RESUMEN
BACKGROUND: Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a proinflammatory cytokine overproduced in several inflammatory and autoimmune diseases, including axial spondyloarthritis. Namilumab is a human IgG1 monoclonal anti-GM-CSF antibody that potently neutralises human GM-CSF. We aimed to assess the efficacy of namilumab in participants with moderate-to-severe active axial spondyloarthritis. METHODS: This proof-of-concept, randomised, double-blind, placebo-controlled, phase 2, Bayesian (NAMASTE) trial was done at nine hospitals in the UK. Participants aged 18-75 years with axial spondyloarthritis, meeting the Assessment in SpondyloArthritis international Society (ASAS) criteria and the ASAS-defined MRI criteria, with active disease as defined by a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), were eligible. Those who had inadequately responded or had intolerance to previous treatment with an anti-TNF agent were included. Participants were randomly assigned (6:1) to receive subcutaneous namilumab 150 mg or placebo at weeks 0, 2, 6, and 10. Participants, site staff (except pharmacy staff), and central study staff were masked to treatment assignment. The primary endpoint was the proportion of participants who had an ASAS ≥20% improvement (ASAS20) clinical response at week 12 in the full analysis set (all randomly assigned participants). This trial is registered with ClinicalTrials.gov (NCT03622658). FINDINGS: From Sept 6, 2018, to July 25, 2019, 60 patients with moderate-to-severe active axial spondyloarthritis were assessed for eligibility and 42 were randomly assigned to receive namilumab (n=36) or placebo (n=six). The mean age of participants was 39·5 years (SD 13·3), 17 were women, 25 were men, 39 were White, and seven had previously received anti-TNF therapy. The primary endpoint was not met. At week 12, the proportion of patients who had an ASAS20 clinical response was lower in the namilumab group (14 of 36) than in the placebo group (three of six; estimated between-group difference 6·8%). The Bayesian posterior probability η was 0·72 (>0·927 suggests high clinical significance). The rates of any treatment-emergent adverse events in the namilumab group were similar to those in the placebo group (31 vs five). INTERPRETATION: Namilumab did not show efficacy compared with placebo in patients with active axial spondyloarthritis, but the treatment was generally well tolerated. FUNDING: Izana Bioscience, NIHR Oxford Biomedical Research Centre (BRC), NIHR Birmingham BRC, and Clinical Research Facility.
Asunto(s)
Espondiloartritis Axial , Factor Estimulante de Colonias de Granulocitos y Macrófagos , Humanos , Método Doble Ciego , Femenino , Masculino , Adulto , Persona de Mediana Edad , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/administración & dosificación , Espondiloartritis Axial/tratamiento farmacológico , Reino Unido , Resultado del Tratamiento , Adulto Joven , Anciano , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Índice de Severidad de la Enfermedad , Adolescente , Prueba de Estudio ConceptualAsunto(s)
Tratamiento Farmacológico de COVID-19 , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Factores Inmunológicos/uso terapéutico , SARS-CoV-2/patogenicidad , Sepsis/tratamiento farmacológico , Animales , COVID-19/inmunología , COVID-19/virología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/efectos adversos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Interacciones Huésped-Patógeno , Humanos , Factores Inmunológicos/efectos adversos , Proteínas Recombinantes/uso terapéutico , SARS-CoV-2/inmunología , Sepsis/inmunología , Sepsis/virología , Resultado del TratamientoRESUMEN
A SARS-like coronavirus 2 (SARS-CoV-2) has caused a pandemic Coronavirus Disease 2019 (COVID-19) that killed more than 3.3 million people worldwide. Like the SARS-CoV, SARS-CoV-2 also employs a receptor-binding motif (RBM) of its spike protein to bind a host receptor, the angiotensin-converting enzyme 2 (ACE2), to gain entry. Currently, several mRNA or adenoviral vaccines encoding for the spike protein of SARS-CoV-2 are being used to boost antibodies capable of inhibiting spike-ACE2 interaction and viral entry. However, recent evidence has also suggested an anti-inflammatory effect of spike-reactive antibodies, suggesting that some SARS-CoV-2 spike-based vaccines may elicit protective antibodies capable of inhibiting GM-CSF production and COVID-19 progression.
