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1.
Nat Commun ; 15(1): 5056, 2024 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-38871792

RESUMO

Type 2 innate lymphoid cells (ILC2) initiate early allergic inflammation in the lung, but the factors that promote subsequent resolution of type 2 inflammation and prevent prolonged ILC2 activation are not fully known. Here we show that SLAM-family receptors (SFR) play essential roles in this process. We demonstrate dynamic expression of several SFRs on ILC2s during papain-induced type 2 immunity in mice. SFR deficiency exacerbates ILC2-driven eosinophil infiltration in the lung, and results in a significant increase in IL-13 production by ILC2s exclusively in mediastinal lymph nodes (MLN), leading to increased dendritic cell (DC) and TH2 cell numbers. In MLNs, we observe more frequent interaction between ILC2s and bystander T cells, with T cell-expressed SFRs (especially SLAMF3 and SLAMF5) acting as self-ligands to suppress IL-13 production by ILC2s. Mechanistically, homotypic engagement of SFRs at the interface between ILC2s and T cells delivers inhibitory signaling primarily mediated by SHIP-1. This prevents activation of NF-κB, driven by IL-7 and IL-33, two major drivers of ILC2-mediated type 2 immunity. Thus, our study shows that an ILC2-DC-TH2 regulatory axis may promote the resolution of pulmonary type 2 immune responses, and highlights SLAMF3/SLAMF5 as potential therapeutic targets for ameliorating type 2 immunity.


Assuntos
Imunidade Inata , Inflamação , Pulmão , Linfócitos , Camundongos Endogâmicos C57BL , Família de Moléculas de Sinalização da Ativação Linfocitária , Animais , Camundongos , Inflamação/imunologia , Inflamação/metabolismo , Linfócitos/imunologia , Linfócitos/metabolismo , Pulmão/imunologia , Pulmão/patologia , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Papaína , Células Th2/imunologia , Interleucina-13/metabolismo , Interleucina-13/imunologia , Linfonodos/imunologia , Linfonodos/metabolismo , Interleucina-33/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Camundongos Knockout , Transdução de Sinais , NF-kappa B/metabolismo
2.
Biomed Res ; 45(3): 115-123, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38839354

RESUMO

Mixed lymphocyte culture under the blockade of CD80/CD86-CD28 co-stimulation induces anergic (completely hyporesponsive) T cells with immune suppressive function (inducible suppressing T cells: iTS cells). Previously, iTS cell therapy has demonstrated outstanding benefits in clinical trials for organ transplantation. Here, we examined whether peptide antigen-specific iTS cells are inducible. DO 11.10 iTS cells were obtained from splenocytes of BALB/c DO 11.10 mice by stimulation with OVA peptide and antagonistic anti-CD80/CD86 mAbs. When DO 11.10 iTS or Foxp3- DO 11.10 iTS cells were stimulated with OVA, these cells produced IL-13, but not IL-4. DO 11.10 iTS cells decreased IL-4 and increased IL-13 production from OVA-stimulated naïve DO 11.10 splenocytes. When Foxp3+ DO 11.10 iTS cells were prepared, these cells significantly inhibited the production of IL-4 and IL-13 compared with freshly isolated Foxp3+ DO 11.10 T cells. Moreover, an increase in the population expressing OX40, ICOS, and 4-1BB suggested activation of Foxp3+ DO 11.10 iTS cells. Thus, blockade of CD80/CD86-CD28 co-stimulation during peptide antigen stimulation augments the inhibitory function of Foxp3+ regulatory T cells, and does not induce anergic Foxp3- conventional T cells. Peptide-specific Foxp3+ regulatory iTS cells could be useful for the treatment of allergic and autoimmune diseases without adverse effects.


