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1.
J Allergy Clin Immunol ; 148(4): 953-963, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34625142

RESUMO

Asthma is an inflammatory disease of the airways characterized by intermittent episodes of wheezing, chest tightness, and cough. Many of the inflammatory pathways implicated in asthma involve cytokines and growth factors that activate Janus kinases (JAKs). The discovery of the JAK/signal transducer and activator of transcription (STAT) signaling pathway was a major breakthrough that revolutionized our understanding of cell growth and differentiation. JAK inhibitors are under active investigation for immune and inflammatory diseases, and they have demonstrated clinical efficacy in diseases such as rheumatoid arthritis and atopic dermatitis. Substantial preclinical data support the idea that inhibiting JAKs will ameliorate airway inflammation and hyperreactivity in asthma. Here, we review the rationale for use of JAK inhibitors in different asthma endotypes as well as the preclinical and early clinical evidence supporting such use. We review preclinical data from the use of systemic and inhaled JAK inhibitors in animal models of asthma and safety data based on the use of JAK inhibitors in other diseases. We conclude that JAK inhibitors have the potential to usher in a new era of anti-inflammatory treatment for asthma.


Assuntos
Asma/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Animais , Vias de Administração de Medicamentos , Humanos , Inibidores de Janus Quinases/administração & dosagem , Inibidores de Janus Quinases/efeitos adversos , Janus Quinases/antagonistas & inibidores , Janus Quinases/imunologia , Fatores de Transcrição STAT/imunologia
2.
Leukemia ; 35(10): 2917-2923, 2021 10.
Artigo em Inglês | MEDLINE | ID: mdl-34385593

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 (coronavirus disease 2019), which is associated with high morbidity and mortality, especially in elder patients. Acute respiratory distress syndrome (ARDS) is a life-threatening complication of COVID-19 and has been linked with severe hyperinflammation. Dexamethasone has emerged as standard of care for COVID-19 associated respiratory failure. In a non-randomized prospective phase II multi-center study, we asked whether targeted inhibition of Janus kinase-mediated cytokine signaling using ruxolitinib is feasible and efficacious in SARS-CoV-2- induced ARDS with hyperinflammation. Sixteen SARS-CoV-2 infected patients requiring invasive mechanical ventilation for ARDS were treated with ruxolitinib in addition to standard treatment. Ruxolitinib treatment was well tolerated and 13 patients survived at least the first 28 days on treatment, which was the primary endpoint of the trial. Immediate start of ruxolitinib after deterioration was associated with improved outcome, as was a lymphocyte-to-neutrophils ratio above 0.07. Together, treatment with the janus-kinase inhibitor ruxolitinib is feasible and might be efficacious in COVID-19 induced ARDS patients requiring invasive mechanical ventilation. The trial has been registered under EudraCT-No.: 2020-001732-10 and NCT04359290.


Assuntos
COVID-19/complicações , Inibidores de Janus Quinases/uso terapêutico , Janus Quinases/antagonistas & inibidores , Pirazóis/uso terapêutico , Síndrome do Desconforto Respiratório/tratamento farmacológico , SARS-CoV-2/isolamento & purificação , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Síndrome do Desconforto Respiratório/epidemiologia , Síndrome do Desconforto Respiratório/virologia , Taxa de Sobrevida
3.
Biomolecules ; 11(8)2021 08 06.
Artigo em Inglês | MEDLINE | ID: mdl-34439829

RESUMO

Retinitis pigmentosa (RP) is a hereditary disease of the retina that results in complete blindness. Currently, there are very few treatments for the disease and those that exist work only for the recessively inherited forms. To better understand the pathogenesis of RP, multiple mouse models have been generated bearing mutations found in human patients including the human Q344X rhodopsin knock-in mouse. In recent years, the immune system was shown to play an increasingly important role in RP degeneration. By way of electroretinography, optical coherence tomography, funduscopy, fluorescein angiography, and fluorescent immunohistochemistry, we show degenerative and vascular phenotypes, microglial activation, photoreceptor phagocytosis, and upregulation of proinflammatory pathway proteins in the retinas of the human Q344X rhodopsin knock-in mouse. We also show that an FDA-approved pharmacological agent indicated for the treatment of rheumatoid arthritis is able to halt activation of pro-inflammatory signaling in cultured retinal cells, setting the stage for pre-clinical trials using these mice to inhibit proinflammatory signaling in an attempt to preserve vision. We conclude from this work that pro- and autoinflammatory upregulation likely act to enhance the progression of the degenerative phenotype of rhodopsin Q344X-mediated RP and that inhibition of these pathways may lead to longer-lasting vision in not only the Q344X rhodopsin knock-in mice, but humans as well.


