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1.
Immunity ; 54(2): 235-246.e5, 2021 02 09.
Artículo en Inglés | MEDLINE | ID: mdl-33357409

RESUMEN

The interleukin-6 (IL-6) membrane receptor and its circulating soluble form, sIL-6R, can be targeted by antibody therapy to reduce deleterious immune signaling caused by chronic overexpression of the pro-inflammatory cytokine IL-6. This strategy may also hold promise for treating acute hyperinflammation, such as observed in coronavirus disease 2019 (COVID-19), highlighting a need to define regulators of IL-6 homeostasis. We found that conventional dendritic cells (cDCs), defined in mice via expression of the transcription factor Zbtb46, were a major source of circulating sIL-6R and, thus, systemically regulated IL-6 signaling. This was uncovered through identification of a cDC-dependent but T cell-independent modality that naturally adjuvants plasma cell differentiation and antibody responses to protein antigens. This pathway was then revealed as part of a broader biological buffer system in which cDC-derived sIL-6R set the in-solution persistence of IL-6. This control axis may further inform the development of therapeutic agents to modulate pro-inflammatory immune reactions.


Asunto(s)
Células Dendríticas/inmunología , Interleucina-6/sangre , Interleucina-6/inmunología , Proteína ADAM17 , Animales , Diferenciación Celular , Inmunidad Humoral , Inmunoglobulina M/inmunología , Inflamación , Factores Reguladores del Interferón/genética , Factores Reguladores del Interferón/inmunología , Interleucina-6/genética , Glicoproteínas de Membrana/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Células Plasmáticas/inmunología , Receptores de Interleucina-6/sangre , Receptores de Interleucina-6/inmunología , Transducción de Señal/inmunología , Receptor Toll-Like 4/inmunología , Receptor Toll-Like 7/inmunología
2.
Sci Rep ; 10(1): 17100, 2020 10 13.
Artículo en Inglés | MEDLINE | ID: mdl-33051534

RESUMEN

Off-label tocilizumab use in COVID-19 patients reflects concern for cytokine release syndrome. Comparison of matched COVID-19 pneumonia patients found elevated IL-6 levels correlated with mortality that did not change with tocilizumab administration. Correlating mortality with increased IL-6 doesn't imply causality however lack of improvement by tocilizumab requires further clinical trial alterations.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/inmunología , Betacoronavirus/aislamiento & purificación , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/virología , Femenino , Ferritinas/análisis , Humanos , Interleucina-6/análisis , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Pandemias , Neumonía Viral/mortalidad , Neumonía Viral/virología , Modelos de Riesgos Proporcionales , Receptores de Interleucina-6/inmunología , Tasa de Supervivencia
4.
Eur Cytokine Netw ; 31(2): 44-49, 2020 Jun 01.
Artículo en Inglés | MEDLINE | ID: mdl-32933891

RESUMEN

BACKGROUND: Evidence links COVID-19 severity to hyper-inflammation. Treatment with tocilizumab, a monoclonal antibody directed against the interleukin-6 (IL-6) receptor, was shown to lead to clinical improvement in patients with severe COVID-19. We, therefore, performed the present systematic review and meta-analysis to investigate whether the circulating levels of IL-6 is a reliable indicator of disease severity among patients affected with COVID-19. METHODS: A systematic search was conducted in PubMed, Scopus, Web of Science, and Google Scholar on April 19, 2020. RESULTS: Eleven studies provided data of IL-6 levels in patients with severe to critical COVID-19 (severe) and patients with mild to moderate COVID-19 (non-severe). The included studies were of moderate to high quality. The mean patients' age was 60.9 years, ranging from 45.2 to 76.7 years in the severe group and 46.8 years, ranging from 37.9 to 61 years, in the nonsevere group. Fifty-two percent were male in the severe group, as compared to 46% in the non-severe group. An overall random effects meta-analysis showed significantly higher serum levels of IL-6 in the severe group than in the non-severe group with a mean difference of +23.1 pg/mL (95% CI: 12.42-33.79) and the overall effect of 4.24 (P-value < 0.001). Meta-regressions showed that neither age nor sex significantly influenced the mean difference of IL-6 between the groups. CONCLUSIONS: Meta-analysis and meta-regression reveal a reliable relationship between IL-6 and COVID-19 severity, independent of age and sex. Future research is, however, required to assess the effect of BMI on the pattern of IL-6 production in patients with COVID-19. Also, there might be confounding factors that influence the relationship between IL-6 and COVID-19 severity and remain as yet unknown.


Asunto(s)
Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antivirales/uso terapéutico , Betacoronavirus/inmunología , Infecciones por Coronavirus/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Interleucina-6/antagonistas & inhibidores , Neumonía Viral/tratamiento farmacológico , Anciano , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/virología , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/mortalidad , Síndrome de Liberación de Citoquinas/virología , Femenino , Expresión Génica , Humanos , Unidades de Cuidados Intensivos , Interleucina-6/genética , Interleucina-6/inmunología , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/mortalidad , Neumonía Viral/virología , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/inmunología , Índice de Severidad de la Enfermedad , Análisis de Supervivencia , Resultado del Tratamiento
5.
Biosensors (Basel) ; 10(9)2020 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-32847008

RESUMEN

Cytokines are a family of proteins which play a major role in the regulation of the immune system and the development of several diseases, from rheumatoid arthritis to cancer and, more recently, COVID-19. Therefore, many efforts are currently being developed to improve therapy and diagnosis, as well as to produce inhibitory drugs and biosensors for a rapid, minimally invasive, and effective detection. In this regard, even more efficient cytokine receptors are under investigation. In this paper we analyze a set of IL-6 cytokine receptors, investigating their topological features by means of a theoretical approach. Our results suggest a topological indicator that may help in the identification of those receptors having the highest complementarity with the protein, a feature expected to ensure a stable binding. Furthermore, we propose and discuss the use of these receptors in an idealized experimental setup.