Assuntos
Antígeno B7-1 , Antígeno B7-2 , Antígenos CD28 , Linfócitos T Reguladores , Animais , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Antígenos CD28/imunologia , Antígenos CD28/metabolismo , Camundongos , Antígeno B7-1/metabolismo , Antígeno B7-1/imunologia , Antígeno B7-2/metabolismo , Antígeno B7-2/imunologia , Camundongos Endogâmicos BALB C , Fatores de Transcrição Forkhead/metabolismo , Peptídeos/farmacologia , Peptídeos/imunologia , Ativação Linfocitária/imunologia , Interleucina-4/metabolismo , Interleucina-4/imunologia , Interleucina-13/metabolismo , Interleucina-13/imunologia , Ovalbumina/imunologia , Baço/imunologia , Baço/citologia , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/imunologia
3.
Clin Transl Sci ; 17(6): e13864, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38924698

RESUMO

Lunsekimig is a novel, bispecific NANOBODY® molecule that inhibits both thymic stromal lymphopoietin (TSLP) and interleukin (IL)-13, two key mediators of asthma pathophysiology. In this first-in-human study, we evaluated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of lunsekimig in healthy adult participants. Participants received single ascending doses (SAD) of lunsekimig (10-400 mg intravenous [IV] or 400 mg subcutaneous [SC]) (SAD part) or multiple ascending doses (MAD part) of lunsekimig (100 or 200 mg, every 2 weeks [Q2W] for three SC doses), or placebo. Overall, 48 participants were randomized 3:1 in the SAD part and 4:1 in the MAD part for lunsekimig or placebo. The primary endpoint was safety and tolerability. The secondary endpoints included PK, antidrug antibodies (ADAs) and total target measurement. Lunsekimig was well tolerated and common treatment-emergent adverse events were COVID-19, nasopharyngitis, injection site reactions, and headache. Lunsekimig showed dose-proportional increases in exposure and linear elimination. Mean t1/2z of lunsekimig was around 10 days across all IV and SC doses of the SAD and MAD parts of the study. Increases in the serum concentration of total TSLP and IL-13 for lunsekimig versus placebo indicated target engagement. ADA of low titers were detected in four (11.1%) participants who received lunsekimig in the SAD, and seven (43.8%) in the MAD. In conclusion, lunsekimig was well tolerated in healthy participants with a linear PK profile up to single 400 mg IV and SC dose and multiple doses of 100 and 200 mg SC Q2W, with low immunogenicity.


Assuntos
Citocinas , Voluntários Saudáveis , Interleucina-13 , Anticorpos de Domínio Único , Linfopoietina do Estroma do Timo , Humanos , Adulto , Masculino , Feminino , Interleucina-13/antagonistas & inibidores , Interleucina-13/imunologia , Anticorpos de Domínio Único/administração & dosagem , Anticorpos de Domínio Único/imunologia , Anticorpos de Domínio Único/efeitos adversos , Pessoa de Meia-Idade , Citocinas/imunologia , Citocinas/sangue , Adulto Jovem , Injeções Subcutâneas , Método Duplo-Cego , Relação Dose-Resposta a Droga , Esquema de Medicação
4.
Pediatr Allergy Immunol ; 35(6): e14181, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38934228

RESUMO

Atopic dermatitis (AD) is still a demanding challenge in clinical practice. Type 2 inflammation is the most common inflammatory pathway in children and adolescents with AD. Anti-inflammatory drugs, mainly corticosteroids (CS) and immunomodulant agents are the primary therapeutic approach to dampening type 2 inflammation. However, AD patients may require long-term high CS doses or drug combinations with possibly significant adverse effects to achieve and maintain disease control. In this regard, the advent of biologics constituted a breakthrough in managing this condition. Dupilumab is a monoclonal antibody directed against the IL-4 receptor α-subunit (IL-4Rα), antagonizing both IL-4 and IL-13 and is approved for pediatric severe AD. This review presents and discusses the most recent published studies on dupilumab in children and adolescents with AD. There is convincing evidence that dupilumab is safe and effective in managing AD. It can reduce skin lesions and associated itching, reduce the need for additional medications, and improve disease control and quality of life. However, a thorough diagnostic pathway is mandatory, especially considering the different AD phenotypes. The ideal eligible candidate is a child or adolescent with AD requiring systemic treatment because of severe clinical manifestations and impaired quality of life.