Assuntos
Antirreumáticos/farmacologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Fator Inibidor de Leucemia/farmacologia , Mutação , Retina/efeitos dos fármacos , Retinite Pigmentosa/tratamento farmacológico , Rodopsina/genética , Substituição de Aminoácidos , Animais , Modelos Animais de Doenças , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/imunologia , Endotélio Vascular/patologia , Expressão Gênica , Técnicas de Introdução de Genes , Humanos , Janus Quinases/antagonistas & inibidores , Janus Quinases/genética , Janus Quinases/imunologia , Camundongos , Camundongos Transgênicos , Microglia/efeitos dos fármacos , Microglia/imunologia , Microglia/patologia , NF-kappa B/genética , NF-kappa B/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Retina/imunologia , Retina/patologia , Retinite Pigmentosa/genética , Retinite Pigmentosa/imunologia , Retinite Pigmentosa/patologia , Rodopsina/deficiência , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/genética , Fatores de Transcrição STAT/imunologia , Transdução de Sinais , Transgenes , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
4.
Viruses ; 13(7)2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34372612

RESUMO

Human T-cell leukemia virus type 1 (HTLV-1) is a retrovirus that infects at least 10 million people worldwide and is associated with the development of T-cell lymphoma (TCL). The treatment of TCL remains challenging and new treatment options are urgently needed. With the goal of developing a novel therapeutic approach for TCL, we investigated the activity of the clinical formulation of oncolytic reovirus (Reolysin, Pelareorep) in TCL models. Our studies revealed that HTLV-1-negative TCL cells were highly sensitive to Reolysin-induced cell death, but HTLV-1-positive TCL cells were resistant. Consistent with these data, reovirus displayed significant viral accumulation in HTLV-1-negative cells, but failed to efficiently replicate in HTLV-1-positive cells. Transcriptome analyses of HTLV-1-positive vs. negative cells revealed a significant increase in genes associated with retroviral infection including interleukin-13 and signal transducer and activator of transcription 5 (STAT5). To investigate the relationship between HTLV-1 status and sensitivity to Reolysin, we infected HTLV-1-negative cells with HTLV-1. The presence of HTLV-1 resulted in significantly decreased sensitivity to Reolysin. Treatment with the JAK inhibitor ruxolitinib suppressed STAT5 phosphorylation and expression of the key anti-viral response protein MX1 and enhanced the anti-TCL activity of Reolysin in both HTLV-1-positive and negative cells. Our data demonstrate that the inhibition of the JAK/STAT pathway can be used as a novel approach to antagonize the resistance of HTLV-1-positive cells to oncolytic virus therapy.


Assuntos
Janus Quinases/antagonistas & inibidores , Leucemia-Linfoma de Células T do Adulto/terapia , Leucemia-Linfoma de Células T do Adulto/virologia , Vírus Oncolíticos/fisiologia , Reoviridae/fisiologia , Fator de Transcrição STAT5/antagonistas & inibidores , Linhagem Celular Tumoral , Perfilação da Expressão Gênica , Vírus Linfotrópico T Tipo 1 Humano , Humanos , Nitrilas/farmacologia , Fosforilação , Pirazóis/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos
5.
N Engl J Med ; 385(3): 228-238, 2021 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-34260836

RESUMO

BACKGROUND: Chronic graft-versus-host disease (GVHD), a major complication of allogeneic stem-cell transplantation, becomes glucocorticoid-refractory or glucocorticoid-dependent in approximately 50% of patients. Robust data from phase 3 randomized studies evaluating second-line therapy for chronic GVHD are lacking. In retrospective surveys, ruxolitinib, a Janus kinase (JAK1-JAK2) inhibitor, showed potential efficacy in patients with glucocorticoid-refractory or -dependent chronic GVHD. METHODS: This phase 3 open-label, randomized trial evaluated the efficacy and safety of ruxolitinib at a dose of 10 mg twice daily, as compared with the investigator's choice of therapy from a list of 10 commonly used options considered best available care (control), in patients 12 years of age or older with moderate or severe glucocorticoid-refractory or -dependent chronic GVHD. The primary end point was overall response (complete or partial response) at week 24; key secondary end points were failure-free survival and improved score on the modified Lee Symptom Scale at week 24. RESULTS: A total of 329 patients underwent randomization; 165 patients were assigned to receive ruxolitinib and 164 patients to receive control therapy. Overall response at week 24 was greater in the ruxolitinib group than in the control group (49.7% vs. 25.6%; odds ratio, 2.99; P<0.001). Ruxolitinib led to longer median failure-free survival than control (>18.6 months vs. 5.7 months; hazard ratio, 0.37; P<0.001) and higher symptom response (24.2% vs. 11.0%; odds ratio, 2.62; P = 0.001). The most common (occurring in ≥10% patients) adverse events of grade 3 or higher up to week 24 were thrombocytopenia (15.2% in the ruxolitinib group and 10.1% in the control group) and anemia (12.7% and 7.6%, respectively). The incidence of cytomegalovirus infections and reactivations was similar in the two groups. CONCLUSIONS: Among patients with glucocorticoid-refractory or -dependent chronic GVHD, ruxolitinib led to significantly greater overall response, failure-free survival, and symptom response. The incidence of thrombocytopenia and anemia was greater with ruxolitinib. (Funded by Novartis and Incyte; REACH3 ClinicalTrials.gov number, NCT03112603.).