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Enzima Convertidora de Angiotensina 2/metabolismo , Anticuerpos Neutralizantes/metabolismo , Vacunas contra la COVID-19/uso terapéutico , COVID-19/prevención & control , Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Glicoproteína de la Espiga del Coronavirus/metabolismo , Anticuerpos Neutralizantes/inmunología , COVID-19/metabolismo , COVID-19/virología , Vacunas contra la COVID-19/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Interacciones Huésped-Patógeno/efectos de los fármacos , Humanos , Unión Proteica/efectos de los fármacos , SARS-CoV-2/inmunología , SARS-CoV-2/metabolismo , SARS-CoV-2/fisiología , Glicoproteína de la Espiga del Coronavirus/inmunología , Internalización del Virus/efectos de los fármacos , Replicación Viral/efectos de los fármacosRESUMEN
Pulmonary alveolar proteinosis (PAP) is a devastating lung disease caused by abnormal surfactant homeostasis, with a prevalence of 6-7 cases per million population worldwide. While mutations causing hereditary PAP have been reported, the genetic basis contributing to autoimmune PAP (aPAP) has not been thoroughly investigated. Here, we conducted a genome-wide association study of aPAP in 198 patients and 395 control participants of Japanese ancestry. The common genetic variant, rs138024423 at 6p21, in the major-histocompatibility-complex (MHC) region was significantly associated with disease risk (Odds ratio [OR] = 5.2; P = 2.4 × 10-12). HLA fine-mapping revealed that the common HLA class II allele, HLA-DRB1*08:03, strongly drove this signal (OR = 4.8; P = 4.8 × 10-12), followed by an additional independent risk allele at HLA-DPß1 amino acid position 8 (OR = 0.28; P = 3.4 × 10-7). HLA-DRB1*08:03 was also associated with an increased level of anti-GM-CSF antibody, a key driver of the disease (ß = 0.32; P = 0.035). Our study demonstrated a heritable component of aPAP, suggesting an underlying genetic predisposition toward an abnormal antibody production.
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Autoanticuerpos/genética , Enfermedades Autoinmunes/genética , Predisposición Genética a la Enfermedad , Factor Estimulante de Colonias de Granulocitos y Macrófagos/genética , Cadenas HLA-DRB1/genética , Proteinosis Alveolar Pulmonar/genética , Adulto , Anciano , Alelos , Pueblo Asiatico , Autoanticuerpos/biosíntesis , Enfermedades Autoinmunes/etnología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Estudios de Casos y Controles , Cromosomas Humanos Par 6 , Femenino , Expresión Génica , Frecuencia de los Genes , Estudio de Asociación del Genoma Completo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Cadenas HLA-DRB1/inmunología , Humanos , Japón , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Isoformas de Proteínas/genética , Proteinosis Alveolar Pulmonar/etnología , Proteinosis Alveolar Pulmonar/inmunología , Proteinosis Alveolar Pulmonar/patología , Surfactantes Pulmonares/inmunología , Surfactantes Pulmonares/metabolismo , RiesgoRESUMEN
Diagnosis by biopsy is difficult in the ovary since it is located deep in the abdomen. As a result, ovarian cancer is mostly found insidiously during exploratory laparotomy. Consequently, the early diagnosis of ovarian cancer is often difficult. The likelihood of peritoneal dissemination increases with the progress of ovarian cancer. With further progression, ovarian cancer metastasizes to the momentum, retroperitoneal lymph nodes, large intestine, small intestine, diaphragm, spleen, and other organs. Ovarian cancer has been considered a tumor that has a favorable response to chemotherapy, but more effective treatments are still being explored. Tumors use their own immune escape mechanism to evade host immunity. The immune checkpoint (IC) mechanism, one of the immune escape mechanisms, is established by programmed cell death-1 (PD-1)/PD-ligand-1 (PD-L1) communication. It has been shown that inhibiting PD-1/PD-L1 communication in various malignancies produces antitumor effects. However, the antitumor effect of ICI monotherapy on ovarian cancer is limited in actual clinical practice. In this review, we describe a novel cancer immunotherapeutic agent that targets myeloid-derived suppressor cells (MDSCs).
