monoclonales Humanizados/administración & dosificación , Artritis Psoriásica/tratamiento farmacológico , Articulaciones/fisiopatología , Calidad de Vida , Rango del Movimiento Articular/fisiología , Piel/patología , Artritis Psoriásica/diagnóstico , Artritis Psoriásica/psicología , Fármacos Dermatológicos/administración & dosificación , Progresión de la Enfermedad , Relación Dosis-Respuesta a Droga , Método Doble Ciego , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Índice de Severidad de la Enfermedad , Encuestas y CuestionariosRESUMEN
IL-10 is an immunoregulatory cytokine that has broad effects across the immune system. In Th cell subsets, Th2 cells produce considerable amounts of IL-10. The transcription factors that regulate IL-10 production in Th2 cells are still incompletely described. In this study, we demonstrate that the ETS family transcription factor ETS variant (Etv)5 regulates IL-10 production in Th2 cells. T cell-specific Etv5-deficient and littermate control mice demonstrated that IL-10 production and gene expression were significantly decreased in the absence of Etv5. In an Aspergillus fumigatus extract-induced inflammation model, IL-10-producing CD4+ T cells in bronchoalveolar lavage and lung were significantly decreased in mice that lacked Etv5 in T cells, compared with control mice. We showed that Etv5 directly binds to the Il10 locus conserved noncoding sequence 3 site and that it activates gene expression in a luciferase reporter assay and following retroviral transduction. Etv5 deficiency did not affect the expression of other transcription factors known to be important for expression of IL-10, including Jun family members, GATA3, E4BP4, and IFN regulatory factor 4. However, in the absence of Etv5, binding of these transcription factors to the Il10 locus was dramatically reduced. Ectopic Etv5 expression in Th2 cells that lack Etv5 restored IL-10 production and the binding of IL-10-inducing transcription factors including E4BP4, IFN regulatory factor 4, and GATA3. Taken together, we conclude that Etv5 plays a crucial role in regulating IL-10 production in Th2 cells by facilitating the binding of IL-10-inducing transcription factors at the Il10 locus.
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Proteínas de Unión al ADN/metabolismo , Hipersensibilidad/inmunología , Interleucina-10/metabolismo , Células Th2/inmunología , Células Th2/fisiología , Factores de Transcripción/metabolismo , Alérgenos/inmunología , Animales , Antígenos Fúngicos/inmunología , Aspergillus fumigatus/inmunología , Factores de Transcripción con Cremalleras de Leucina de Carácter Básico/metabolismo , Diferenciación Celular , Células Cultivadas , Proteínas de Unión al ADN/genética , Interleucina-10/inmunología , Activación de Linfocitos , Ratones , Ratones Noqueados , Unión Proteica , Factores de Transcripción/genéticaRESUMEN
Th cell subsets develop in response to multiple activating signals, including the cytokine environment. IL-9-secreting T cells develop in response to the combination of IL-4 and TGF-ß, although they clearly require other cytokine signals, leading to the activation of transcription factors including STAT5. In Th17 cells, there is a molecular antagonism of STAT5 with STAT3 signaling, although whether this paradigm exists in other Th subsets is not clear. In this paper, we demonstrate that STAT3 attenuates the ability of STAT5 to promote the development of IL-9-secreting T cells. We demonstrate that production of IL-9 is increased in the absence of STAT3 and cytokines that result in a sustained activation of STAT3, including IL-6, have the greatest potency in repressing IL-9 production in a STAT3-dependent manner. Increased IL-9 production in the absence of STAT3 correlates with increased endogenous IL-2 production and STAT5 activation, and blocking IL-2 responses eliminates the difference in IL-9 production between wild-type and STAT3-deficient T cells. Moreover, transduction of developing Th9 cells with a constitutively active STAT5 eliminates the ability of IL-6 to reduce IL-9 production. Thus, STAT3 functions as a negative regulator of IL-9 production through attenuation of STAT5 activation and function.
