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1.
Front Immunol ; 15: 1343362, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38327518

RESUMO

Introduction: Clinical remission (CliR) achievement has been recognized as a new potential outcome in severe asthma. Nevertheless, we still lack a detailed profile of what features could better identify patients undergoing clinical remission. In this study, we aim to address this issue, tracing a possible identikit of patients fulfilling remission criteria. Methods: We enrolled 266 patients with severe eosinophilic asthma (SEA) treated with a 12-month course of anti-IL5/IL5 receptor (IL5r) monoclonal antibodies. Patients with no exacerbation, OCS withdrawal, ACT ≥ 20 and FEV1 ≥ 80% after 1 year of biologic treatment were classified as in clinical remission. Results: 30.5% of the enrolled patients achieved remission after biologic administration. CliR group showed a lower number of baseline asthma exacerbations and better lung function parameters, with a trend for higher ACT scores and a less frequent history of a positive skin prick test. CliR achievement was unlikely in presence of a higher BMI, a positive skin prick test, an increased number of asthma exacerbations before biologic treatment, anti-muscarinic administration, and a previous diagnosis of EGPA, bronchiectasis or osteoporosis. In contrast, a better lung function, an increased blood eosinophilic count, the presence of chronic rhinosinusitis with nasal polyps and a more frequent use of reliever therapy predicts remission development. Changes in exacerbations number, OCS use, ACT scores and FEV1% between remittent and non-remittent patients arise at specific follow up timepoints and are positively associated with CliR achievement. Discussion: anti-IL5/IL5r biologics can induce CliR in a proportion of patients with SEA. Patients achieving remission demonstrate specific clinical, functional and inflammatory features, as well as a specific moment of improvement in all the CliR items.


Assuntos
Asma , Bronquiectasia , Pólipos Nasais , Osteoporose , Eosinofilia Pulmonar , Humanos , Asma/tratamento farmacológico , Receptores de Interleucina-5
2.
Eur J Pharmacol ; 965: 176331, 2024 Feb 15.
Artigo em Inglês | MEDLINE | ID: mdl-38220140

RESUMO

Inflammatory bowel disease (IBD) is a condition characterized by inflammation in the gastrointestinal tract. Reducing intestinal inflammation is a promising approach for treating IBD. The nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein 3 (NLRP3) inflammasome, a critical component of the innate immune system, is implicated in the pathogenesis of IBD. Therefore, inhibiting NLRP3 inflammasome activation is a potential therapeutic strategy for IBD. In this study, we investigated the effects of the interleukin-5 (IL-5) receptor antagonist YM-90709 on dextran sulfate sodium-induced experimental colitis in mice. We found that YM-90709 reduced the expressions of IL-1ß and caspase-1 p20 in the colon and ameliorated colitis. Furthermore, we identified YM-90709 as an effective agent for inhibiting NLRP3 inflammasome activation. Knockdown of IL-5 receptor or using an inhibitor of STAT5, a key transcription factor downstream of the IL-5/IL-5 receptor signal pathway, also reduced NLRP3 inflammasome-dependent IL-1ß release and ASC speck formation. Our study is the first to demonstrate that the NLRP3 inflammasome may be a downstream signal of IL-5/IL-5 receptor and that YM-90709 protects against IBD by inhibiting IL-5 receptor. These findings suggest a new strategy for regulating intestinal inflammation and managing IBD.


Assuntos
Colite , Doenças Inflamatórias Intestinais , Animais , Camundongos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Sulfato de Dextrana/toxicidade , Receptores de Interleucina-5 , Interleucina-5/efeitos adversos , Colite/induzido quimicamente , Colite/tratamento farmacológico , Inflamação , Caspase 1/metabolismo , Interleucina-1beta/metabolismo , Camundongos Endogâmicos C57BL
3.
Pulm Pharmacol Ther ; 84: 102286, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38191068