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Antineoplásicos Inmunológicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Bevacizumab/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Células Supresoras de Origen Mieloide/efectos de los fármacos , Neoplasias Ováricas/tratamiento farmacológico , Escape del Tumor/efectos de los fármacos , Animales , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab/efectos adversos , Resistencia a Antineoplásicos , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Células Supresoras de Origen Mieloide/inmunología , Células Supresoras de Origen Mieloide/metabolismo , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/metabolismo , Neoplasias Ováricas/patología , Resultado del Tratamiento , Microambiente Tumoral , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/inmunología , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
OBJECTIVE: To assess the efficacy and safety of lenzilumab in patients with severe coronavirus disease 2019 (COVID-19) pneumonia. METHODS: Hospitalized patients with COVID-19 pneumonia and risk factors for poor outcomes were treated with lenzilumab 600 mg intravenously for three doses through an emergency single-use investigational new drug application. Patient characteristics, clinical and laboratory outcomes, and adverse events were recorded. We also identified a cohort of patients matched to the lenzilumab patients for age, sex, and disease severity. Study dates were March 13, 2020, to June 18, 2020. All patients were followed through hospital discharge or death. RESULTS: Twelve patients were treated with lenzilumab; 27 patients comprised the matched control cohort (untreated). Clinical improvement, defined as improvement of at least 2 points on the 8-point ordinal clinical endpoints scale, was observed in 11 of 12 (91.7%) patients treated with lenzilumab and 22 of 27 (81.5%) untreated patients. The time to clinical improvement was significantly shorter for the lenzilumab-treated group compared with the untreated cohort with a median of 5 days versus 11 days (P=.006). Similarly, the proportion of patients with acute respiratory distress syndrome (oxygen saturation/fraction of inspired oxygen<315 mm Hg) was significantly reduced over time when treated with lenzilumab compared with untreated (P<.001). Significant improvement in inflammatory markers (C-reactive protein and interleukin 6) and markers of disease severity (absolute lymphocyte count) were observed in patients who received lenzilumab, but not in untreated patients. Cytokine analysis showed a reduction in inflammatory myeloid cells 2 days after lenzilumab treatment. There were no treatment-emergent adverse events attributable to lenzilumab. CONCLUSION: In high-risk COVID-19 patients with severe pneumonia, granulocyte-macrophage colony-stimulating factor neutralization with lenzilumab was safe and associated with faster improvement in clinical outcomes, including oxygenation, and greater reductions in inflammatory markers compared with a matched control cohort of patients hospitalized with severe COVID-19 pneumonia. A randomized, placebo-controlled clinical trial to validate these findings is ongoing (NCT04351152).
Asunto(s)
Anticuerpos Monoclonales Humanizados/administración & dosificación , Tratamiento Farmacológico de COVID-19 , Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , SARS-CoV-2 , Anciano , COVID-19/epidemiología , COVID-19/metabolismo , Relación Dosis-Respuesta a Droga , Femenino , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Infusiones Intravenosas , Masculino , Persona de Mediana Edad , Pandemias , Resultado del TratamientoRESUMEN
Health problems caused by airborne particulate matter with a diameter less than 2.5 (PM2.5), especially in the respiratory system, have become a worldwide problem, but the influence and mechanisms of PM2.5 on the ocular surface have not been sufficiently elucidated. We investigated in vitro the onset and pathogenesis of corneal damage induced by PM2.5. Two types of PM2.5 samples originating from Beijing (designated #28) and the Gobi Desert (designated #30) were added to the culture medium of immortalized cultured human corneal epithelial cells (HCECs) to examine the effects on survival rates, autophagy, and proinflammatory cytokine production. Both types of PM2.5 significantly reduced the HCEC survival rate in a concentration-dependent manner by triggering autophagy. In particular, compared with #30, #28 induced much more severe damage in HCECs. Physical contact between PM2.5 and HCECs was not a primary contributor to PM2.5-induced HCEC damage. Among the 38 proinflammatory cytokines examined in this study, significant increases in the granulocyte macrophage colony-stimulating factor (GM-CSF) and interleukin-6 levels and a significant reduction in the interleukin-8 level were detected in culture medium of PM2.5-exposed HCECs. Simultaneous addition of a GM-CSF inhibitor, suramin, alleviated the HCEC impairment induced by PM2.5. In conclusion, PM2.5 induces HCEC death by triggering autophagy. Some cytokines that are released from HCECs, including GM-CSF, may be involved in HCEC damage caused by PM2.5 exposure.