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Interleucina-6/metabolismo , Interleucina-9/metabolismo , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT5/antagonistas & inhibidores , Células Th17/inmunología , Animales , Diferenciación Celular/inmunología , Células Cultivadas , Interleucina-2/biosíntesis , Interleucina-2/inmunología , Interleucina-2/metabolismo , Interleucina-4/inmunología , Interleucina-4/metabolismo , Interleucina-6/inmunología , Interleucina-9/biosíntesis , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Factor de Transcripción STAT3/inmunología , Factor de Transcripción STAT5/genética , Factor de Transcripción STAT5/metabolismo , Células Th17/citología , Transducción GenéticaRESUMEN
The IL-9-secreting Th9 subset of CD4 Th cells develop in response to an environment containing IL-4 and TGF-ß, promoting allergic disease, autoimmunity, and resistance to pathogens. We previously identified a requirement for the ETS family transcription factor PU.1 in Th9 development. In this report, we demonstrate that the ETS transcription factor ETS variant 5 (ETV5) promotes IL-9 production in Th9 cells by binding and recruiting histone acetyltransferases to the Il9 locus at sites distinct from PU.1. In cells that are deficient in both PU.1 and ETV5 there is lower IL-9 production than in cells lacking either factor alone. In vivo loss of PU.1 and ETV5 in T cells results in distinct effects on allergic inflammation in the lung, suggesting that these factors function in parallel. Together, these data define a role for ETV5 in Th9 development and extend the paradigm of related transcription factors having complementary functions during differentiation.
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Proteínas de Unión al ADN/metabolismo , Interleucina-9/inmunología , Proteínas Proto-Oncogénicas/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Transactivadores/metabolismo , Factores de Transcripción/metabolismo , Animales , Diferenciación Celular , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Expresión Génica , Hipersensibilidad/inmunología , Hipersensibilidad/metabolismo , Inflamación/inmunología , Interleucina-9/biosíntesis , Pulmón/inmunología , Ratones , Ratones Endogámicos C57BL , Proteínas Proto-Oncogénicas/deficiencia , Proteínas Proto-Oncogénicas/genética , Transducción de Señal/inmunología , Linfocitos T Colaboradores-Inductores/fisiología , Transactivadores/deficiencia , Transactivadores/genética , Factores de Transcripción/deficiencia , Factores de Transcripción/genéticaRESUMEN
PU.1 is an ETS family transcription factor that is important for the development of multiple hematopoietic cell lineages. Previous work demonstrated a critical role for PU.1 in promoting Th9 development and in limiting Th2 cytokine production. Whether PU.1 has functions in other Th lineages is not clear. In this study, we examined the effects of ectopic expression of PU.1 in CD4(+) T cells and observed decreased expression of genes involved with the function of T follicular helper (Tfh) cells, including Il21 and Tnfsf5 (encoding CD40L). T cells from conditional mutant mice that lack expression of PU.1 in T cells (Sfpi1(lck-/-)) demonstrated increased production of CD40L and IL-21 in vitro. Following adjuvant-dependent or adjuvant-independent immunization, we observed that Sfpi1(lck-/-) mice had increased numbers of Tfh cells, increased germinal center B cells (GCB cells), and increased Ab production in vivo. This correlated with increased expression of IL-21 and CD40L in Tfh cells from Sfpi1(lck-/-) mice compared with control mice. Finally, although blockade of IL-21 did not affect GCB cells in Sfpi1(lck-/-) mice, anti-CD40L treatment of immunized Sfpi1(lck-/-) mice decreased GCB cell numbers and Ag-specific Ig concentrations. Together, these data indicate an inhibitory role for PU.1 in the function of Tfh cells, germinal centers, and Tfh-dependent humoral immunity.