Asunto(s)
Técnicas Biosensibles/métodos , Interleucina-6/análisis , Receptores de Interleucina-6/análisis , Anticuerpos Monoclonales/análisis , Anticuerpos Monoclonales/inmunología , Anticuerpos Monoclonales Humanizados/química , Anticuerpos Monoclonales Humanizados/inmunología , Aptámeros de Nucleótidos/química , Betacoronavirus/aislamiento & purificación , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/metabolismo , Infecciones por Coronavirus/virología , Humanos , Fragmentos Fab de Inmunoglobulinas/análisis , Fragmentos Fab de Inmunoglobulinas/inmunología , Interleucina-6/inmunología , Límite de Detección , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/metabolismo , Neumonía Viral/virología , Receptores de Interleucina-6/inmunología
6.
Nat Commun ; 11(1): 3924, 2020 08 06.
Artículo en Inglés | MEDLINE | ID: mdl-32764665

RESUMEN

Several studies show that the immunosuppressive drugs targeting the interleukin-6 (IL-6) receptor, including tocilizumab, ameliorate lethal inflammatory responses in COVID-19 patients infected with SARS-CoV-2. Here, by employing single-cell analysis of the immune cell composition of two severe-stage COVID-19 patients prior to and following tocilizumab-induced remission, we identify a monocyte subpopulation that contributes to the inflammatory cytokine storms. Furthermore, although tocilizumab treatment attenuates the inflammation, immune cells, including plasma B cells and CD8+ T cells, still exhibit robust humoral and cellular antiviral immune responses. Thus, in addition to providing a high-dimensional dataset on the immune cell distribution at multiple stages of the COVID-19, our work also provides insights into the therapeutic effects of tocilizumab, and identifies potential target cell populations for treating COVID-19-related cytokine storms.


Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Betacoronavirus/inmunología , Infecciones por Coronavirus/inmunología , Citocinas/inmunología , Monocitos/inmunología , Neumonía Viral/inmunología , Anticuerpos Monoclonales Humanizados/administración & dosificación , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/inmunología , Biología Computacional , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/virología , Citocinas/sangre , Humanos , Inflamación/tratamiento farmacológico , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Pandemias , Neumonía Viral/sangre , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/virología , Receptores de Interleucina-6/inmunología , Análisis de la Célula Individual/métodos
7.
Rev Med Virol ; 30(5): e2123, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32648313

RESUMEN

The outbreak of coronavirus disease 2019 (COVID-19) and pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has become a major concern globally. As of 14 April 2020, more than 1.9 million COVID-19 cases have been reported in 185 countries. Some patients with COVID-19 develop severe clinical manifestations, while others show mild symptoms, suggesting that dysregulation of the host immune response contributes to disease progression and severity. In this review, we have summarized and discussed recent immunological studies focusing on the response of the host immune system and the immunopathology of SARS-CoV-2 infection as well as immunotherapeutic strategies for COVID-19. Immune evasion by SARS-CoV-2, functional exhaustion of lymphocytes, and cytokine storm have been discussed as part of immunopathology mechanisms in SARS-CoV-2 infection. Some potential immunotherapeutic strategies to control the progression of COVID-19, such as passive antibody therapy and use of interferon αß and IL-6 receptor (IL-6R) inhibitor, have also been discussed. This may help us to understand the immune status of patients with COVID-19, particularly those with severe clinical presentation, and form a basis for further immunotherapeutic investigations.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Antivirales/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/prevención & control , Evasión Inmune/efectos de los fármacos , Factores Inmunológicos/uso terapéutico , Interferón Tipo I/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Betacoronavirus/efectos de los fármacos , Betacoronavirus/inmunología , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/terapia , Infecciones por Coronavirus/virología , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/virología , Progresión de la Enfermedad , Regulación de la Expresión Génica , Humanos , Evasión Inmune/genética , Evasión Inmune/inmunología , Inmunización Pasiva/métodos , Linfocitos/efectos de los fármacos , Linfocitos/inmunología , Linfocitos/virología , Terapia Molecular Dirigida/métodos , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/virología , Receptores de Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/inmunología , Índice de Severidad de la Enfermedad , Transducción de Señal
8.
Eur Rev Med Pharmacol Sci ; 24(10): 5783-5787, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32495916

RESUMEN

In December 2019, Coronavirus disease 2019 (COVID-19) emerged in Wuhan and rapidly spread throughout China and the rest of the world. COVID-19 is currently a global pandemic. There are cytokine storms in severe COVID-19 patients. Interleukin-6 plays an important role in cytokine storm. Tocilizumab is a blocker of interleukin-6 receptor, which is likely to become an effective drug for patients with severe COVID-19. Here, we reported a case in which tocilizumab was effective for a critical COVID-19 patient.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Neumonía Viral/tratamiento farmacológico , Betacoronavirus/aislamiento & purificación , Proteína C-Reactiva/análisis , Infecciones por Coronavirus/patología , Infecciones por Coronavirus/virología , Humanos , Recuento de Leucocitos , Recuento de Linfocitos , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/patología , Neumonía Viral/virología , Receptores de Interleucina-6/inmunología , Tomografía Computarizada por Rayos X
9.
Trials ; 21(1): 468, 2020 Jun 03.
Artículo en Inglés | MEDLINE | ID: mdl-32493441