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Contaminantes Atmosféricos/toxicidad , Córnea/efectos de los fármacos , Córnea/metabolismo , Células Epiteliales/efectos de los fármacos , Células Epiteliales/metabolismo , Material Particulado/química , Material Particulado/toxicidad , Autofagia , Línea Celular , Supervivencia Celular , China , Córnea/citología , Células Epiteliales/citología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Interleucina-2/metabolismo , Interleucina-6/antagonistas & inhibidores , Interleucina-6/metabolismo , Interleucina-8/metabolismo , Suramina/farmacología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has highlighted the urgent need to rapidly develop therapeutic strategies for such emerging viruses without effective vaccines or drugs. Here, we report a decoy nanoparticle against COVID-19 through a powerful two-step neutralization approach: virus neutralization in the first step followed by cytokine neutralization in the second step. The nanodecoy, made by fusing cellular membrane nanovesicles derived from human monocytes and genetically engineered cells stably expressing angiotensin converting enzyme II (ACE2) receptors, possesses an antigenic exterior the same as source cells. By competing with host cells for virus binding, these nanodecoys effectively protect host cells from the infection of pseudoviruses and authentic SARS-CoV-2. Moreover, relying on abundant cytokine receptors on the surface, the nanodecoys efficiently bind and neutralize inflammatory cytokines including interleukin 6 (IL-6) and granulocyte-macrophage colony-stimulating factor (GM-CSF), and significantly suppress immune disorder and lung injury in an acute pneumonia mouse model. Our work presents a simple, safe, and robust antiviral nanotechnology for ongoing COVID-19 and future potential epidemics.
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Infecciones por Coronavirus/terapia , Citocinas/antagonistas & inhibidores , Nanopartículas/uso terapéutico , Neumonía Viral/terapia , Internalización del Virus/efectos de los fármacos , Enzima Convertidora de Angiotensina 2 , Animales , Betacoronavirus , COVID-19 , Membrana Celular/química , Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Células HEK293 , Humanos , Interleucina-6/antagonistas & inhibidores , Ratones , Ratones Endogámicos ICR , Monocitos , Nanopartículas/química , Pandemias , Peptidil-Dipeptidasa A/metabolismo , Receptores de Citocinas/metabolismo , SARS-CoV-2 , Células THP-1RESUMEN
COVID-19 is a clinical syndrome ranging from mild symptoms to severe pneumonia that often leads to respiratory failure, need for mechanical ventilation, and death. Most of the lung damage is driven by a surge in inflammatory cytokines [interleukin-6, interferon-γ, and granulocyte-monocyte stimulating factor (GM-CSF)]. Blunting this hyperinflammation with immunomodulation may lead to clinical improvement. GM-CSF is produced by many cells, including macrophages and T-cells. GM-CSF-derived signals are involved in differentiation of macrophages, including alveolar macrophages (AMs). In animal models of respiratory infections, the intranasal administration of GM-CSF increased the proliferation of AMs and improved outcomes. Increased levels of GM-CSF have been recently described in patients with COVID-19 compared to healthy controls. While GM-CSF might be beneficial in some circumstances as an appropriate response, in this case the inflammatory response is maladaptive by virtue of being later and disproportionate. The inhibition of GM-CSF signaling may be beneficial in improving the hyperinflammation-related lung damage in the most severe cases of COVID-19. This blockade can be achieved through antagonism of the GM-CSF receptor or the direct binding of circulating GM-CSF. Initial findings from patients with COVID-19 treated with a single intravenous dose of mavrilimumab, a monoclonal antibody binding GM-CSF receptor α, showed oxygenation improvement and shorter hospitalization. Prospective, randomized, placebo-controlled trials are ongoing. Anti-GM-CSF monoclonal antibodies, TJ003234 and gimsilumab, will be tested in clinical trials in patients with COVID-19, while lenzilumab received FDA approval for compassionate use. These trials will help inform whether blunting the inflammatory signaling provided by the GM-CSF axis in COVID-19 is beneficial.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Betacoronavirus/inmunología , Infecciones por Coronavirus , Sistemas de Liberación de Medicamentos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Pandemias , Neumonía Viral , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Animales , COVID-19 , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Modelos Animales de Enfermedad , Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Humanos , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Macrófagos Alveolares/inmunología , Macrófagos Alveolares/patología , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/inmunología , Neumonía Viral/patología , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , SARS-CoV-2 , Transducción de Señal/efectos de los fármacos , Transducción de Señal/inmunología , Linfocitos T/inmunología , Linfocitos T/patologíaRESUMEN
The COVID-19 pandemic is a global public health crisis, with considerable mortality and morbidity exerting pressure on health-care resources, including critical care. An excessive host inflammatory response in a subgroup of patients with severe COVID-19 might contribute to the development of acute respiratory distress syndrome (ARDS) and multiorgan failure. Timely therapeutic intervention with immunomodulation in patients with hyperinflammation could prevent disease progression to ARDS and obviate the need for invasive ventilation. Granulocyte macrophage colony-stimulating factor (GM-CSF) is an immunoregulatory cytokine with a pivotal role in initiation and perpetuation of inflammatory diseases. GM-CSF could link T-cell-driven acute pulmonary inflammation with an autocrine, self-amplifying cytokine loop leading to monocyte and macrophage activation. This axis has been targeted in cytokine storm syndromes and chronic inflammatory disorders. Here, we consider the scientific rationale for therapeutic targeting of GM-CSF in COVID-19-associated hyperinflammation. Since GM-CSF also has a key role in homoeostasis and host defence, we discuss potential risks associated with inhibition of GM-CSF in the context of viral infection and the challenges of doing clinical trials in this setting, highlighting in particular the need for a patient risk-stratification algorithm.