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Linfocitos B/inmunología , Ligando de CD40/inmunología , Regulación de la Expresión Génica/inmunología , Centro Germinal/inmunología , Proteínas Proto-Oncogénicas/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Transactivadores/inmunología , Animales , Linfocitos B/citología , Linfocitos B/metabolismo , Ligando de CD40/genética , Ligando de CD40/metabolismo , Centro Germinal/citología , Centro Germinal/metabolismo , Inmunidad Humoral/fisiología , Interleucinas/biosíntesis , Interleucinas/genética , Interleucinas/inmunología , Ratones , Ratones Noqueados , Proteínas Proto-Oncogénicas/biosíntesis , Proteínas Proto-Oncogénicas/genética , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/metabolismo , Transactivadores/biosíntesis , Transactivadores/genéticaRESUMEN
Influenza A virus (IAV) infection in the respiratory tract triggers robust innate and adaptive immune responses, resulting in both virus clearance and lung inflammation and injury. After virus clearance, resolution of ongoing inflammation and tissue repair occur during a distinct recovery period. B7 family co-stimulatory molecules such as CD80 and CD86 have important roles in modulating T cell activity during the initiation and effector stages of the host response to IAV infection, but their potential role during recovery and resolution of inflammation is unknown. We found that antibody-mediated CD86 blockade in vivo after virus clearance led to a delay in recovery, characterized by increased numbers of lung neutrophils and inflammatory cytokines in airways and lung interstitium, but no change in conventional IAV-specific T cell responses. However, CD86 blockade led to decreased numbers of FoxP3+ regulatory T cells (Tregs), and adoptive transfer of Tregs into αCD86 treated mice rescued the effect of the blockade, supporting a role for Tregs in promoting recovery after virus clearance. Specific depletion of Tregs late after infection mimicked the CD86 blockade phenotype, confirming a role for Tregs during recovery after virus clearance. Furthermore, we identified neutrophils as a target of Treg suppression since neutrophil depletion in Treg-depleted mice reduced excess inflammatory cytokines in the airways. These results demonstrate that Tregs, in a CD86 dependent mechanism, contribute to the resolution of disease after IAV infection, in part by suppressing neutrophil-driven cytokine release into the airways.
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Antígeno B7-2/inmunología , Infecciones por Orthomyxoviridae/inmunología , Linfocitos T Reguladores/inmunología , Traslado Adoptivo , Animales , Citometría de Flujo , Factores de Transcripción Forkhead/inmunología , Virus de la Influenza A/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Reacción en Cadena de la Polimerasa de Transcriptasa InversaRESUMEN
Influenza virus infection induces a potent initial innate immune response, which serves to limit the extent of viral replication and virus spread. However, efficient (and eventual) viral clearance within the respiratory tract requires the subsequent activation, rapid proliferation, recruitment, and expression of effector activities by the adaptive immune system, consisting of antibody producing B cells and influenza-specific T lymphocytes with diverse functions. The ensuing effector activities of these T lymphocytes ultimately determine (along with antibodies) the capacity of the host to eliminate the viruses and the extent of tissue damage. In this review, we describe this effector T cell response to influenza virus infection. Based on information largely obtained in experimental settings (i.e., murine models), we will illustrate the factors regulating the induction of adaptive immune T cell responses to influenza, the effector activities displayed by these activated T cells, the mechanisms underlying the expression of these effector mechanisms, and the control of the activation/differentiation of these T cells, in situ, in the infected lungs.
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Gripe Humana/inmunología , Linfocitos T/inmunología , Inmunidad Adaptativa , Animales , Presentación de Antígeno , Células Dendríticas/inmunología , Exocitosis , Humanos , Inmunidad Innata , Pulmón/inmunología , Activación de LinfocitosRESUMEN
Because of its essential role in gas exchange and oxygen delivery, the lung has evolved a variety of strategies to control inflammation and maintain homeostasis. Invasion of the lung by pathogens (and in some instances exposure to certain noninfectious particulates) disrupts this equilibrium and triggers a cascade of events aimed at preventing or limiting colonization (and more importantly infection) by pathogenic microorganisms. In this review we focus on viral infection of the lung and summarize recent advances in our understanding of the triggering of innate and adaptive immune responses to viral respiratory tract infection, mechanisms of viral clearance, and the well-recognized consequences of acute viral infection complicating underlying lung diseases, such as asthma.