RESUMO

Pulmonary fibrosis is a progressive and debilitating lung disease characterized by the excessive accumulation of extracellular matrix (ECM) components within the lung parenchyma. However, the underlying mechanism remains largely elusive, and the treatment options available for pulmonary fibrosis are limited. Interleukin 5 receptor, alpha (IL5RA) is a well-established regulator of eosinophil activation, involved in eosinophil-mediated anti-parasitic activities and allergic reactions. Recent studies have indicated additional roles of IL5RA in lung epithelium and fibroblasts. Nevertheless, its involvement in pulmonary fibrosis remains unclear. In present study, we employed single-cell analyses alongside molecular and cellular assays to unveil the expression of IL5RA in lung epithelial cells. Moreover, using both in vitro and in vivo models, we demonstrated a notable upregulation of epithelial IL5RA during the progression of pulmonary fibrosis. This upregulated IL5RA expression subsequently promotes epithelial-mesenchymal transition (EMT), leading to the generation of mesenchymal phenotype with augmented capability for ECM production. Importantly, our findings uncovered that the pro-fibrotic function of IL5RA is mediated by Jak2/STAT3 signaling cascades. Inhibiting IL5RA has the potential to deactivate Jak2/STAT3 and suppress the downstream EMT process and ECM production, thereby offering a promising therapeutic strategy for pulmonary fibrosis.


Assuntos
Fibrose Pulmonar , Humanos , Transição Epitelial-Mesenquimal/fisiologia , Fibrose , Subunidade alfa de Receptor de Interleucina-5/metabolismo , Pulmão/metabolismo , Fibrose Pulmonar/metabolismo , Receptores de Interleucina-5/metabolismo , Fator de Transcrição STAT3/metabolismo
4.
Chem Biol Drug Des ; 103(1): e14387, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37926515

RESUMO

Human interleukin-5 (IL-5) functions as an important pro-inflammatory factor by binding to its specific receptor, IL-5Rα, which has been implicated in the pathogenesis of asthma. Previously, a disulfide-bonded cyclic peptide AF17121 obtained from random library screening and sequence variation was found to competitively disrupt the cognate IL-5Rα/IL-5 interaction with moderate potency. In this study, the crystal complex of IL-5Rα with AF17121 was investigated at structural and energetic levels. It is revealed that the side-chain indole moiety of the AF17121 Trp5 residue is a potential site for a stem putative halogen bond (X-bond) with IL-5Rα, which is just located within the key 3 EXXR6 motif region recognized specifically by IL-5Rα. We systematically examined four halogen substitution types at five positions of the indole moiety; QM/MM calculations theoretically unraveled that only halogenations at 5 and 6 positions can form effective X-bonds with the side-chain hydroxyl oxygen of the IL-5Rα Thr21 residue and the backbone carbonyl oxygen of Ala66 residue, respectively. Binding assays observed that I-substitution at the 5 position and Br-substitution at the 6 position can result in two potent halogenated peptides, [5I]AF17121 and [6Br]AF17121, which are improved by 1.6-fold and 3.5-fold relative to the native AF17121, respectively. 5I/6Br-double substitution, resulting in [5I/6Br]AF17121, can further enhance the peptide affinity by 7.5-fold. Structural analysis revealed that the X-bond stemming from 6Br-substitution is also involved in an orthogonal interaction system with a H-bond; they share a common backbone carbonyl oxygen acceptor of IL-5Rα Ala66 residue and exhibit a significant synergistic effect between them.


Assuntos
Asma , Peptídeos Cíclicos , Humanos , Receptores de Interleucina-5 , Peptídeos Cíclicos/química , Interleucina-5/metabolismo , Halogênios/química , Ligantes , Peptídeos/química , Indóis , Oxigênio
5.
Thorax ; 78(11): 1138-1141, 2023 11.
Artigo em Inglês | MEDLINE | ID: mdl-37657926

RESUMO

Several clinical trials have demonstrated that anti-IL-5(R) biologics were able to improve lung function, asthma control and chronic oral corticosteroid exposure and reduce exacerbations among eosinophilic asthmatic patients. However, a certain variability in clinical responses to anti-IL-5(R) biologics was brought to light. Our study aimed at evaluating the role of baseline sputum eosinophils in identifying super-responders to mepolizumab and benralizumab. Our study reinforces the importance to examine sputum eosinophils in patients suffering from severe asthma before starting a biologic as it is associated with the intensity of response to mepolizumab and benralizumab.