Assuntos
Anticorpos Monoclonais Humanizados , Dermatite Atópica , Humanos , Dermatite Atópica/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Adolescente , Criança , Subunidade alfa de Receptor de Interleucina-4/antagonistas & inibidores , Subunidade alfa de Receptor de Interleucina-4/imunologia , Índice de Gravidade de Doença , Interleucina-4/antagonistas & inibidores , Interleucina-4/imunologia , Qualidade de Vida , Interleucina-13/antagonistas & inibidores , Interleucina-13/imunologia , Resultado do Tratamento
5.
Front Immunol ; 15: 1356298, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38690264

RESUMO

Chronic rhinosinusitis with nasal polyps (CRSwNP) is predominantly a type 2 inflammatory disease associated with type 2 (T2) cell responses and epithelial barrier, mucociliary, and olfactory dysfunction. The inflammatory cytokines interleukin (IL)-4, IL-13, and IL-5 are key mediators driving and perpetuating type 2 inflammation. The inflammatory responses driven by these cytokines include the recruitment and activation of eosinophils, basophils, mast cells, goblet cells, M2 macrophages, and B cells. The activation of these immune cells results in a range of pathologic effects including immunoglobulin E production, an increase in the number of smooth muscle cells within the nasal mucosa and a reduction in their contractility, increased deposition of fibrinogen, mucus hyperproduction, and local edema. The cytokine-driven structural changes include nasal polyp formation and nasal epithelial tissue remodeling, which perpetuate barrier dysfunction. Type 2 inflammation may also alter the availability or function of olfactory sensory neurons contributing to loss of sense of smell. Targeting these key cytokine pathways has emerged as an effective approach for the treatment of type 2 inflammatory airway diseases, and a number of biologic agents are now available or in development for CRSwNP. In this review, we provide an overview of the inflammatory pathways involved in CRSwNP and describe how targeting key drivers of type 2 inflammation is an effective therapeutic option for patients.


Assuntos
Interleucina-13 , Interleucina-4 , Pólipos Nasais , Rinite , Sinusite , Humanos , Sinusite/imunologia , Sinusite/metabolismo , Pólipos Nasais/imunologia , Pólipos Nasais/metabolismo , Rinite/imunologia , Rinite/metabolismo , Doença Crônica , Interleucina-13/metabolismo , Interleucina-13/imunologia , Interleucina-4/metabolismo , Interleucina-4/imunologia , Transdução de Sinais , Inflamação/imunologia , Inflamação/metabolismo , Animais , Mucosa Nasal/imunologia , Mucosa Nasal/metabolismo , Mucosa Nasal/patologia , Rinossinusite
6.
Immunity ; 57(6): 1260-1273.e7, 2024 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-38744292

RESUMO

Upon parasitic helminth infection, activated intestinal tuft cells secrete interleukin-25 (IL-25), which initiates a type 2 immune response during which lamina propria type 2 innate lymphoid cells (ILC2s) produce IL-13. This causes epithelial remodeling, including tuft cell hyperplasia, the function of which is unknown. We identified a cholinergic effector function of tuft cells, which are the only epithelial cells that expressed choline acetyltransferase (ChAT). During parasite infection, mice with epithelial-specific deletion of ChAT had increased worm burden, fitness, and fecal egg counts, even though type 2 immune responses were comparable. Mechanistically, IL-13-amplified tuft cells release acetylcholine (ACh) into the gut lumen. Finally, we demonstrated a direct effect of ACh on worms, which reduced their fecundity via helminth-expressed muscarinic ACh receptors. Thus, tuft cells are sentinels in naive mice, and their amplification upon helminth infection provides an additional type 2 immune response effector function.