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Asma/inmunología , Asma/fisiopatología , Interacciones Huésped-Patógeno , Pulmón/inmunología , Neumonía Viral/inmunología , Inmunidad Adaptativa , Animales , Humanos , Inmunidad Innata , Pulmón/virologíaRESUMEN
INTRODUCTION: Bamlanivimab and etesevimab (BAM + ETE) are monoclonal antibodies (mAbs) effective in reducing COVID-19-related hospitalizations and all-cause mortality in adult participants at increased risk for severe disease. We present pharmacokinetic (PK), efficacy, and safety results from pediatric participants (< 18 years of age) with COVID-19 who were treated with BAM + ETE. METHODS: In an addendum to the phase 2/3 BLAZE-1 clinical trial (NCT04427501), pediatric participants received open-label weight-based dosing (WBD, n = 94) based on exposure-matching to the authorized dose of BAM + ETE in adult participants. For efficacy and safety assessments, placebo (n = 14) and BAM + ETE (n = 20)-treated adolescent participants (> 12 to < 18 years of age) from the BLAZE-1 trial were included in the overall pediatric population (N = 128). All participants had mild to moderate COVID-19 upon enrollment and ≥ 1 risk factor for severe COVID-19. The primary objective was to characterize the PK of BAM and ETE in the WBD population. RESULTS: The median age of the participants was 11.2 years, 46.1% were female, 57.9% were Black/African American, and 19.7% were Hispanic/Latino. The area under the curve for BAM and ETE in the WBD population was similar to that previously observed in adults. There were no COVID-19-related hospitalizations or deaths. All adverse events (AE) except one were mild or moderate, with one participant reporting a serious AE. CONCLUSION: WBD in pediatric participants achieved similar drug exposures compared to adult participants that received the authorized BAM + ETE dose. The pediatric efficacy and safety data were consistent with adults receiving mAbs for COVID-19. TRIAL REGISTRATION NUMBER: NCT04427501.
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Background: In the phase 2/3 BLAZE-1 trial, bamlanivimab and etesevimab together reduced coronavirus disease 2019 (COVID-19)-related hospitalizations and any-cause mortality in ambulatory patients. Herein, we assess the impact of bamlanivimab and etesevimab treatment on the severity and length of symptoms and health outcomes among patients at increased risk for severe COVID-19. Methods: In the phase 3 portion of BLAZE-1 (NCT04427501), symptomatic patients with increased risk for severe COVID-19 were randomized (2:1) to a single infusion of 700 mg bamlanivimab and 1400 mg etesevimab or placebo. Hospitalization events, vital signs, and symptomatology were monitored throughout the trial. Results: Overall, 769 patients were randomized to bamlanivimab and etesevimab together (nâ =â 511) or placebo (nâ =â 258). The time to sustained symptom resolution was significantly shorter among patients who received bamlanivimab and etesevimab compared with placebo (8 vs 10 days; Pâ <â .01). The median time to first sustained symptom resolution of body aches and pain, chills, fatigue, feeling feverish, headache, and shortness of breath was significantly different in patients receiving bamlanivimab and etesevimab compared to placebo (Pâ <â .05). The proportion of patients who experienced COVID-19-related hospitalization by day 29 was significantly reduced among the bamlanivimab and etesevimab group compared with placebo (0.8% vs 5.4%; Pâ <â .01). The mean duration of hospital stay was numerically shorter among patients who received bamlanivimab and etesevimab (7.3 vs 13.5 days; Pâ =â .16), with fewer intensive care admissions. Conclusions: Patients receiving bamlanivimab and etesevimab together resolved their symptoms more rapidly than those receiving placebo. Bamlanivimab and etesevimab treatment was associated with reduced rates of hospitalizations and shorter hospital stays. Clinical Trials Registration: NCT04427501.
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Several neutralizing monoclonal antibodies (mAbs) to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have been developed and are now under evaluation in clinical trials. With the US Food and Drug Administration recently granting emergency use authorizations for neutralizing mAbs in non-hospitalized patients with mild-to-moderate COVID-19, there is an urgent need to discuss the broader potential of these novel therapies and to develop strategies to deploy them effectively in clinical practice, given limited initial availability. Here, we review the precedent for passive immunization and lessons learned from using antibody therapies for viral infections such as respiratory syncytial virus, Ebola virus and SARS-CoV infections. We then focus on the deployment of convalescent plasma and neutralizing mAbs for treatment of SARS-CoV-2. We review specific clinical questions, including the rationale for stratification of patients, potential biomarkers, known risk factors and temporal considerations for optimal clinical use. To answer these questions, there is a need to understand factors such as the kinetics of viral load and its correlation with clinical outcomes, endogenous antibody responses, pharmacokinetic properties of neutralizing mAbs and the potential benefit of combining antibodies to defend against emerging viral variants.