RESUMEN

OBJECTIVES: The purpose of this study is to test the safety and effectiveness of individually or simultaneously blocking IL-6, IL-6 receptor and IL-1 versus standard of care on blood oxygenation and systemic cytokine release syndrome in patients with COVID-19 coronavirus infection and acute hypoxic respiratory failure and systemic cytokine release syndrome. TRIAL DESIGN: A phase 3 prospective, multi-center, interventional, open label, 6-arm 2x2 factorial design study. PARTICIPANTS: Subjects will be recruited at the specialized COVID-19 wards and/or ICUs at 16 Belgian participating hospitals. Only adult (≥18y old) patients will be recruited with recent (≤16 days) COVID-19 infection and acute hypoxia (defined as PaO2/FiO2 below 350mmHg or PaO2/FiO2 below 280 on supplemental oxygen and immediately requiring high flow oxygen device or mechanical ventilation) and signs of systemic cytokine release syndrome characterized by high serum ferritin, or high D-dimers, or high LDH or deep lymphopenia or a combination of those, who have not been on mechanical ventilation for more than 24 hours before randomisation. Patients should have had a chest X-ray and/or CT scan showing bilateral infiltrates within the last 2 days before randomisation. Patients with active bacterial or fungal infection will be excluded. INTERVENTION AND COMPARATOR: Patients will be randomized to 1 of 5 experimental arms versus usual care. The experimental arms consist of Anakinra alone (anti-IL-1 binding the IL-1 receptor), Siltuximab alone (anti-IL-6 chimeric antibody), a combination of Siltuximab and Anakinra, Tocilizumab alone (humanised anti-IL-6 receptor antibody) or a combination of Anakinra with Tocilizumab in addition to standard care. Patients treated with Anakinra will receive a daily subcutaneous injection of 100mg for a maximum of 28 days or until hospital discharge, whichever comes first. Siltuximab (11mg/kg) or Tocilizumab (8mg/kg, with a maximum dose of 800mg) are administered as a single intravenous injection immediately after randomization. MAIN OUTCOMES: The primary end point is the time to clinical improvement defined as the time from randomization to either an improvement of two points on a six-category ordinal scale measured daily till day 28 or discharge from the hospital or death. This ordinal scale is composed of (1) Death; (2) Hospitalized, on invasive mechanical ventilation or ECMO; (3) Hospitalized, on non-invasive ventilation or high flow oxygen devices; (4) Hospitalized, requiring supplemental oxygen; (5) Hospitalized, not requiring supplemental oxygen; (6) Not hospitalized. RANDOMISATION: Patients will be randomized using an Interactive Web Response System (REDCap). A 2x2 factorial design was selected with a 2:1 randomization regarding the IL-1 blockade (Anakinra) and a 1:2 randomization regarding the IL-6 blockade (Siltuximab and Tocilizumab). BLINDING (MASKING): In this open-label trial neither participants, caregivers, nor those assessing the outcomes are blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 342 participants will be enrolled: 76 patients will receive usual care, 76 patients will receive Siltuximab alone, 76 patients will receive Tocilizumab alone, 38 will receive Anakinra alone, 38 patients will receive Anakinra and Siltuximab and 38 patients will receive Anakinra and Tocilizumab. TRIAL STATUS: COV-AID protocol version 3.0 (15 Apr 2020). Participant recruitment is ongoing and started on April 4th 2020. Given the current decline of the COVID-19 pandemic in Belgium, it is difficult to anticipate the rate of participant recruitment. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on April 1st, 2020 (ClinicalTrials.gov Identifier: NCT04330638) and on EudraCT on April 3rd 2020 (Identifier: 2020-001500-41). FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Asunto(s)
Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales/uso terapéutico , Betacoronavirus/efectos de los fármacos , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Antiinflamatorios/efectos adversos , Anticuerpos Monoclonales/efectos adversos , Anticuerpos Monoclonales Humanizados/efectos adversos , Bélgica , Betacoronavirus/inmunología , Betacoronavirus/patogenicidad , Ensayos Clínicos Fase III como Asunto , Infecciones por Coronavirus/sangre , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/virología , Quimioterapia Combinada , Interacciones Huésped-Patógeno , Humanos , Proteína Antagonista del Receptor de Interleucina 1/efectos adversos , Interleucina-1/antagonistas & inhibidores , Interleucina-1/sangre , Interleucina-1/inmunología , Interleucina-6/antagonistas & inhibidores , Interleucina-6/sangre , Interleucina-6/inmunología , Estudios Multicéntricos como Asunto , Pandemias , Neumonía Viral/sangre , Neumonía Viral/diagnóstico , Neumonía Viral/inmunología , Neumonía Viral/virología , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores de Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/sangre , Receptores de Interleucina-6/inmunología , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del Tratamiento
10.
J Korean Med Sci ; 35(6): e40, 2020 Feb 17.
Artículo en Inglés | MEDLINE | ID: mdl-32056400