Assuntos
Doença Enxerto-Hospedeiro/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Janus Quinases/antagonistas & inibidores , Pirazóis/uso terapêutico , Adolescente , Adulto , Idoso , Criança , Infecções por Citomegalovirus/etiologia , Feminino , Glucocorticoides/uso terapêutico , Humanos , Fatores Imunológicos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Fotoferese , Pirazóis/efeitos adversos , Análise de Sobrevida , Trombocitopenia/induzido quimicamente , Falha de Tratamento , Adulto Jovem
6.
Cells ; 10(7)2021 06 25.
Artigo em Inglês | MEDLINE | ID: mdl-34202258

RESUMO

Hutchinson-Gilford progeria syndrome (HGPS) is a segmental premature aging disease caused by a mutation in LMNA. The mutation generates a truncated and farnesylated form of prelamin A, called progerin. Affected individuals develop several features of normal aging, including lipodystrophy caused by the loss of general subcutaneous fat. To determine whether premature cellular senescence is responsible for the altered adipogenesis in patients with HGPS, we evaluated the differentiation of HGPS skin-derived precursor stem cells (SKPs) into adipocytes. The SKPs were isolated from primary human HGPS and normal fibroblast cultures, with senescence of 5 and 30%. We observed that the presence of high numbers of senescent cells reduced SKPs' adipogenic differentiation potential. Treatment with baricitinib, a JAK-STAT inhibitor, ameliorated the ability of HGPS SKPs to differentiate into adipocytes. Our findings suggest that the development of lipodystrophy in patients with HGPS may be associated with an increased rate of cellular senescence and chronic inflammation.


Assuntos
Lamina Tipo A/metabolismo , Progéria/patologia , Pele/patologia , Células-Tronco/metabolismo , Células 3T3-L1 , Adipócitos/efeitos dos fármacos , Adipócitos/metabolismo , Adipócitos/patologia , Adipogenia/efeitos dos fármacos , Adolescente , Animais , Azetidinas/farmacologia , Compostos de Boro , Diferenciação Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Criança , Pré-Escolar , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Proteínas de Ligação a Ácido Graxo/metabolismo , Feminino , Fibroblastos/efeitos dos fármacos , Fibroblastos/metabolismo , Fibroblastos/patologia , Humanos , Interleucina-8/metabolismo , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Masculino , Camundongos , PPAR gama/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Purinas/farmacologia , Pirazóis/farmacologia , Células-Tronco/efeitos dos fármacos , Sulfonamidas/farmacologia
7.
Front Immunol ; 12: 672461, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34248953

RESUMO

Objectives: Psoriatic arthritis (PsA) is a chronic inflammatory disease associated with psoriasis. Janus Kinase inhibitors (JAKi) have emerged as an encouraging class of drugs for the treatment of PsA. Here, we compare the effect of four JAKi on primary PsA synovial fibroblasts (PsAFLS) activation, metabolic function, and invasive and migratory capacity. Methods: Primary PsAFLS were isolated and cultured with JAKi (Peficitinib, Filgotinib, Baricitinib and Upadacitinib) in the presence of Oncostatin M (OSM). pSTAT3 expression in response to OSM was quantified by Western Blot analysis. Pro-inflammatory cytokines/chemokines were quantified by ELISA and cell migration by wound-repair scratch assays. Invasive capacity was examined using Matrigel™ invasion chambers and MMP multiplex MSD assays. PsAFLS bioenergetics was assessed using the Seahorse XFe Extracellular Flux Analyzer, which simultaneously quantifies two energetic pathways- glycolysis (ECAR) and oxidative phosphorylation (OCR). In parallel, inflammatory, invasive, and migratory genes were quantified by RT-PCR. Results: OSM induces pSTAT3 expression in PsAFLS. OSM-induced secretion of MCP-1 and IL-6 was inhibited by all JAKi with Peficitinib, Baricitinib and Upadacitinib showing the greatest effect. In contrast, JAKi had no significant impact on IL-8 expression in response to OSM. PsAFLS cell invasion, migratory capacity and MMP1, 3, and 9 were suppressed following JAKi treatment, with Peficitinib showing the greatest effect. These functional effects were accompanied by a change in the cellular bioenergetic profile of PsAFLS, where JAKi significantly decreased glycolysis and the ECAR/OCR, resulting in a shift to a more quiescent phenotype, with Peficitinib demonstrating the most pronounced effect. Conclusion: This study demonstrates that JAK/STAT signalling mediates the complex interplay between inflammation and cellular metabolism in PsA pathogenesis. This inhibition shows effective suppression of inflammatory mechanisms that drive pathogenic functions of PsAFLS, further supporting the role of JAKi as a therapeutic target for the treatment of PsA.