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Betacoronavirus/inmunología , Infecciones por Coronavirus/tratamiento farmacológico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Factores Inmunológicos/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/prevención & control , COVID-19 , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/virología , Progresión de la Enfermedad , Humanos , Inmunomodulación , Pandemias , Neumonía Viral/complicaciones , Neumonía Viral/virología , Síndrome de Dificultad Respiratoria/virología , SARS-CoV-2 , Tratamiento Farmacológico de COVID-19RESUMEN
Background: Coronavirus disease 2019 (COVID-19) is a novel disease associated with a cytokine-mediated, severe, acute respiratory syndrome. Tocilizumab and lenzilumab are recombinant monoclonal antibodies against IL-6 and granulocyte macrophage colony-stimulating factor, respectively, and have been proposed as a potential treatment for acute, hypoxic respiratory failure associated with COVID-19. Results & methodology: We present the case of a 68-year-old man with COVID-19 who was initially treated with hydroxychloroquine and lenzilumab, but continued to develop hypoxemia, requiring an increase in respiratory support with an associated rise in serum inflammatory markers. He was subsequently treated with tocilizumab with marked clinical improvement and a decrease in acute phase reactants within 48 h. Discussion & conclusion: This case demonstrates the effective use of tocilizumab in the treatment of COVID-19 and suggests the superiority of tocilizumab over lenzilumab in the management of this cytokine-mediated syndrome.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Infecciones por Coronavirus/terapia , Neumonía Viral/terapia , Anciano , Betacoronavirus , COVID-19 , Terapia Combinada , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/patología , Síndrome de Liberación de Citoquinas/patología , Síndrome de Liberación de Citoquinas/terapia , Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Humanos , Masculino , Pandemias , Neumonía Viral/patología , Receptores de Interleucina-6/antagonistas & inhibidores , Insuficiencia Respiratoria/patología , Insuficiencia Respiratoria/terapia , SARS-CoV-2 , Resultado del Tratamiento , Tratamiento Farmacológico de COVID-19RESUMEN
The present study is based on the concept of neuro-aging and how it may affect surrounding skin cells. It has been shown that many factors play a significant role in skin homeostasis by interfering with various cytokines, either through activation or inhibition. Granulocyte macrophage colony-stimulating factor (GM-CSF) is generally recognized as an inflammatory cytokine, and our previous study has shown its effects on neuronal senescence after ultraviolet (UV) irradiation of skin cells. Following our previous work, this study was performed to investigate the neuroprotective effects of a GM-CSF antagonist, and how it may play an essential role in mediating anti-senescence and anti-inflammatory effects in the keratinocyte/nerve aging model. When human blastoma cells (SH-SY5Y) were treated with 10âng/ml of GM-CSF, the levels of regulatory RNAs associated with aging, such as matrix metalloproteinase-9 (MMP9), nuclear factor NF-kappa-B p50 subunit (NFKB), inducible nitric oxide synthase (iNOS), and interleukin 1 beta (IL-1ß) increased, whereas GM-CSF inhibition caused their expression to decrease. A decrease in the antioxidant, glutathione (GSH) was observed after SH-SY5Y cells were treated with GM-CSF. This study confirms that this GM-CSF antagonist may play an important role in neural senescence, where inhibition may be a new target in the skin/nerve aging model.