RESUMEN

BACKGROUND: Immune cells express the vitamin (vit) D receptor, and vit D is a potent immune-modulator. A negative correlation between serum vit D levels and rheumatoid arthritis (RA) disease activity has been reported. Therefore, we aimed to investigate if the sufficient serum vit D level is helpful to control disease activity in RA patients treated with interleukin (IL)-6 receptor antibody tocilizumab. METHODS: RA patients taking tocilizumab were enrolled, and data were collected retrospectively. Disease activity scores (DAS) 28, serum vit D levels, modified Sharp scores of hand X-ray at the time of tocilizumab initiation, and follow-up data were analysed. Peripheral blood mononuclear cells were differentiated into T-helper (Th) 17 or osteoclasts in the presence of various concentrations of tocilizumab and/or 1,25(OH)2D. Th17 proportions were analysed by fluorescence-activated cell sorting. Supernatant cytokine levels were determined by enzyme-linked immunosorbent assay. RESULTS: Among 98 RA patients taking tocilizumab, 34 (34.7%) had sufficient serum 25(OH)D levels (≥ 30 ng/mL) when tocilizumab was initiated. At 24 weeks, vit D sufficient patients had greater DAS28 reduction (64.6% ± 15.5% vs. 52.7% ± 20.7%, P = 0.004), and lower disease activity (91.2% vs. 70.3%, P = 0.018) or remission (82.4% vs. 57.8%, P = 0.014). These differences in DAS28 reduction and the proportion of patients with remission persisted at 48 weeks. However, there was no significant difference in hand and wrist erosion progression. In vitro, tocilizumab and 1,25(OH)2D treatment synergistically suppressed IL-17 production and osteoclastogenesis. CONCLUSION: RA patients treated with IL-6 antibody show a better response when they have sufficient serum vit D. Tocilizumab and 1,25(OH)2D synergistically suppress IL-17 production and osteoclast differentiation in RA patients.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Antirreumáticos , Artritis Reumatoide , Vitamina D/análogos & derivados , Anticuerpos Monoclonales Humanizados/uso terapéutico , Antirreumáticos/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Humanos , Leucocitos Mononucleares , Osteogénesis/efectos de los fármacos , Receptores de Interleucina-6/inmunología , Estudios Retrospectivos , Vitamina D/sangre , Vitamina D/uso terapéutico
11.
Gynecol Oncol ; 156(3): 662-668, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31918995

RESUMEN

OBJECTIVE: To identify novel immunologic targets and biomarkers associated with overall survival (OS) in high-grade serous ovarian cancer (HGSC). METHODS: In this retrospective study, microarray data from 51 HGSC specimens were analyzed (Affymetrix HG-U133A). A panel of 183 immune/inflammatory response related genes linked to 279 probe sets was constructed a priori and screened. Associations between gene expression and OS were assessed using logrank tests. Multiple testing was addressed within the False Discovery Rate (FDR) framework. For external validation, TCGA Ovarian dataset and five GSE publicly available HGSC datasets were evaluated. RESULTS: In Duke data, 110 probe sets linked to 83 immunologic/inflammatory-related genes were differentially expressed in tumors from long versus short-term HGSC survivors (adjusted p < 0.05). In TCGA, concordant with the results from the Duke discovery cohort, high expression of one probe (IL6R) demonstrated a consistent significance and concordant association with higher expression in long-term HGSC survivors (Duke q-value = 0.022) and improved OS in the TCGA dataset (p-value = 0.015, HR = 0.8). Thirteen genes in GSE14764 (N = 4) and GSE26712 (N = 9) datasets had significant p-values and consistent concordant with Duke Data. Despite the significant associations of gene expression and OS in the individual GSE datasets, in the GSE meta-analysis no genes were consistently concordant and significantly associated with survival. CONCLUSIONS: Evaluation of IL6R expression may be warranted based on higher expression in long-term survivors and association with improved survival in advanced HGSC. The other candidate genes may also be of worthy of further exploration to enhance immuno-oncology drug discovery.


Asunto(s)
Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/inmunología , Neoplasias Ováricas/genética , Neoplasias Ováricas/inmunología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/genética , Carcinoma Epitelial de Ovario/inmunología , Carcinoma Epitelial de Ovario/cirugía , Cistadenocarcinoma Seroso/tratamiento farmacológico , Cistadenocarcinoma Seroso/cirugía , Bases de Datos Genéticas , Femenino , Expresión Génica , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Análisis de Secuencia por Matrices de Oligonucleótidos , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/cirugía , Receptores de Interleucina-6/biosíntesis , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/inmunología , Estudios Retrospectivos
12.
PLoS One ; 15(1): e0227261, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-31914141