Assuntos
Acetilcolina , Mucosa Intestinal , Animais , Acetilcolina/metabolismo , Camundongos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/parasitologia , Colina O-Acetiltransferase/metabolismo , Interleucina-13/metabolismo , Interleucina-13/imunologia , Camundongos Knockout , Camundongos Endogâmicos C57BL , Helmintíase/imunologia , Helmintíase/parasitologia , Células Epiteliais/imunologia , Células Epiteliais/metabolismo , Imunidade Inata , Nematospiroides dubius/imunologia , Células em Tufo
7.
Nat Immunol ; 25(6): 1059-1072, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38802511

RESUMO

Asthma, the most prevalent respiratory disease, affects more than 300 million people and causes more than 250,000 deaths annually. Type 2-high asthma is characterized by interleukin (IL)-5-driven eosinophilia, along with airway inflammation and remodeling caused by IL-4 and IL-13. Here we utilize IL-5 as the targeting domain and deplete BCOR and ZC3H12A to engineer long-lived chimeric antigen receptor (CAR) T cells that can eradicate eosinophils. We call these cells immortal-like and functional IL-5 CAR T cells (5TIF) cells. 5TIF cells were further modified to secrete an IL-4 mutein that blocks IL-4 and IL-13 signaling, designated as 5TIF4 cells. In asthma models, a single infusion of 5TIF4 cells in fully immunocompetent mice, without any conditioning regimen, led to sustained repression of lung inflammation and alleviation of asthmatic symptoms. These data show that asthma, a common chronic disease, can be pushed into long-term remission with a single dose of long-lived CAR T cells.


Assuntos
Asma , Receptores de Antígenos Quiméricos , Animais , Asma/imunologia , Asma/terapia , Camundongos , Receptores de Antígenos Quiméricos/imunologia , Receptores de Antígenos Quiméricos/genética , Receptores de Antígenos Quiméricos/metabolismo , Imunoterapia Adotiva/métodos , Linfócitos T/imunologia , Interleucina-5/imunologia , Interleucina-5/metabolismo , Modelos Animais de Doenças , Humanos , Interleucina-4/imunologia , Interleucina-4/metabolismo , Camundongos Endogâmicos C57BL , Eosinófilos/imunologia , Feminino , Interleucina-13/metabolismo , Interleucina-13/imunologia
8.
J Food Sci ; 89(5): 3037-3047, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38563099

RESUMO

Bovine casein is a major allergen present in cow milk to induce anaphylaxis. In this study, the potential allergenicity of enzymatically hydrolyzed casein (HC) was evaluated based on in vitro and in vivo. The results showed that Alcalase and Protamex treatment (AT, PT) reduced the potential allergenicity of CN, with the greatest reductions of 68.25% and 50.75%, respectively. In addition, in vivo results showed that HC effectively alleviated allergic response symptoms of Balb/c mice; a significant tendency toward decreased serum IgG1 and mast cell tryptase levels was observed, accompanied by a decrease of Th2-associated IL-4, IL-5, and IL-13 and an increase of IFN-γ levels in spleen. Moreover, the inflammation of the lung, jejunum, and ileum was remarkably ameliorated. The findings indicated that HC induced a shift toward Th1 response and maintained the Th1/Th2 immune balance. Importantly, our results provide the basis for the production of hypoallergenic dairy products.


Assuntos
Alérgenos , Caseínas , Camundongos Endogâmicos BALB C , Células Th2 , Animais , Camundongos , Caseínas/imunologia , Alérgenos/imunologia , Feminino , Células Th2/imunologia , Hidrólise , Imunoglobulina G/sangue , Modelos Animais de Doenças , Bovinos , Baço/imunologia , Hipersensibilidade a Leite/imunologia , Interferon gama/metabolismo , Células Th1/imunologia , Interleucina-4/metabolismo , Triptases/metabolismo , Citocinas/metabolismo , Jejuno/imunologia , Leite/imunologia , Leite/química , Interleucina-13/imunologia , Interleucina-13/metabolismo , Anafilaxia/imunologia , Anafilaxia/induzido quimicamente , Anafilaxia/prevenção & controle , Interleucina-5/imunologia
9.
J Allergy Clin Immunol ; 153(5): 1355-1368, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38310974