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Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Neuronas/efectos de los fármacos , Piel/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Interleucina-1beta/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Subunidad p50 de NF-kappa B/metabolismo , Tejido Nervioso/efectos de los fármacos , Tejido Nervioso/metabolismo , Neuronas/metabolismo , Óxido Nítrico Sintasa de Tipo II/metabolismo , Piel/metabolismo , Envejecimiento de la Piel/efectos de los fármacos , Rayos UltravioletaAsunto(s)
Enfermedades Autoinmunes/tratamiento farmacológico , Enfermedades Autoinmunes/inmunología , Hipoglucemiantes/uso terapéutico , Macrófagos Alveolares/efectos de los fármacos , Pioglitazona/uso terapéutico , Proteinosis Alveolar Pulmonar/tratamiento farmacológico , Proteinosis Alveolar Pulmonar/inmunología , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/patología , Líquido del Lavado Bronquioalveolar/inmunología , Fibrosis/diagnóstico por imagen , Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Humanos , Hipoglucemiantes/administración & dosificación , Consentimiento Informado/legislación & jurisprudencia , Masculino , Persona de Mediana Edad , Uso Fuera de lo Indicado/legislación & jurisprudencia , Pioglitazona/administración & dosificación , Proteinosis Alveolar Pulmonar/sangre , Proteinosis Alveolar Pulmonar/patología , Resultado del TratamientoRESUMEN
To identify the mechanisms relevant for the therapeutic effect of glatiramer acetate (GA), we studied T- and B- regulatory cells as well as GM-CSF expression in mice recovered from experimental autoimmune encephalomyelitis (EAE). Selective depletion of Tregs reduced but did not eliminate the ability of GA to ameliorate EAE, indicating a role for additional immune-subsets. The prevalence of Bregs in the periphery and the CNS of EAE-mice increased following GA-treatment. Furthermore, GA downregulated the pathological expression of GM-CSF, on both the protein and mRNA levels. These findings corroborate the broad immunomodulatory mechanism of action of GA in EAE/MS.
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Linfocitos B Reguladores/metabolismo , Acetato de Glatiramer/farmacología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Inmunosupresores/farmacología , Esclerosis Múltiple/metabolismo , Linfocitos T Reguladores/metabolismo , Animales , Linfocitos B Reguladores/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Acetato de Glatiramer/uso terapéutico , Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Inmunosupresores/uso terapéutico , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Esclerosis Múltiple/tratamiento farmacológico , Linfocitos T Reguladores/efectos de los fármacosRESUMEN
The pandemic caused by the novel coronavirus SARS-CoV-2 has placed an unprecedented burden on healthcare systems around the world. In patients who experience severe disease, acute respiratory distress is often accompanied by a pathological immune reaction, sometimes referred to as 'cytokine storm'. One hallmark feature of the profound inflammatory state seen in patients with COVID-19 who succumb to pneumonia and hypoxia is marked elevation of serum cytokines, especially interferon gamma, tumor necrosis factor alpha, interleukin 17 (IL-17), interleukin 8 (IL-8) and interleukin 6 (IL-6). Initial experience from the outbreaks in Italy, China and the USA has anecdotally demonstrated improved outcomes for critically ill patients with COVID-19 with the administration of cytokine-modulatory therapies, especially anti-IL-6 agents. Although ongoing trials are investigating anti-IL-6 therapies, access to these therapies is a concern, especially as the numbers of cases worldwide continue to climb. An immunology-informed approach may help identify alternative agents to modulate the pathological inflammation seen in patients with COVID-19. Drawing on extensive experience administering these and other immune-modulating therapies, the Society for Immunotherapy of Cancer offers this perspective on potential alternatives to anti-IL-6 that may also warrant consideration for management of the systemic inflammatory response and pulmonary compromise that can be seen in patients with severe COVID-19.
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Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/tratamiento farmacológico , Inmunoterapia , Interleucina-6/antagonistas & inhibidores , Interleucina-6/inmunología , Neumonía Viral/complicaciones , Neumonía Viral/tratamiento farmacológico , Síndrome de Dificultad Respiratoria/complicaciones , Síndrome de Dificultad Respiratoria/tratamiento farmacológico , Sociedades Médicas , Traslado Adoptivo , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Anticuerpos Monoclonales Humanizados/farmacología , Anticuerpos Monoclonales Humanizados/uso terapéutico , COVID-19 , Infecciones por Coronavirus/inmunología , Infecciones por Coronavirus/patología , Síndrome de Liberación de Citoquinas/complicaciones , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/inmunología , Síndrome de Liberación de Citoquinas/patología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Humanos , Inflamación/complicaciones , Inflamación/tratamiento farmacológico , Inflamación/inmunología , Inflamación/patología , Interferón gamma/antagonistas & inhibidores , Interleucina-1/antagonistas & inhibidores , Interleucina-17/antagonistas & inhibidores , Interleucina-23/antagonistas & inhibidores , Interleucina-6/genética , Interleucina-6/metabolismo , Quinasas Janus/antagonistas & inhibidores , Neoplasias/inmunología , Neoplasias/terapia , Pandemias , Neumonía Viral/inmunología , Neumonía Viral/patología , Síndrome de Dificultad Respiratoria/inmunología , Síndrome de Dificultad Respiratoria/patología , Factores de Transcripción STAT/antagonistas & inhibidores , Síndrome Respiratorio Agudo Grave/patología , Transducción de Señal/efectos de los fármacos , Factor de Necrosis Tumoral alfa/antagonistas & inhibidoresAsunto(s)