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Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Neutralizantes/uso terapéutico , Anticuerpos Antivirales/uso terapéutico , COVID-19/terapia , SARS-CoV-2 , Anticuerpos Monoclonales Humanizados/uso terapéutico , Acrecentamiento Dependiente de Anticuerpo , COVID-19/inmunología , COVID-19/virología , Desarrollo de Medicamentos , Farmacorresistencia Viral/genética , Farmacorresistencia Viral/inmunología , Humanos , Inmunización Pasiva/efectos adversos , Inmunización Pasiva/métodos , Modelos Inmunológicos , Pandemias , SARS-CoV-2/efectos de los fármacos , SARS-CoV-2/genética , SARS-CoV-2/inmunología , Sueroterapia para COVID-19RESUMEN
Aim: We present a novel methodology to compare results between distinct immunogenicity assays, performed by two laboratories, for the same biotherapeutic. Materials & methods: Human serum pools from clinical trials were generated to provide representative immunogenicity titers. Pools were evaluated at two laboratories in a blinded fashion to assess the effect of assay format and laboratory change on clinical interpretation of immunogenicity results. Results: The laboratories validated two different assay formats and demonstrated comparable sensitivity and drug tolerance. Overall, the comparisons in assay format and laboratory ensured a comparable ability to detect treatment-emergent antidrug antibodies for a biotherapeutic. Conclusion: We have established an approach, using pooling of patient samples, that allows for the interlaboratory comparisons without creating duplicative results.
Lay abstract Measuring immunogenicity, an immune response to a drug, is important in understanding the benefits and risks associated with a drug. Immunogenicity is measured by specific tests within a laboratory; however, these tests and laboratories may change over time. This paper proposes a method to determine if a change in test and laboratory will impact the interpretation of immunogenicity for a drug. Blood samples from clinical trial patients were combined in order to provide representative samples for the immunogenicity tests. The samples were tested at two laboratories with two tests to measure if any interpretation of immunogenicity results would change due to the different tests and laboratories. Laboratories and tests demonstrated similar and reliable results of the samples. This study has established a method which allows for the comparison of immunogenicity results when tests and/or laboratories are changed.
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BACKGROUND: The efficacy and safety of ixekizumab (IXE) with and without continuous concomitant methotrexate (MTX), for up to 52 weeks of treatment, were evaluated in patients with active psoriatic arthritis (PsA). METHODS: Patients with active PsA who were biologic-naive (SPIRIT-P1) or had prior inadequate response to tumor necrosis factor inhibitors (SPIRIT-P2) were randomized to 80 mg IXE every 4 (IXE Q4W) or 2 weeks (IXE Q2W), after a 160-mg initial dose. In this post hoc analysis, efficacy and safety were assessed up to week 52 in the subgroups of patients who received (i) IXE as monotherapy and (ii) IXE along with a stable dose of MTX (no dose tapering or increase). Efficacy outcomes included, but were not limited to, the percentage of patients achieving the American College of Rheumatology (ACR) responses. RESULTS: Out of 455 patients initially randomized to IXE, 177 (38.9%) received monotherapy, 230 (50.5%) had concomitant MTX use, and 48 (10.5%) had other concomitant medication. Overall, 183 (40.2%) received IXE with a stable dose of concomitant MTX for 1 year. At week 52, the percentage of patients achieving ACR20/50/70 responses in IXE Q4W monotherapy versus concomitant MTX groups were 66.3% versus 55.3%, 48.4% versus 38.8%, and 35.8% versus 27.1%, respectively; these responses were generally similar with IXE Q2W. The safety profiles were similar between patients receiving IXE with or without concomitant MTX. CONCLUSIONS: In this post hoc analysis, treatment with IXE demonstrated sustained efficacy in patients with PsA up to 1 year of treatment, with or without concomitant MTX therapy. TRIAL REGISTRATION: ClinicalTrials.gov NCT01695239 and NCT02349295 .