Assuntos
Artrite Psoriásica , Fibroblastos/efeitos dos fármacos , Inibidores de Janus Quinases/farmacologia , Janus Quinases/antagonistas & inibidores , Fatores de Transcrição STAT/antagonistas & inibidores , Adamantano/análogos & derivados , Adamantano/farmacologia , Adulto , Idoso , Artrite Psoriásica/imunologia , Artrite Psoriásica/metabolismo , Azetidinas/farmacologia , Células Cultivadas , Feminino , Fibroblastos/enzimologia , Compostos Heterocíclicos com 3 Anéis/farmacologia , Humanos , Inflamação/imunologia , Inflamação/metabolismo , Masculino , Pessoa de Meia-Idade , Niacinamida/análogos & derivados , Niacinamida/farmacologia , Purinas/farmacologia , Pirazóis/farmacologia , Piridinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Membrana Sinovial/efeitos dos fármacos , Triazóis/farmacologia
8.
Int J Mol Sci ; 22(12)2021 Jun 09.
Artigo em Inglês | MEDLINE | ID: mdl-34207510

RESUMO

Interstitial lung diseases (ILDs) comprise different fibrotic lung disorders characterized by cellular proliferation, interstitial inflammation, and fibrosis. The JAK/STAT molecular pathway is activated under the interaction of a broad number of profibrotic/pro-inflammatory cytokines, such as IL-6, IL-11, and IL-13, among others, which are increased in different ILDs. Similarly, several growth factors over-expressed in ILDs, such as platelet-derived growth factor (PDGF), transforming growth factor ß1 (TGF-ß1), and fibroblast growth factor (FGF) activate JAK/STAT by canonical or non-canonical pathways, which indicates a predominant role of JAK/STAT in ILDs. Between the different JAK/STAT isoforms, it appears that JAK2/STAT3 are predominant, initiating cellular changes observed in ILDs. This review analyzes the expression and distribution of different JAK/STAT isoforms in ILDs lung tissue and different cell types related to ILDs, such as lung fibroblasts and alveolar epithelial type II cells and analyzes JAK/STAT activation. The effect of JAK/STAT phosphorylation on cellular fibrotic processes, such as proliferation, senescence, autophagy, endoplasmic reticulum stress, or epithelial/fibroblast to mesenchymal transition will be described. The small molecules directed to inhibit JAK/STAT activation were assayed in vitro and in in vivo models of pulmonary fibrosis, and different JAK inhibitors are currently approved for myeloproliferative disorders. Recent evidence indicates that JAK inhibitors or monoclonal antibodies directed to block IL-6 are used as compassionate use to attenuate the excessive inflammation and lung fibrosis related to SARS-CoV-2 virus. These altogether indicate that JAK/STAT pathway is an attractive target to be proven in future clinical trials of lung fibrotic disorders.


Assuntos
Janus Quinases/metabolismo , Doenças Pulmonares Intersticiais/patologia , Fatores de Transcrição STAT/metabolismo , Senescência Celular , Estresse do Retículo Endoplasmático , Humanos , Interleucinas/metabolismo , Janus Quinases/antagonistas & inibidores , Janus Quinases/genética , Doenças Pulmonares Intersticiais/tratamento farmacológico , Doenças Pulmonares Intersticiais/metabolismo , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/metabolismo , Inibidores de Proteínas Quinases/uso terapêutico , Fatores de Transcrição STAT/antagonistas & inibidores , Fatores de Transcrição STAT/genética , Transdução de Sinais
11.
Cytokine ; 144: 155593, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34074585