Anticuerpos Monoclonales/inmunología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Paraproteinemias/diagnóstico , Paraproteinemias/inmunología , Proteinosis Alveolar Pulmonar/tratamiento farmacológico , Anticuerpos Monoclonales/sangre , Autoanticuerpos/sangre , Autoanticuerpos/inmunología , Biopsia , Médula Ósea/patología , Cromatografía Liquida , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Cadenas gamma de Inmunoglobulina/sangre , Cadenas gamma de Inmunoglobulina/inmunología , Masculino , Gammopatía Monoclonal de Relevancia Indeterminada/sangre , Gammopatía Monoclonal de Relevancia Indeterminada/diagnóstico , Gammopatía Monoclonal de Relevancia Indeterminada/inmunología , Paraproteinemias/sangre , Proteinosis Alveolar Pulmonar/diagnóstico , Proteinosis Alveolar Pulmonar/etiología , Espectrometría de Masas en Tándem , Tomografía Computarizada por Rayos XRESUMEN
The interactions between tumor immune microenvironment (TIME) and pancreatic cancer cells can affect chemotherapeutic efficacy; however, the mechanisms still remain largely unknown. Thirty items in TIME were comprehensively screened by using tissue microarray from pancreatic cancer patients. Their expressions, interconnections and predictive roles for survival were analyzed. Twenty-one of 30 items could stratify the survival of the patients; however, multivariate analysis found that only 5 independent risk factors could predict worse survival (M2-polarized tumor-associated macrophages (TAMs), IgG4 positive cells, TGF-ß1, GM-CSF and lymphangiogenesis). They had a much higher expression levels in tumoral tissue, compared to peritumoral tissue. The Spearman analysis showed that M2-polarized TAM, TGF-ß1 and GM-CSF were positively correlated with pancreatic cancer stem cells (PCSC), angiogenesis and lymphangiogenesis. Both human and murine pancreatic cancer cells could induce M2-polarized TAM, which showed substantial roles to decease chemotherapeutic effects. After treated by gemcitabine, both human and murine pancreatic cancer cell lines expressed higher level of immune check points, PCSC markers and varieties of immunosuppressive factors; however, TGF-ß1 and GM-CSF had the highest increase. Based on the above results, TGF-ß1 and GM-CSF were proposed to be the optimal potential targets to improve chemotherapeutic effects. In immunocompetent murine models, we demonstrated that combined blockade of TGF-ß1 and GM-CSF improved the chemotherapeutic effects by inhibition of M2-polarized TAM and induction of CD8 positive T cells. This study presents a novel promising combined strategy to improve the chemotherapeutic effects for pancreatic cancer.
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Carcinoma Ductal Pancreático/tratamiento farmacológico , Desoxicitidina/análogos & derivados , Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Células Madre Neoplásicas/efectos de los fármacos , Neoplasias Pancreáticas/tratamiento farmacológico , Factor de Crecimiento Transformador beta1/antagonistas & inhibidores , Microambiente Tumoral/efectos de los fármacos , Animales , Antimetabolitos Antineoplásicos/farmacología , Apoptosis , Biomarcadores de Tumor/metabolismo , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patología , Proliferación Celular , Estudios de Cohortes , Desoxicitidina/farmacología , Femenino , Regulación Neoplásica de la Expresión Génica , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Humanos , Linfangiogénesis/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Neovascularización Patológica/patología , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patología , Pronóstico , Tasa de Supervivencia , Factor de Crecimiento Transformador beta1/metabolismo , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de Xenoinjerto , GemcitabinaRESUMEN
OBJECTIVES: Pharmacological options for treating osteoarthritis (OA) are limited and alternative treatments are required. Given the clinical data indicating that granulocyte macrophage-colony stimulating factor (GM-CSF) may be a therapeutic target in human OA, we evaluated different treatment regimens with a neutralizing anti-GM-CSF monoclonal antibody (mAb) in an experimental OA model to determine their effectiveness on amelioration of pain and disease. METHODS: The collagenase-induced osteoarthritis (CiOA) model was induced in C57BL/6 mice, followed by different treatment regimens of anti-GM-CSF mAb or isotype control. Anti-CCL17 mAb treatment was also administered continually during the late stage of CiOA. Pain-related behavior (change in weight distribution of hind limbs), and disease (cartilage damage and osteophyte size) were assessed. RESULTS: Blocking GM-CSF only during early synovitis in CiOA prevented pain and disease development. Once OA pain was established, regardless of the treatment regimen, anti-GM-CSF mAb treatment rapidly and efficiently ameliorated it; however, unless the treatment was continued, pain returned and disease progressed. Continual late stage blockade of GM-CSF was able to ameliorate pain (between-group difference: -6.567; 95% confidence interval (CI): -10.12, -3.011) and suppress cartilage damage (P = 0.0317, 95% CI: -1.75, -0.0556). Continual late stage blockade of CCL17 showed similar effects on pain and disease development. CONCLUSIONS: Early and short-term GM-CSF neutralization is effective at preventing CiOA pain and disease development but, once pain is evident, continual GM-CSF blockade is required to prevent pain from returning and to suppress disease progression in mice. These data reinforce the potential benefits of anti-GM-CSF (and anti-CCL17) mAb therapy in OA and should inform further clinical trials.