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Antirreumáticos , Artritis Psoriásica , Anticuerpos Monoclonales Humanizados , Antirreumáticos/uso terapéutico , Artritis Psoriásica/tratamiento farmacológico , Método Doble Ciego , Quimioterapia Combinada , Humanos , Metotrexato/uso terapéutico , Resultado del TratamientoRESUMEN
OBJECTIVE: To evaluate the effect of withdrawing ixekizumab in patients with psoriatic arthritis (PsA) in whom minimal disease activity (MDA) has been achieved after open-label ixekizumab treatment. METHODS: SPIRIT-P3 was a multicenter, randomized, double-blind withdrawal study of biologic treatment-naive adult patients with PsA who were treated with open-label ixekizumab for 36 weeks (160 mg at week 0, then 80 mg every 2 weeks). Patients in whom MDA was sustained for >3 consecutive months were randomized 1:1, between weeks 36 and 64, to undergo blinded withdrawal of ixekizumab treatment (placebo) or to continue ixekizumab treatment every 2 weeks up to week 104. The primary efficacy end point was time to relapse (loss of MDA) for randomized patients. Patients who experienced a relapse were re-treated with ixekizumab every 2 weeks up to week 104. RESULTS: A total of 394 patients were enrolled and received open-label ixekizumab every 2 weeks. Of those patients, 158 (40%) achieved sustained MDA and were randomized to undergo withdrawal of ixekizumab treatment (placebo every 2 weeks; n = 79) or to continue ixekizumab treatment every 2 weeks (n = 79). Disease relapse occurred more rapidly with treatment withdrawal (median 22.3 weeks [95% confidence interval (95% CI) 16.1-28.3]) compared to those who continued treatment with ixekizumab (median not estimable; P < 0.0001). Sixty-seven patients (85%) compared to 30 patients (38%) experienced relapse in the placebo group and the continued treatment group, respectively. Median time to achieving MDA again with re-treatment was 4.1 weeks (95% CI 4.1-4.3); in 64 of 67 patients (96%) who experienced relapse with treatment withdrawal, MDA was achieved again with re-treatment. Safety was consistent with the known safety profile for ixekizumab. CONCLUSION: Continued ixekizumab therapy is superior to ixekizumab withdrawal in maintaining low disease activity in biologic treatment-naive patients with PsA. Re-treatment with ixekizumab following a relapse may restore disease control in cases of treatment interruption.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Psoriásica/tratamiento farmacológico , Fármacos Dermatológicos/uso terapéutico , Adulto , Método Doble Ciego , Femenino , Humanos , Masculino , Persona de Mediana Edad , Inducción de Remisión , Resultado del Tratamiento , Privación de TratamientoRESUMEN
INTRODUCTION: Psoriatic arthritis (PsA) is a chronic, systemic, inflammatory disease where disease burden and quality of life (QoL) are affected by both joint and skin manifestations. METHODS: Patient and physician reported data were collected about 3200 patients in a cross-sectional survey of patients from nine countries. Patient-reported outcomes (PROs) included perceptions of symptom importance, EuroQol questionnaire (EQ-5D), Psoriatic Arthritis Impact of Disease (PsAID12), and Work Productivity and Activity Impairment (WPAI) Index. Outcomes were compared in patients with 'joint-only' and 'joint and skin' disease symptoms. RESULTS: Of the 3200 patients, 2703 had complete information for 'joint-only' or 'joint and skin' involvement and were included in the analysis. Patients had a mean age of 49.2 years, 45.2% were female, and 64.5% had 'joint and skin' involvement. Patients with 'joint and skin' involvement had higher mean tender and swollen joint counts (5.2 and 4.8) than patients who were 'joint-only' (2.0 and 1.5). Significantly more patients with active 'joint and skin' symptoms experienced a flare (currently or within the last 12 months) compared with 'joint-only' patients (34.9 vs. 23.2%, p < 0.001). When asked to prioritize the burden of symptoms, 61.6% of patients prioritized joints, 38.4% prioritized skin. Anxiety/depression was experienced by 41.4% of patients, 62.4% of whom indicated that both joint and skin symptoms were the cause. Patients with 'joint and skin' involvement reported significantly worse QoL, work productivity and activity impairment than 'joint-only' patients (EQ-5D index 0.79 vs. 0.85, p < 0.001; EQ-5D VAS 71.98 vs. 77.68, p < 0.001; PsAID12 2.91 vs. 1.66, p < 0.001; WPAI overall work impairment 25.61 vs. 16.32, p < 0.001). CONCLUSIONS: PsA patients who experience 'joint and skin' symptoms had significantly worse clinical outcomes, health-related QoL, and work productivity compared with patients with 'joint-only' symptoms.