RESUMEN

The epidermal growth factor receptor inhibitor cetuximab is the only oncogene-targeted agent that has been FDA approved for the treatment of head and neck squamous cell carcinoma (HNSCC). Currently, there are no biomarkers used in the clinic to predict which HNSCC tumors will respond to cetuximab, and even in tumors that regress with treatment, acquired resistance occurs in the majority of cases. Though a number of mechanisms of acquired resistance to cetuximab have been identified in preclinical studies, no therapies targeting these resistance pathways have yet been effectively translated into the clinic. To address this unmet need, we examined the role of the cytokine interleukin 6 (IL-6) in acquired cetuximab resistance in preclinical models of HNSCC. We found that IL-6 secretion was increased in PE/CA-PJ49 cells that had acquired resistance to cetuximab compared to the parental cells from which they were derived. However, addition of exogenous IL-6 to parental cells did not promote cetuximab resistance, and inhibition of the IL-6 pathway did not restore cetuximab sensitivity in the cetuximab-resistant cells. Further examination of the IL-6 pathway revealed that expression of IL6R, which encodes a component of the IL-6 receptor, was decreased in cetuximab-resistant cells compared to parental cells, and that treatment of the cetuximab-resistant cells with exogenous IL-6 did not induce phosphorylation of signal transducer and activator of transcription 3, suggesting that the IL-6 pathway was functionally impaired in the cetuximab-resistant cells. These findings demonstrate that, even if IL-6 is increased in the context of cetuximab resistance, it is not necessarily required for maintenance of the resistant phenotype, and that targeting the IL-6 pathway may not restore sensitivity to cetuximab in cetuximab-refractory HNSCC.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Resistencia a Antineoplásicos/inmunología , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Interleucina-6/metabolismo , Receptores de Interleucina-6/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carbazoles , Línea Celular Tumoral , Cetuximab/farmacología , Cetuximab/uso terapéutico , Cisplatino/farmacología , Cisplatino/uso terapéutico , Resistencia a Antineoplásicos/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Receptores ErbB/antagonistas & inhibidores , Técnicas de Silenciamiento del Gen , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/patología , Humanos , Interleucina-6/genética , Interleucina-6/inmunología , Fosforilación , ARN Interferente Pequeño/metabolismo , Receptores de Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/inmunología , Proteínas Recombinantes/inmunología , Factor de Transcripción STAT3/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/genética , Transducción de Señal/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología
13.
Circulation ; 141(8): 667-677, 2020 02 25.
Artículo en Inglés | MEDLINE | ID: mdl-31931613

RESUMEN

BACKGROUND: Proinflammatory cytokines play an important role in the pathogenesis of heart failure. The mechanisms responsible for maintaining sterile inflammation within failing hearts remain poorly defined. Although transcriptional control is important for proinflammatory cytokine gene expression, the stability of mRNA also contributes to the kinetics of immune responses. Regnase-1 is an RNase involved in the degradation of a set of proinflammatory cytokine mRNAs in immune cells. The role of Regnase-1 in nonimmune cells such as cardiomyocytes remains to be elucidated. METHODS: To examine the role of proinflammatory cytokine degradation by Regnase-1 in cardiomyocytes, cardiomyocyte-specific Regnase-1-deficient mice were generated. The mice were subjected to pressure overload by means of transverse aortic constriction to induce heart failure. Cardiac remodeling was assessed by echocardiography as well as histological and molecular analyses 4 weeks after operation. Inflammatory cell infiltration was examined by immunostaining. Interleukin-6 signaling was inhibited by administration with its receptor antibody. Overexpression of Regnase-1 in the heart was performed by adeno-associated viral vector-mediated gene transfer. RESULTS: Cardiomyocyte-specific Regnase-1-deficient mice showed no cardiac phenotypes under baseline conditions, but exhibited severe inflammation and dilated cardiomyopathy after 4 weeks of pressure overload compared with control littermates. Four weeks after transverse aortic constriction, the Il6 mRNA level was upregulated, but not other cytokine mRNAs, including tumor necrosis factor-α, in Regnase-1-deficient hearts. Although the Il6 mRNA level increased 1 week after operation in both Regnase-1-deficient and control hearts, it showed no increase in control hearts 4 weeks after operation. Administration of anti-interleukin-6 receptor antibody attenuated the development of inflammation and cardiomyopathy in cardiomyocyte-specific Regnase-1-deficient mice. In severe pressure overloaded wild-type mouse hearts, sustained induction of Il6 mRNA was observed, even though the protein level of Regnase-1 increased. Adeno-associated virus 9-mediated cardiomyocyte-targeted gene delivery of Regnase-1 or administration of anti-interleukin-6 receptor antibody attenuated the development of cardiomyopathy induced by severe pressure overload in wild-type mice. CONCLUSIONS: The degradation of cytokine mRNA by Regnase-1 in cardiomyocytes plays an important role in restraining sterile inflammation in failing hearts and the Regnase-1-mediated pathway might be a therapeutic target to treat patients with heart failure.


Asunto(s)
Inflamación/patología , Interleucina-6/metabolismo , Miocitos Cardíacos/metabolismo , ARN Mensajero/metabolismo , Ribonucleasas/genética , Animales , Anticuerpos/inmunología , Anticuerpos/uso terapéutico , Cardiomiopatía Dilatada/etiología , Cardiomiopatía Dilatada/metabolismo , Cardiomiopatía Dilatada/patología , Vectores Genéticos/metabolismo , Insuficiencia Cardíaca/etiología , Insuficiencia Cardíaca/prevención & control , Inflamación/prevención & control , Interleucina-6/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Interleucina-6/inmunología , Ribonucleasas/deficiencia , Ribonucleasas/metabolismo , Regulación hacia Arriba
14.
J Immunol ; 204(4): 747-751, 2020 02 15.
Artículo en Inglés | MEDLINE | ID: mdl-31924653

RESUMEN

IL-6 binds to the IL-6R α-chain (IL-6Rα) and signals via the signal transducer gp130. Recently, IL-6 was found to also bind to the cell surface glycoprotein CD5, which would then engage gp130 in the absence of IL-6Rα. However, the biological relevance of this alternative pathway is under debate. In this study, we developed a mouse model, in which murine IL-6 is overexpressed in a CD11c-Cre-dependent manner. Transgenic mice developed a lethal immune dysregulation syndrome with increased numbers of Ly-6G+ neutrophils and Ly-6Chi monocytes/macrophages. IL-6 overexpression promoted activation of CD4+ T cells while suppressing CD5+ B-1a cell development. However, additional ablation of IL-6Rα protected IL-6-overexpressing mice from IL-6-triggered inflammation and fully phenocopied IL-6Rα-deficient mice without IL-6 overexpression. Mechanistically, IL-6Rα deficiency completely prevented downstream activation of STAT3 in response to IL-6. Altogether, our data clarify that IL-6Rα is the only biologically relevant receptor for IL-6 in mice.