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Anticuerpos Neutralizantes/farmacología , Cartílago Articular/efectos de los fármacos , Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Osteoartritis de la Rodilla/patología , Rodilla de Cuadrúpedos/efectos de los fármacos , Membrana Sinovial/efectos de los fármacos , Animales , Artritis Experimental/inducido químicamente , Artritis Experimental/patología , Cartílago Articular/patología , Quimiocina CCL17/antagonistas & inhibidores , Colagenasas/toxicidad , Progresión de la Enfermedad , Intervención Médica Temprana , Inyecciones Intraarticulares , Ratones , Osteoartritis de la Rodilla/inducido químicamente , Osteofito/patología , Dimensión del Dolor , Rodilla de Cuadrúpedos/patología , Membrana Sinovial/patología , Sinovitis/patologíaRESUMEN
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a multipotent cytokine that prompts the proliferation of bone marrow-derived macrophages and granulocytes. In addition to its effects as a growth factor, GM-CSF plays an important role in chronic inflammatory autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Reports have identified monocytes as the primary target of GM-CSF; however, its effect on monocyte activation has been under-estimated. Here, using flow cytometry and ELISA we show that GM-CSF induces an inflammatory profile in human monocytes, which includes an upregulated expression of HLA-DR and CD86 molecules and increased production of TNF-α and IL-1ß. Conversely, blockage of endogenous GM-CSF with antibody treatment not only inhibited the inflammatory profile of these cells, but also induced an immunomodulatory one, as shown by increased IL-10 production by monocytes. Further analysis with qPCR, flow cytometry and ELISA experiments revealed that GM-CSF blockage in monocytes stimulated production of the chemokine CXCL-11, which suppressed T cell proliferation. Blockade of CXCL-11 abrogated anti-GM-CSF treatment and induced inflammatory monocytes. Our findings show that anti-GM-CSF treatment induces modulatory monocytes that act in a CXCL-11-dependent manner, a mechanism that can be used in the development of novel approaches to treat chronic inflammatory autoimmune diseases.
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Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Monocitos/efectos de los fármacos , Antígeno B7-2/metabolismo , Quimiocina CXCL11/antagonistas & inhibidores , Quimiocina CXCL11/metabolismo , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/fisiología , Antígenos HLA-DR/metabolismo , Humanos , Interleucina-10/metabolismo , Interleucina-1beta/metabolismo , Monocitos/metabolismo , Monocitos/fisiología , Fenotipo , Reacción en Cadena en Tiempo Real de la Polimerasa , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
The transcription factor BHLHE40 is an emerging regulator of the immune system. Recent studies suggest that BHLHE40 regulates type 2 immunity, but this has not been demonstrated in vivo. We found that BHLHE40 is required in T cells for a protective TH2 cell response in mice infected with the helminth Heligmosomoides polygyrus bakeri H. polygyrus elicited changes in gene and cytokine expression by lamina propria CD4+ T cells, many of which were BHLHE40 dependent, including production of the common ß (CSF2RB) chain family cytokines GM-CSF and IL-5. In contrast to deficiency in GM-CSF or IL-5 alone, loss of both GM-CSF and IL-5 signaling impaired protection against H. polygyrus Overall, we show that BHLHE40 regulates the TH2 cell transcriptional program during helminth infection to support normal expression of Csf2, Il5, and other genes required for protection and reveal unexpected redundancy of common ß chain-dependent cytokines previously thought to possess substantially divergent functions.