Assuntos
Antiasmáticos , Asma , Produtos Biológicos , Eosinofilia , Humanos , Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Eosinófilos , Escarro , Interleucina-5/antagonistas & inibidores , Interleucina-5/imunologia , Receptores de Interleucina-5/antagonistas & inibidores , Receptores de Interleucina-5/imunologia
6.
Int J Mol Sci ; 24(3)2023 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-36768778

RESUMO

Add-on biological therapy has proven to be effective in many patients with severe eosinophilic asthma. In this observational multicenter retrospective study, we report the results obtained with mepolizumab and benralizumab in severe asthmatics treated for 12 months in a real-life setting. In these patients, peripheral eosinophil levels, pulmonary function trends, exacerbation rates, systemic corticosteroid use, and symptom control were evaluated during the observation period, to understand which patients met all the criteria in order to be considered in disease remission. The percentage of remittent patients was 30.12% in the mepolizumab-treated subgroup, while in the benralizumab-treated subgroup, patients in complete disease remission were 40%, after 12 months. The results of this study confirm the efficacy of anti-IL-5 biologic drugs in the treatment of severe eosinophilic asthma in a real-life setting.


Assuntos
Antiasmáticos , Asma , Produtos Biológicos , Eosinofilia Pulmonar , Humanos , Antiasmáticos/farmacologia , Antiasmáticos/uso terapêutico , Produtos Biológicos/uso terapêutico , Interleucina-5 , Estudos Retrospectivos , Receptores de Interleucina-5/metabolismo
9.
Vet J ; 288: 105896, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-36126798

RESUMO

Previously, virus-like particle (VLP)-based self-vaccinations targeting interleukin (IL)-5 or IL-31 have been suggested to treat equine insect bite hypersensitivity (IBH), a seasonal recurrent allergic dermatitis in horses. The IL-5-targeting equine vaccine significantly reduced blood eosinophil counts in horses, similar to human monoclonal antibodies targeting IL-5 or the IL-5 receptor alpha (IL-5Rα). Previous studies in humans have also reported an additional effect on reduction of basophil counts. The aim of the present study was to evaluate whether an equine anti-IL-5 vaccine affected blood basophil counts. Horses with IBH were followed in a 3-year trial consisting of a placebo administered in the 1st year, followed by vaccination using an equine (e)IL-5-VLP vaccine in the 2nd and 3rd years. There was a strong reduction in circulating eosinophil counts after vaccination against IL-5. Additionally, there were reduced basophil counts, but only in the 3rd year of the study, suggesting a bystander effect of the anti-IL-5 vaccine on basophil counts.


Assuntos
Eosinófilos , Doenças dos Cavalos , Hipersensibilidade , Mordeduras e Picadas de Insetos , Interleucina-5 , Animais , Anticorpos Monoclonais , Basófilos , Doenças dos Cavalos/terapia , Cavalos , Hipersensibilidade/veterinária , Mordeduras e Picadas de Insetos/veterinária , Receptores de Interleucina-5 , Vacinação/veterinária
12.
Arerugi ; 71(3): 242-247, 2022.
Artigo em Japonês | MEDLINE | ID: mdl-35569946

RESUMO

Eosinophilic granulomatosis with polyangiitis (EGPA) is a type of ANCA-related vasculitis. Asthma and sinusitis occur first in the course of EGPA, followed by vasculitis symptoms such as fever, weight loss, and peripheral neuropathy. Otitis media with effusion and sensorineural hearing loss occur occasionally in EGPA patients. Here we report a case of a 39-years-old female patient with asthma that developed at age 37 and sinusitis. The patient was diagnosed with EGPA and treatment was started with oral corticosteroids. During the course of treatment, otitis media with effusion and sensorineural hearing loss developed. Benralizumab was administered for severe asthma. After treatment with benralizumab, the symptoms of asthma, otitis media with effusion and sinusitis dramatically improved. This is the first reported case in which benralizumab was used for treating otitis media and sinusitis associated with EGPA. The findings suggest that benralizumab may be effective for otitis media and sinusitis associated with EGPA.


Assuntos
Asma , Síndrome de Churg-Strauss , Granulomatose com Poliangiite , Perda Auditiva Neurossensorial , Otite Média com Derrame , Otite Média , Sinusite , Adulto , Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/complicações , Asma/tratamento farmacológico , Síndrome de Churg-Strauss/complicações , Feminino , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/diagnóstico , Granulomatose com Poliangiite/tratamento farmacológico , Perda Auditiva Neurossensorial/complicações , Humanos , Otite Média/complicações , Otite Média com Derrame/complicações , Otite Média com Derrame/tratamento farmacológico , Receptores de Interleucina-5 , Sinusite/complicações , Sinusite/tratamento farmacológico
13.
Infect Immun ; 90(5): e0031721, 2022 05 19.
Artigo em Inglês | MEDLINE | ID: mdl-35467360