Asunto(s)
Interleucina-6/inmunología , Receptores de Interleucina-6/inmunología , Transducción de Señal/inmunología , Animales , Ratones , Ratones Transgénicos
15.
Keio J Med ; 68(4): 96, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31875623

RESUMEN

A series of our studies on IL-6 have revealed that it has a pleiotropic activity in various tissues and cells and its deregulated expression is responsible for several chronic inflammations and hemopoietic malignancies.Humanized antibody against 80kd IL-6R (Tocilizumab) has shown significant therapeutic effect in RA, JIA, Castleman's diseases and several other autoimmune inflammatory diseases, such as, giant cell arteritis, reactive arthritis, polymyalgia rheumatica and adult still's disease. Cytokine storm induced by CAR-T cell therapy has been shown to be controlled by Tocilizumab.Therapeutic effect of Tocilizumab confirmed that over and constitutive-production of IL-6 is responsible for the pathogenesis of autoimmune diseases.Then, the question to be asked is how is IL-6 production regulated. We identified a novel molecule called Arid5a which binds with the 3'-UTR of IL-6 mRNA and protects its degradation by competing with Regnase-1. Interestingly, this molecule is present in nuclei and inflammatory stimulation induced translocation of Arid5a from nuclei into cytoplasm and it competes with Regnase-1 for the protection of mRNA of IL-6.Our study indicates that Arid5a is one of the key molecules for inflammation as well as the development of septic shock.The results also suggest the therapeutic potential of anti-agonistic agents for Arid5a in the prevention of various inflammatory diseases and septic shock.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Artritis Reumatoide/tratamiento farmacológico , Proteínas de Unión al ADN/genética , Factores Inmunológicos/uso terapéutico , Interleucina-6/genética , Receptores de Interleucina-6/genética , Regiones no Traducidas 3' , Anticuerpos Monoclonales Humanizados/biosíntesis , Artritis Reactiva/tratamiento farmacológico , Artritis Reactiva/genética , Artritis Reactiva/inmunología , Artritis Reactiva/patología , Artritis Reumatoide/genética , Artritis Reumatoide/inmunología , Artritis Reumatoide/patología , Enfermedad de Castleman/tratamiento farmacológico , Enfermedad de Castleman/genética , Enfermedad de Castleman/inmunología , Enfermedad de Castleman/patología , Proteínas de Unión al ADN/inmunología , Regulación de la Expresión Génica , Arteritis de Células Gigantes/tratamiento farmacológico , Arteritis de Células Gigantes/genética , Arteritis de Células Gigantes/inmunología , Arteritis de Células Gigantes/patología , Humanos , Factores Inmunológicos/biosíntesis , Interleucina-6/inmunología , Polimialgia Reumática/tratamiento farmacológico , Polimialgia Reumática/genética , Polimialgia Reumática/inmunología , Polimialgia Reumática/patología , Unión Proteica , Proteolisis , Receptores de Interleucina-6/antagonistas & inhibidores , Receptores de Interleucina-6/inmunología , Ribonucleasas/genética , Ribonucleasas/inmunología , Transducción de Señal
16.
Cell Death Dis ; 10(11): 836, 2019 11 04.
Artículo en Inglés | MEDLINE | ID: mdl-31685825

RESUMEN

Tumor-associated macrophages (TAMs) are versatile immune cells that promote a variety of malignant behaviors of pancreatic cancer. CD59 is a GPI-anchored membrane protein that prevents complement activation by inhibiting the formation of the membrane attack complex, which may protect cancer cells from complement-dependent cytotoxicity (CDC). The interactions between CD59, TAMs and pancreatic cancer remain largely unknown. A tissue microarray of pancreatic cancer patients was used to evaluate the interrelationship of CD59 and TAMs and their survival impacts were analyzed. In a coculture system, THP-1 cells were used as a model to study the function of TAMs and the roles of pancreatic cancer-educated macrophages in regulating the expression of CD59 in pancreatic cancer cells were demonstrated by real-time PCR, western blot and immunofluorescence staining. The effects of macrophages on regulating CDC in pancreatic cancer cells were demonstrated by an in vitro study. To explore the potential mechanisms, RNA sequencing of pancreatic cancer cells with or without co-culture of THP-1 macrophages was performed, and the results showed that the IL-6R/STAT3 signaling pathway might participate in the regulation, which was further demonstrated by target-siRNA transfection, antibody neutralization and STAT3 inhibitors. Our data revealed that the infiltration of TAMs and the expression of CD59 of pancreatic cancer were paralleled, and higher infiltration of TAMs and higher expression of CD59 predicted worse survival of pancreatic cancer patients. Pancreatic cancer-educated macrophages could protect cancer cells from CDC by up-regulating CD59 via the IL-6R/STAT3 signaling pathway. These findings uncovered the novel mechanisms between TAMs and CD59, and contribute to providing a new promising target for the immunotherapy of pancreatic cancer.