RESUMO

An analysis of published data appertaining to the cytokine storms of COVID-19, H1N1 influenza, cytokine release syndrome (CRS), and macrophage activation syndrome (MAS) reveals many common immunological and biochemical abnormalities. These include evidence of a hyperactive coagulation system with elevated D-dimer and ferritin levels, disseminated intravascular coagulopathy (DIC) and microthrombi coupled with an activated and highly permeable vascular endothelium. Common immune abnormalities include progressive hypercytokinemia with elevated levels of TNF-α, interleukin (IL)-6, and IL-1ß, proinflammatory chemokines, activated macrophages and increased levels of nuclear factor kappa beta (NFκB). Inflammasome activation and release of damage associated molecular patterns (DAMPs) is common to COVID-19, H1N1, and MAS but does not appear to be a feature of CRS. Elevated levels of IL-18 are detected in patients with COVID-19 and MAS but have not been reported in patients with H1N1 influenza and CRS. Elevated interferon-γ is common to H1N1, MAS, and CRS but levels of this molecule appear to be depressed in patients with COVID-19. CD4+ T, CD8+ and NK lymphocytes are involved in the pathophysiology of CRS, MAS, and possibly H1N1 but are reduced in number and dysfunctional in COVID-19. Additional elements underpinning the pathophysiology of cytokine storms include Inflammasome activity and DAMPs. Treatment with anakinra may theoretically offer an avenue to positively manipulate the range of biochemical and immune abnormalities reported in COVID-19 and thought to underpin the pathophysiology of cytokine storms beyond those manipulated via the use of, canakinumab, Jak inhibitors or tocilizumab. Thus, despite the relative success of tocilizumab in reducing mortality in COVID-19 patients already on dexamethasone and promising results with Baricitinib, the combination of anakinra in combination with dexamethasone offers the theoretical prospect of further improvements in patient survival. However, there is currently an absence of trial of evidence in favour or contravening this proposition. Accordingly, a large well powered blinded prospective randomised controlled trial (RCT) to test this hypothesis is recommended.


Assuntos
Anti-Inflamatórios/uso terapêutico , Antivirais/uso terapêutico , COVID-19 , Síndrome da Liberação de Citocina , Vírus da Influenza A Subtipo H1N1/imunologia , SARS-CoV-2/imunologia , COVID-19/tratamento farmacológico , COVID-19/imunologia , COVID-19/mortalidade , COVID-19/patologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/patologia , Intervalo Livre de Doença , Humanos , Influenza Humana/tratamento farmacológico , Influenza Humana/imunologia , Influenza Humana/mortalidade , Influenza Humana/patologia , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Linfócitos/imunologia , Linfócitos/patologia , Taxa de Sobrevida
12.
Brasília; CONITEC; jun. 2021.
Não convencional em Português | BRISA/RedTESA | ID: biblio-1293255

RESUMO

INTRODUÇÃO: A retocolite ulcerativa (RCU), ou colite ulcerativa, é uma doença caracterizada pela ocorrência de episódios de inflamação restrita à mucosa do cólon, podendo envolver o reto e se estender por outras partes proximais do cólon. Os pacientes apresentam diarreia, podendo ser associada com a presença de sangue. Os sintomas incluem dor abdominal, urgência, incontinência e tenesmo, que apresentam de forma gradual e progressiva, podendo estender-se por várias semanas. Febre, fadiga, perda de peso, dispneia, palpitação, anemia e deficiência de ferro podem ocorrer. A RCU pode ser dividida em fase ativa e estádio de remissão. A fase ativa é caracterizada pela presença de sintomas e lesões ativas da mucosa e a remissão é caracterizada pela resolução dos sintomas e desaparecimento de achados na mucosa. A doença ocorre gradualmente, seguida de períodos de remissão espontânea e recaídas subsequentes. A incidência da doença é semelhante entre homens e mulheres, sendo que a idade de início é entre 30 e 40 anos. O tratamento da RCU consiste em aminossalicilatos orais e por via retal, corticoides, imunossupressores e medicamentos biológicos, e é feito d


Assuntos
Humanos , Proctocolite/tratamento farmacológico , Azatioprina/efeitos adversos , Corticosteroides/efeitos adversos , Janus Quinases/antagonistas & inibidores , Mercaptopurina/efeitos adversos , Sistema Único de Saúde , Brasil , Análise Custo-Benefício
13.
Front Immunol ; 12: 635018, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33936047