RESUMO

A molecule we termed Brugia malayi IL-5 receptor (IL-5R) binding protein (BmIL5Rbp; also known as Bm8757) was identified from B. malayi filarial worms and found to inhibit human interleukin-5 (IL-5) binding to its human receptor competitively. After the expression and purification of a recombinant BmIL5Rbp and generation of BmIL5Rbp-specific rabbit antibody, we localized the molecule on B. malayi worms through immunohistochemistry and immunoelectron microscopy. RNA interference (RNAi) was used to inhibit BmIL5Rbp mRNA and protein production. BmIL5Rbp was shown to localize to the cuticle of Brugia malayi and to be released in its excretory/secretory products. RNAi inhibited BmIL5Rbp mRNA production by 33%, reduced the surface protein expression by ~50%, and suppressed the release of BmIL5Rbp in the excretory/secretory products. RNAi has been used successfully to knock down the mRNA and protein expression of BmIL5Rbp in the early larval stages of B. malayi and provided a proof of principle for the local inhibition of the human IL-5R. These findings provide evidence that a parasite-encoded IL-5R antagonist may locally inhibit a vital host innate immune activation of IL-5 on eosinophils.


Assuntos
Brugia Malayi , Animais , Brugia Malayi/genética , Interleucina-5/genética , Interferência de RNA , RNA Mensageiro/metabolismo , Coelhos , Receptores de Interleucina-5/genética , Receptores de Interleucina-5/metabolismo
14.
Cell Death Dis ; 13(2): 137, 2022 02 10.
Artigo em Inglês | MEDLINE | ID: mdl-35145069

RESUMO

Acute respiratory distress syndrome (ARDS) is triggered by various aetiological factors such as trauma, sepsis and respiratory viruses including SARS-CoV-2 and influenza A virus. Immune profiling of severe COVID-19 patients has identified a complex pattern of cytokines including granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-5, which are significant mediators of viral-induced hyperinflammation. This strong response has prompted the development of therapies that block GM-CSF and other cytokines individually to limit inflammation related pathology. The common cytokine binding site of the human common beta (ßc) receptor signals for three inflammatory cytokines: GM-CSF, IL-5 and IL-3. In this study, ßc was targeted with the monoclonal antibody (mAb) CSL311 in engineered mice devoid of mouse ßc and ßIL-3 and expressing human ßc (hßcTg mice). Direct pulmonary administration of lipopolysaccharide (LPS) caused ARDS-like lung injury, and CSL311 markedly reduced lung inflammation and oedema, resulting in improved oxygen saturation levels in hßcTg mice. In a separate model, influenza (HKx31) lung infection caused viral pneumonia associated with a large influx of myeloid cells into the lungs of hßcTg mice. The therapeutic application of CSL311 potently decreased accumulation of monocytes/macrophages, neutrophils, and eosinophils without altering lung viral loads. Furthermore, CSL311 treatment did not limit the viral-induced expansion of NK and NKT cells, or the tissue expression of type I/II/III interferons needed for efficient viral clearance. Simultaneously blocking GM-CSF, IL-5 and IL-3 signalling with CSL311 may represent an improved and clinically applicable strategy to reducing hyperinflammation in the ARDS setting.


Assuntos
Subunidade beta Comum dos Receptores de Citocinas/genética , Subunidade beta Comum dos Receptores de Citocinas/fisiologia , Síndrome do Desconforto Respiratório/imunologia , Animais , Anticorpos Monoclonais/imunologia , Subunidade beta Comum dos Receptores de Citocinas/imunologia , Citocinas , Eosinófilos/imunologia , Feminino , Humanos , Imunidade/genética , Imunidade/fisiologia , Inflamação/imunologia , Leucócitos/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Neutrófilos/metabolismo , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos , Receptores de Interleucina-3 , Receptores de Interleucina-5 , Síndrome do Desconforto Respiratório/fisiopatologia
15.
Front Immunol ; 12: 714838, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34912327