Asunto(s)
Activación de Complemento/inmunología , Macrófagos/inmunología , Neoplasias Pancreáticas/inmunología , Transducción de Señal/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD59/inmunología , Femenino , Humanos , Macrófagos/patología , Masculino , Persona de Mediana Edad , Proteínas de Neoplasias/inmunología , Neoplasias Pancreáticas/patología , Receptores de Interleucina-6/inmunología , Factor de Transcripción STAT3/inmunología , Células THP-1
17.
Sci Rep ; 9(1): 17558, 2019 11 26.
Artículo en Inglés | MEDLINE | ID: mdl-31772282

RESUMEN

Postoperative adhesion formation often ruins the quality of life or is an obstacle to illnesses with curative operation such as cancer. Previously we demonstrated that interferon-γ-promoted fibrin deposition drove postoperative adhesion formation. However, its underlying cellular and molecular mechanisms remain poorly understood. We found that myofibroblasts of the adhesion predominantly expressed signature molecules of mesothelial cells that line the serosa. Microarray analysis revealed IL-6 as a key underlying player, supported by elevated IL-6 levels in the peritoneal fluid of post-laparotomy human subjects. Injured serosa of cecum-cauterized mice also exhibited induction of Il6, which was followed by Tnf, concomitant with rapid accumulation of neutrophils, substantial population of which expressed TGF-ß1, a master regulator of fibrosis. Besides, neutrophil-ablated mice showed reduction in induction of the adhesion, suggesting that TGF-ß1+neutrophils triggered the adhesion. Human neutrophils expressed TGFB1 in response to TNF-α and TNF in response to IL-6. Moreover, anti-IL-6 receptor monoclonal antibody abrogated neutrophil recruitment and adhesion formation. Thus, IL-6 signaling represents a potential target for the prevention of postoperative adhesions.


Asunto(s)
Anticuerpos Monoclonales/uso terapéutico , Complicaciones Posoperatorias/prevención & control , Receptores de Interleucina-6/inmunología , Adherencias Tisulares/prevención & control , Animales , Anticuerpos Monoclonales/inmunología , Líquido Ascítico/química , Humanos , Interleucina-6/análisis , Interleucina-6/metabolismo , Ratones , Ratones Endogámicos C57BL , Miofibroblastos/metabolismo , Neutrófilos/metabolismo , Receptores de Interleucina-6/fisiología , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Necrosis Tumoral alfa/metabolismo
18.
N Engl J Med ; 381(22): 2114-2124, 2019 11 28.
Artículo en Inglés | MEDLINE | ID: mdl-31774956

RESUMEN

BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune disease of the central nervous system and is associated with autoantibodies to anti-aquaporin-4 (AQP4-IgG) in approximately two thirds of patients. Interleukin-6 is involved in the pathogenesis of the disorder. Satralizumab is a humanized monoclonal antibody targeting the interleukin-6 receptor. The efficacy of satralizumab added to immunosuppressant treatment in patients with NMOSD is unclear. METHODS: In a phase 3, randomized, double-blind, placebo-controlled trial, we randomly assigned, in a 1:1 ratio, patients with NMOSD who were seropositive or seronegative for AQP4-IgG to receive either satralizumab, at a dose of 120 mg, or placebo, administered subcutaneously at weeks 0, 2, and 4 and every 4 weeks thereafter, added to stable immunosuppressant treatment. The primary end point was the first protocol-defined relapse in a time-to-event analysis. Key secondary end points were the change from baseline to week 24 in the visual-analogue scale (VAS) pain score (range, 0 to 100, with higher scores indicating more pain) and the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) score (range, 0 to 52, with lower scores indicating more fatigue). Safety was also assessed. RESULTS: A total of 83 patients were enrolled, with 41 assigned to the satralizumab group and 42 to the placebo group. The median treatment duration with satralizumab in the double-blind period was 107.4 weeks. Relapse occurred in 8 patients (20%) receiving satralizumab and in 18 (43%) receiving placebo (hazard ratio, 0.38; 95% confidence interval [CI], 0.16 to 0.88). Multiple imputation for censored data resulted in hazard ratios ranging from 0.34 to 0.44 (with corresponding P values of 0.01 to 0.04). Among 55 AQP4-IgG-seropositive patients, relapse occurred in 11% of those in the satralizumab group and in 43% of those in the placebo group (hazard ratio, 0.21; 95% CI, 0.06 to 0.75); among 28 AQP4-IgG-seronegative patients, relapse occurred in 36% and 43%, respectively (hazard ratio, 0.66; 95% CI, 0.20 to 2.24). The between-group difference in the change in the mean VAS pain score was 4.08 (95% CI, -8.44 to 16.61); the between-group difference in the change in the mean FACIT-F score was -3.10 (95% CI, -8.38 to 2.18). The rates of serious adverse events and infections did not differ between groups. CONCLUSIONS: Among patients with NMOSD, satralizumab added to immunosuppressant treatment led to a lower risk of relapse than placebo but did not differ from placebo in its effect on pain or fatigue. (Funded by Chugai Pharmaceutical; ClinicalTrials.gov number, NCT02028884.).