RESUMO

Objective: Bacterial and viral infectious triggers are linked to spondyloarthritis (SpA) including psoriatic arthritis (PsA) development, likely via dendritic cell activation. We investigated spinal entheseal plasmacytoid dendritic cells (pDCs) toll-like receptor (TLR)-7 and 9 activation and therapeutic modulation, including JAK inhibition. We also investigated if COVID-19 infection, a potent TLR-7 stimulator triggered PsA flares. Methods: Normal entheseal pDCs were characterized and stimulated with imiquimod and CpG oligodeoxynucleotides (ODN) to evaluate TNF and IFNα production. NanoString gene expression assay of total pDCs RNA was performed pre- and post- ODN stimulation. Pharmacological inhibition of induced IFNα protein was performed with Tofacitinib and PDE4 inhibition. The impact of SARS-CoV2 viral infection on PsA flares was evaluated. Results: CD45+HLA-DR+CD123+CD303+CD11c- entheseal pDCs were more numerous than blood pDCs (1.9 ± 0.8% vs 0.2 ± 0.07% of CD45+ cells, p=0.008) and showed inducible IFNα and TNF protein following ODN/imiquimod stimulation and were the sole entheseal IFNα producers. NanoString data identified 11 significantly upregulated differentially expressed genes (DEGs) including TNF in stimulated pDCs. Canonical pathway analysis revealed activation of dendritic cell maturation, NF-κB signaling, toll-like receptor signaling and JAK/STAT signaling pathways following ODN stimulation. Both tofacitinib and PDE4i strongly attenuated ODN induced IFNα. DAPSA scores elevations occurred in 18 PsA cases with SARS-CoV2 infection (9.7 ± 4 pre-infection and 35.3 ± 7.5 during infection). Conclusion: Entheseal pDCs link microbes to TNF/IFNα production. SARS-CoV-2 infection is associated with PsA Flares and JAK inhibition suppressed activated entheseal plasmacytoid dendritic Type-1 interferon responses as pointers towards a novel mechanism of PsA and SpA-related arthropathy.


Assuntos
Artrite Psoriásica/complicações , COVID-19/complicações , Células Dendríticas/metabolismo , Interferon-alfa/metabolismo , Janus Quinases/antagonistas & inibidores , Adjuvantes Imunológicos/farmacologia , Adulto , Idoso , COVID-19/genética , COVID-19/metabolismo , Biologia Computacional , Nucleotídeo Cíclico Fosfodiesterase do Tipo 4/metabolismo , Células Dendríticas/efeitos dos fármacos , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Regulação da Expressão Gênica/genética , Humanos , Imiquimode/farmacologia , Janus Quinases/metabolismo , Masculino , Pessoa de Meia-Idade , NF-kappa B/metabolismo , Oligonucleotídeos/farmacologia , Inibidores da Fosfodiesterase 4/farmacologia , Piperidinas/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Pirimidinas/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Receptor 7 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo , Transcriptoma , Fator de Necrose Tumoral alfa/metabolismo
14.
Front Immunol ; 12: 650708, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33927721

RESUMO

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) and a CD4+ T cell-mediated autoimmune disease. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is recognized as the major mechanism that regulates the differentiation and function of T helper (Th) 1 and Th17 cells, which are recognized as pivotal effector cells responsible for the development of EAE. We used baricitinib, a JAK 1/2 inhibitor, to investigate the therapeutic efficacy of inhibiting the JAK/STAT pathway in EAE mice. Our results showed that baricitinib significantly delayed the onset time, decreased the severity of clinical symptoms, shortened the duration of EAE, and alleviated demyelination and immune cell infiltration in the spinal cord. In addition, baricitinib treatment downregulated the proportion of interferon-γ+CD4+ Th1 and interleukin-17+CD4+ Th17 cells, decreased the levels of retinoic acid-related orphan receptor γ t and T-bet mRNA, inhibited lymphocyte proliferation, and decreased the expression of proinflammatory cytokines and chemokines in the spleen of mice with EAE. Furthermore, our results showed the role of baricitinib in suppressing the phosphorylation of STATs 1, 3, and 4 in the spleen of EAE mice. Therefore, our study demonstrates that baricitinib could potentially alleviate inflammation in mice with EAE and may be a promising candidate for treating MS.