RESUMO

CD4+CD25+Foxp3+T cell population is heterogenous and contains three major sub-groups. First, thymus derived T regulatory cells (tTreg) that are naïve/resting. Second, activated/memory Treg that are produced by activation of tTreg by antigen and cytokines. Third, effector lineage CD4+CD25+T cells generated from CD4+CD25- T cells' activation by antigen to transiently express CD25 and Foxp3. We have shown that freshly isolated CD4+CD25+T cells are activated by specific alloantigen and IL-4, not IL-2, to Ts2 cells that express the IL-5 receptor alpha. Ts2 cells are more potent than naïve/resting tTreg in suppressing specific alloimmunity. Here, we showed rIL-5 promoted further activation of Ts2 cells to Th2-like Treg, that expressed foxp3, irf4, gata3 and il5. In vivo, we studied the effects of rIL-5 treatment on Lewis heart allograft survival in F344 rats. Host CD4+CD25+T cells were assessed by FACS, in mixed lymphocyte culture and by RT-PCR to examine mRNA of Ts2 or Th2-like Treg markers. rIL-5 treatment given 7 days after transplantation reduced the severity of rejection and all grafts survived ≥60d whereas sham treated rats fully rejected by day 31 (p<0.01). Treatment with anti-CD25 or anti-IL-4 monoclonal antibody abolished the benefits of treatment with rIL-5 and accelerated rejection. After 10d treatment with rIL-5, hosts' CD4+CD25+ cells expressed more Il5ra and responded to specific donor Lewis but not self. Enriched CD4+CD25+ cells from rIL-5 treated rats with allografts surviving >60 days proliferated to specific donor only when rIL-5 was present and did not proliferate to self or third party. These cells had more mRNA for molecules expressed by Th2-like Treg including Irf4, gata3 and Il5. These findings were consistent with IL-5 treatment preventing rejection by activation of Ts2 cells and Th2-like Treg.


Assuntos
Rejeição de Enxerto/imunologia , Interleucina-5/farmacologia , Ativação Linfocitária/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Aloenxertos , Animais , Transplante de Coração/efeitos adversos , Ratos , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Receptores de Interleucina-5/imunologia
16.
Intern Med ; 60(22): 3631-3634, 2021 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-34092731

RESUMO

Eosinophilic granulomatosis with polyangiitis (EGPA) is an anti-neutrophilic cytoplasm antibody (ANCA)-associated vasculitis characterized by asthma and eosinophilia. Although EGPA involves multiple organs, ocular involvement is infrequent and often carries a poor visual prognosis. We herein report a rare case of EGPA presenting with central retinal artery occlusion (CRAO) in which visual loss developed during treatment with anti-interleukin (IL)-5 receptor monoclonal antibody, and improvement in visual outcomes was attained after treatment combining high-dose oral corticosteroids, cyclophosphamide and an anticoagulant. Physicians should consider CRAO as an ophthalmic manifestation of EGPA in patients with severe eosinophilic asthma.


Assuntos
Síndrome de Churg-Strauss , Granulomatose com Poliangiite , Oclusão da Artéria Retiniana , Anticorpos Monoclonais , Síndrome de Churg-Strauss/complicações , Síndrome de Churg-Strauss/diagnóstico , Síndrome de Churg-Strauss/tratamento farmacológico , Humanos , Receptores de Interleucina-5 , Oclusão da Artéria Retiniana/induzido quimicamente , Oclusão da Artéria Retiniana/diagnóstico , Oclusão da Artéria Retiniana/tratamento farmacológico
17.
Int J Mol Sci ; 22(8)2021 Apr 12.
Artigo em Inglês | MEDLINE | ID: mdl-33921360

RESUMO

Severe asthma greatly affects patients' quality of life. Major advances have occurred in the management of severe eosinophilic asthma the past few years due to the new targeted biological therapies. There are three anti-IL-5 mAbs, mepolizumab, reslizumab and benralizumab. Despite the different mechanism of blocking IL-5 the clinical effects are quite similar as randomized controlled trials and real-life studies have shown. Moreover, there are reports of responding to one after failing to respond to another anti-IL-5 therapy. Accordingly, it is challenging to explore the possible differences in the response to anti-IL-5 treatments. This might help us not only understand possible mechanisms that contribute to the resistance to treatment in this particular asthma endotype, but also to phenotype within severe eosinophilic asthma in order to treat our patients more efficiently.


Assuntos
Antiasmáticos/uso terapêutico , Asma/tratamento farmacológico , Interleucina-5/genética , Receptores de Interleucina-5/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Asma/genética , Asma/patologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/patologia , Humanos , Interleucina-5/antagonistas & inibidores , Receptores de Interleucina-5/antagonistas & inibidores , Transdução de Sinais/efeitos dos fármacos
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