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Neuromielitis Óptica/tratamiento farmacológico , Receptores de Interleucina-6/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Acuaporina 4/inmunología , Autoanticuerpos/sangre , Método Doble Ciego , Quimioterapia Combinada , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunosupresores/uso terapéutico , Masculino , Persona de Mediana Edad , Neuromielitis Óptica/inmunología , Receptores de Interleucina-6/inmunología , Recurrencia , Adulto Joven
19.
Blood ; 134(23): 2092-2106, 2019 12 05.
Artículo en Inglés | MEDLINE | ID: mdl-31578204

RESUMEN

Graft-versus-host disease (GVHD) after allogeneic stem cell transplantation (alloSCT) is characterized by interleukin-6 (IL-6) dysregulation. IL-6 can mediate effects via various pathways, including classical, trans, and cluster signaling. Given the recent availability of agents that differentially inhibit these discrete signaling cascades, understanding the source and signaling and cellular targets of this cytokine is paramount to inform the design of clinical studies. Here we demonstrate that IL-6 secretion from recipient dendritic cells (DCs) initiates the systemic dysregulation of this cytokine. Inhibition of DC-driven classical signaling after targeted IL-6 receptor (IL-6R) deletion in T cells eliminated pathogenic donor Th17/Th22 cell differentiation and resulted in long-term survival. After engraftment, donor DCs assume the same role, maintaining classical IL-6 signaling-dependent GVHD responses. Surprisingly, cluster signaling was not active after transplantation, whereas inhibition of trans signaling with soluble gp130Fc promoted severe, chronic cutaneous GVHD. The latter was a result of exaggerated polyfunctional Th22-cell expansion that was reversed by IL-22 deletion or IL-6R inhibition. Importantly, inhibition of IL-6 classical signaling did not impair the graft-versus-leukemia effect. Together, these data highlight IL-6 classical signaling and downstream Th17/Th22 differentiation as important therapeutic targets after alloSCT.


Asunto(s)
Células Dendríticas/inmunología , Enfermedad Injerto contra Huésped/inmunología , Interleucina-6/inmunología , Transducción de Señal/inmunología , Enfermedades de la Piel/inmunología , Trasplante de Células Madre , Aloinjertos , Animales , Diferenciación Celular/inmunología , Células Dendríticas/patología , Eliminación de Gen , Enfermedad Injerto contra Huésped/genética , Enfermedad Injerto contra Huésped/patología , Efecto Injerto vs Leucemia/genética , Efecto Injerto vs Leucemia/inmunología , Interleucina-6/genética , Interleucinas/genética , Interleucinas/inmunología , Ratones , Ratones Transgénicos , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/inmunología , Transducción de Señal/genética , Enfermedades de la Piel/genética , Enfermedades de la Piel/patología , Células Th17/inmunología , Células Th17/patología
20.
Infect Immun ; 87(10)2019 10.
Artículo en Inglés | MEDLINE | ID: mdl-31383744

RESUMEN

Reproductive tract pathology caused by Chlamydia trachomatis infection is an important global cause of human infertility. To better understand the mechanisms associated with Chlamydia-induced genital tract pathogenesis in humans, we used CRISPR genome editing to disrupt Toll-like receptor 3 (TLR3) function in the human oviduct epithelial (hOE) cell line OE-E6/E7 in order to investigate the possible role(s) of TLR3 signaling in the immune response to Chlamydia Disruption of TLR3 function in these cells significantly diminished the Chlamydia-induced synthesis of several inflammation biomarkers, including interferon beta (IFN-ß), interleukin-6 (IL-6), interleukin-6 receptor alpha (IL-6Rα), soluble interleukin-6 receptor beta (sIL-6Rß, or gp130), IL-8, IL-20, IL-26, IL-34, soluble tumor necrosis factor receptor 1 (sTNF-R1), tumor necrosis factor ligand superfamily member 13B (TNFSF13B), matrix metalloproteinase 1 (MMP-1), MMP-2, and MMP-3. In contrast, the Chlamydia-induced synthesis of CCL5, IL-29 (IFN-λ1), and IL-28A (IFN-λ2) was significantly increased in TLR3-deficient hOE cells compared to their wild-type counterparts. Our results indicate a role for TLR3 signaling in limiting the genital tract fibrosis, scarring, and chronic inflammation often associated with human chlamydial disease. Interestingly, we saw that Chlamydia infection induced the production of biomarkers associated with persistence, tumor metastasis, and autoimmunity, such as soluble CD163 (sCD163), chitinase-3-like protein 1, osteopontin, and pentraxin-3, in hOE cells; however, their expression levels were significantly dysregulated in TLR3-deficient hOE cells. Finally, we demonstrate using hOE cells that TLR3 deficiency resulted in an increased amount of chlamydial lipopolysaccharide (LPS) within Chlamydia inclusions, which is suggestive that TLR3 deficiency leads to enhanced chlamydial replication and possibly increased genital tract pathogenesis during human infection.


Asunto(s)
Chlamydia trachomatis/inmunología , Células Epiteliales/microbiología , Regulación de la Expresión Génica/inmunología , Interacciones Huésped-Patógeno/inmunología , Receptor Toll-Like 3/inmunología , Factor Activador de Células B/genética , Factor Activador de Células B/inmunología , Línea Celular Transformada , Quimiocina CCL5/genética , Quimiocina CCL5/inmunología , Chlamydia trachomatis/crecimiento & desarrollo , Chlamydia trachomatis/patogenicidad , Receptor gp130 de Citocinas/genética , Receptor gp130 de Citocinas/inmunología , Células Epiteliales/inmunología , Trompas Uterinas/inmunología , Trompas Uterinas/microbiología , Femenino , Eliminación de Gen , Células HeLa , Interacciones Huésped-Patógeno/genética , Humanos , Interferón gamma/genética , Interferón gamma/inmunología , Interleucina-6/genética , Interleucina-6/inmunología , Interleucinas/genética , Interleucinas/inmunología , Metaloproteinasa 1 de la Matriz/genética , Metaloproteinasa 1 de la Matriz/inmunología , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/inmunología , Transducción de Señal , Receptor Toll-Like 3/deficiencia , Receptor Toll-Like 3/genética
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