Assuntos
Azetidinas/farmacologia , Encefalomielite Autoimune Experimental/prevenção & controle , Janus Quinases/antagonistas & inibidores , Purinas/farmacologia , Pirazóis/farmacologia , Fatores de Transcrição STAT/imunologia , Transdução de Sinais/efeitos dos fármacos , Sulfonamidas/farmacologia , Administração Oral , Animais , Azetidinas/administração & dosagem , Linfócitos T CD4-Positivos/efeitos dos fármacos , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/metabolismo , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Citocinas/imunologia , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/imunologia , Encefalomielite Autoimune Experimental/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Expressão Gênica/efeitos dos fármacos , Expressão Gênica/imunologia , Janus Quinases/imunologia , Janus Quinases/metabolismo , Camundongos Endogâmicos C57BL , Purinas/administração & dosagem , Pirazóis/administração & dosagem , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais/imunologia , Sulfonamidas/administração & dosagem
15.
Cells ; 10(5)2021 04 27.
Artigo em Inglês | MEDLINE | ID: mdl-33925695

RESUMO

Myelofibrosis is a myeloproliferative neoplasm characterized by splenomegaly, constitutional symptoms, bone marrow fibrosis, and a propensity towards transformation to acute leukemia. JAK inhibitors are the only approved therapy for myelofibrosis and have been successful in reducing spleen and symptom burden. However, they do not significantly impact disease progression and many patients are ineligible due to coexisting cytopenias. Patients who are refractory to JAK inhibition also have a dismal survival. Therefore, non-JAK inhibitor-based therapies are being explored in pre-clinical and clinical settings. In this review, we discuss novel treatments in development for myelofibrosis with targets outside of the JAK-STAT pathway. We focus on the mechanism, preclinical rationale, and available clinical efficacy and safety information of relevant agents including those that target apoptosis (navitoclax, KRT-232, LCL-161, imetelstat), epigenetic modulation (CPI-0610, bomedemstat), the bone marrow microenvironment (PRM-151, AVID-200, alisertib), signal transduction pathways (parsaclisib), and miscellaneous agents (tagraxofusp. luspatercept). We also provide commentary on the future of therapeutic development in myelofibrosis.


Assuntos
Mielofibrose Primária/tratamento farmacológico , Apoptose/efeitos dos fármacos , Apoptose/genética , Epigênese Genética/efeitos dos fármacos , Humanos , Janus Quinases/antagonistas & inibidores , Janus Quinases/metabolismo , Mielofibrose Primária/enzimologia , Mielofibrose Primária/genética , Mielofibrose Primária/patologia , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Transdução de Sinais/efeitos dos fármacos
16.
Eur J Immunol ; 51(7): 1615-1627, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33930196

RESUMO

The European Journal of Immunology was launched 50 years ago, coinciding with the discovery of many cytokines and growth factors and the emergence of an entirely new field of research. Ultimately, our knowledge about the biological activity of these factors allowed us to better understand how the immune system functions in the context of inflammatory and autoimmune diseases leading to the development of targeted biologic therapies. The study of cytokine signal transduction led to the discovery of Janus kinases (JAK), and the consideration of therapeutically targeting JAKs to treat immune and inflammatory diseases. This year also marks the tenth anniversary of the approval of the first JAK inhibitor (jakinib) and now there are a total of nine approved jakinibs for treatment of rheumatologic, dermatologic, gastrointestinal, and neoplastic indications and most recently COVID-19. Here, we summarized the discoveries that led to development of first-generation jakinibs, discussed some of the newer, possibly more selective jakinibs, as well as jakinibs that also target other kinases. We also illustrated the rationale behind the application of these drugs in the treatment of COVID-19 cytokine storm. In this review, we will discuss the clinical success of jakinibs, the gaps in our understanding of their biological activities as well as challenges in regard to their clinical application.


Assuntos
Doenças Autoimunes/tratamento farmacológico , COVID-19/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Hipersensibilidade/tratamento farmacológico , Inibidores de Janus Quinases/uso terapêutico , Síndrome da Liberação de Citocina/patologia , Citocinas/biossíntese , Citocinas/imunologia , Humanos , Janus Quinases/antagonistas & inibidores , SARS-CoV-2/efeitos dos fármacos , Transdução de Sinais/imunologia
17.
Pediatr Hematol Oncol ; 38(4): 331-345, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33661711

RESUMO

Ruxolitinib, a selective Janus Kinase (JAK) 1/2 inhibitor, is a promising treatment for the steroid-refractory graft-vs-host disease (GvHD) after hematopoietic stem cell transplantation (HSCT). Most studies have been performed in the adult population showing efficacy against GvHD. In this retrospective study, we evaluated the outcomes of 19 children who received ruxolitinib for refractory acute or chronic GvHD (cGvHD) after HSCT from two Pediatric Hemato-Oncology Departments in Spain between March 2017 and December 2018. Patients received a median number of 4 (IQR 2) previous lines of treatment before starting ruxolitinib. The overall response rate in acute GvHD (aGvHD) and cGvHD was 87% and 91%, respectively. Complete response (CR) was observed in 37% of aGvHD and 8.3% of cGvHD. Remarkably, 43% and 40% of patients with steroid-refractory gastrointestinal aGvHD and lung cGvHD achieved CR. During ruxolitinib treatment, there were 36%, 31%, and 10% infections caused by viruses, bacteria, and fungi, respectively. Overall, four patients interrupted ruxolitinib due to infectious complications, hematological, and liver toxicity. The 2-year overall survival was 71.9% (CI 95% 58.6-85.2). Our experience supports the use of ruxolitinib as an effective treatment for steroid-refractory acute and cGvHD in children with a moderate toxicity profile.