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The specialized cytokine secretion profiles of T helper (TH) cells are the basis for a focused and efficient immune response. On the twentieth anniversary of the first descriptions of the cytokine signals that promote the differentiation of interleukin-9 (IL-9)-secreting T cells, this Review focuses on the extracellular signals and the transcription factors that promote the development of what we now term TH9 cells, which are characterized by the production of this cytokine. We summarize our current understanding of the contribution of TH9 cells to both effective immunity and immunopathological disease, and we propose that TH9 cells could be targeted for the treatment of allergic and autoimmune disease.
Asunto(s)
Interleucina-9/metabolismo , Subgrupos de Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Diferenciación Celular/inmunología , Citocinas/inmunología , Humanos , Transducción de Señal/inmunología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Colaboradores-Inductores/metabolismo , Factores de Transcripción/inmunologíaRESUMEN
A hallmark of infection by respiratory viruses is productive infection of and the subsequent destruction of the airway epithelium. These viruses can also target other stromal cell types as well as in certain instances, CD45(+) hematopoietic cells either resident in the lungs or part of the inflammatory response to infection. The mechanisms by which the virus produces injury to these cell types include direct infection with cytopathic effects as a consequence of replication. Host mediated damage is also a culprit in pulmonary injury as both innate and adaptive immune cells produce soluble and cell-associated pro-inflammatory mediators. Recently, it has become increasingly clear that in addition to control of excess inflammation and virus elimination, the resolution of infection requires an active repair process, which is necessary to regain normal respiratory function and restore the lungs to homeostasis. The repair response must re-establish the epithelial barrier and regenerate the microarchitecture of the lung. Emerging areas of research have highlighted the importance of innate immune cells, particularly the newly described innate lymphoid cells, as well as alternatively activated macrophages and pulmonary stem cells in the repair process. The mechanisms by which respiratory viruses may impede or alter the repair response will be important areas of research for identifying therapeutic targets aimed at limiting virus and host mediated injury and expediting recovery.
Asunto(s)
Neumonía Viral/inmunología , Neumonía Viral/patología , Sistema Respiratorio/inmunología , Virosis/inmunología , Virosis/patología , Animales , Humanos , Inflamación/inmunología , Inflamación/patología , Mucosa Respiratoria/inmunología , Mucosa Respiratoria/patologíaRESUMEN
Influenza A virus (IAV) is a leading cause of respiratory tract disease worldwide. Anti-viral CD8(+) T lymphocytes responding to IAV infection are believed to eliminate virally infected cells by direct cytolysis but may also contribute to pulmonary inflammation and tissue damage via the release of pro-inflammatory mediators following recognition of viral antigen displaying cells. We have previously demonstrated that IAV antigen expressing inflammatory cells of hematopoietic origin within the infected lung interstitium serve as antigen presenting cells (APC) for infiltrating effector CD8(+) T lymphocytes; however, the spectrum of inflammatory cell types capable of serving as APC was not determined. Here, we demonstrate that viral antigen displaying neutrophils infiltrating the IAV infected lungs are an important cell type capable of acting as APC for effector CD8(+) T lymphocytes in the infected lungs and that neutrophils expressing viral antigen as a result of direct infection by IAV exhibit the most potent APC activity. Our findings suggest that in addition to their suggested role in induction of the innate immune responses to IAV, virus clearance, and the development of pulmonary injury, neutrophils can serve as APCs to anti-viral effector CD8(+) T cells within the infected lung interstitium.