Assuntos
Doença Enxerto-Hospedeiro/tratamento farmacológico , Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Adolescente , Criança , Pré-Escolar , Feminino , Doença Enxerto-Hospedeiro/etiologia , Humanos , Lactente , Janus Quinases/antagonistas & inibidores , Masculino , Inibidores de Proteínas Quinases/efeitos adversos , Pirazóis/efeitos adversos , Estudos Retrospectivos , Resultado do Tratamento
19.
Int J Mol Sci ; 22(5)2021 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-33671049

RESUMO

Recent advances in immunology enabled the characterization of several signal transmitting pathways responsible for proper cytokine and chemokine signaling. Among them, Janus kinases (JAKs) are essential components of receptor activation systems. The discovery of JAK kinases enabled the synthesis of JAK kinase inhibitors (JAKi or Jakinibs), which have proven to be efficacious in the treatment of hematologic malignancies and several rheumatological disorders and continue to be investigated in many clinical indications. Blocking multiple cytokines belonging to several cytokine families with a single small molecule may, however, create a potential risk for the patients. Recently, a higher risk of thromboembolic complications, namely, deep vein thrombosis and pulmonary embolism, has been recognized as the main concern during treatment with Jakinibs. At present, it is not entirely clear whether this increased risk is related to direct cytokine blockade, the presence of concomitant diseases in treated patients or other unknown circumstances that work together to increase the risk of this side effect. In this review, we discuss data on the risk of thromboembolic side effects, with special emphasis on the mechanism that may be responsible for this increased risk. Many indirect data indicate that higher thromboembolic risk may be related to the specificity of JAK inhibitor action, such that preferentially blocking one signaling pathway upsets the balance between pro and anti-thrombotic activities.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Inibidores de Janus Quinases/efeitos adversos , Janus Quinases/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Tromboembolia/patologia , Animais , Artrite Reumatoide/enzimologia , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/etiologia , Humanos , Neoplasias/enzimologia , Transdução de Sinais , Tromboembolia/induzido quimicamente
20.
Eur J Haematol ; 106(5): 654-661, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33523540

RESUMO

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a cytokine storm syndrome associated with mortality rates of up to 88%. Standard therapy with high-dose glucocorticoids and etoposide used in adults is extrapolated from pediatric trials, with significant toxicity in older patients and those with poor performance status. The JAK1/2 inhibitor ruxolitinib has recently gained attention as a treatment option for HLH due to its broad cytokine-modulating abilities and safety profile. Herein we report our center's experience using ruxolitinib in the treatment of adult-onset secondary HLH. CASE SERIES: We report four patients with profound secondary HLH provoked by diverse triggers, including invasive pulmonary aspergillosis on background systemic lupus erythematosus, disseminated tuberculosis, and T-cell lymphoma treated with ruxolitinib as monotherapy or combination therapy in upfront and salvage settings. RESULTS: All four patients had rapid, sustained improvement in clinical status, inflammatory markers, and hematological cell counts followed by durable remission. Three patients developed manageable infectious complications postruxolitinib. CONCLUSIONS: This series demonstrates the effective use of JAK inhibition with ruxolitinib to control pathological immune activation in critically ill patients with secondary HLH and otherwise limited therapeutic options. JAK inhibition is also an area of urgent investigation for the treatment of cytokine storm associated with COVID-19.


Assuntos
Janus Quinases/antagonistas & inibidores , Linfo-Histiocitose Hemofagocítica/tratamento farmacológico , Inibidores de Proteínas Quinases/uso terapêutico , Pirazóis/uso terapêutico , Adulto , COVID-19/complicações , Terapia Combinada , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/etiologia , Citocinas/sangue , Feminino , Humanos , Aspergilose Pulmonar Invasiva/complicações , Lúpus Eritematoso Sistêmico/complicações , Linfo-Histiocitose Hemofagocítica/etiologia , Linfoma de Células T/complicações , Masculino , Pessoa de Meia-Idade , SARS-CoV-2 , Terapia de Salvação , Tuberculose/complicações , Adulto Jovem
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