RESUMO

BACKGROUND: Eosinophilic esophagitis (EoE) is an increasingly common inflammatory condition of the esophagus; however, the underlying immunologic mechanisms remain poorly understood. The epithelium-derived cytokine IL-33 is associated with type 2 immune responses and elevated in esophageal biopsy specimens from patients with EoE. OBJECTIVE: We hypothesized that overexpression of IL-33 by the esophageal epithelium would promote the immunopathology of EoE. METHODS: We evaluated the functional consequences of esophageal epithelial overexpression of a secreted and active form of IL-33 in a novel transgenic mouse, EoE33. EoE33 mice were analyzed for clinical and immunologic phenotypes. Esophageal contractility was assessed. Epithelial cytokine responses were analyzed in three-dimensional organoids. EoE33 phenotypes were further characterized in ST2-/-, eosinophil-deficient, and IL-13-/- mice. Finally, EoE33 mice were treated with dexamethasone. RESULTS: EoE33 mice displayed ST2-dependent, EoE-like pathology and failed to thrive. Esophageal tissue remodeling and inflammation included basal zone hyperplasia, eosinophilia, mast cells, and TH2 cells. Marked increases in levels of type 2 cytokines, including IL-13, and molecules associated with immune responses and tissue remodeling were observed. Esophageal organoids suggested reactive epithelial changes. Genetic deletion of IL-13 in EoE33 mice abrogated pathologic changes in vivo. EoE33 mice were responsive to steroids. CONCLUSIONS: IL-33 overexpression by the esophageal epithelium generated immunopathology and clinical phenotypes resembling human EoE. IL-33 may play a pivotal role in the etiology of EoE by activating the IL-13 pathway. EoE33 mice are a robust experimental platform for mechanistic investigation and translational discovery.


Assuntos
Esofagite Eosinofílica , Interleucina-13 , Interleucina-33 , Animais , Humanos , Camundongos , Modelos Animais de Doenças , Esofagite Eosinofílica/imunologia , Esofagite Eosinofílica/genética , Esofagite Eosinofílica/patologia , Eosinófilos/imunologia , Mucosa Esofágica/patologia , Mucosa Esofágica/imunologia , Esôfago/patologia , Esôfago/imunologia , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/metabolismo , Interleucina-13/genética , Interleucina-13/imunologia , Interleucina-13/metabolismo , Interleucina-33/genética , Interleucina-33/imunologia , Interleucina-33/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos
10.
J Asthma ; 61(7): 762-765, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38152869

RESUMO

INTRODUCTION: Interleukin (IL)-4 and IL-13 are considered key drivers of type 2 inflammatory diseases. Dupilumab is a fully human monoclonal antibody that blocks the shared receptor component for IL-4 and IL-13, thus inhibiting signaling of both cytokines. CASE STUDY: We report a case of a patient with uncontrolled severe asthma and other T2 inflammatory diseases (atopic dermatitis, chronic rhinosinusitis with nasal polyposis and eosinophilic esophagitis) treated with dupilumab. RESULTS: After one year of treatment, dupilumab improved asthma control together with lung function parameters and airway inflammation. Additionally, a positive impact on quality of life (QoL), evaluated by validated questionnaires, across all the diseases was observed. CONCLUSION: In this case report, a positive and objectively measurable of global improvement on QoL across all four T2 comorbidities was observed after treatment with dupilumab, demonstrating the important role of IL-4 and IL-13 and the existence of a unifying pathological mechanism in T2 diseases.


Assuntos
Anticorpos Monoclonais Humanizados , Asma , Dermatite Atópica , Esofagite Eosinofílica , Pólipos Nasais , Qualidade de Vida , Rinite , Sinusite , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Sinusite/tratamento farmacológico , Sinusite/complicações , Pólipos Nasais/tratamento farmacológico , Pólipos Nasais/complicações , Pólipos Nasais/imunologia , Asma/tratamento farmacológico , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/complicações , Rinite/tratamento farmacológico , Esofagite Eosinofílica/tratamento farmacológico , Doença Crônica , Masculino , Interleucina-13/antagonistas & inibidores , Interleucina-13/imunologia , Multimorbidade , Interleucina-4/antagonistas & inibidores , Interleucina-4/imunologia , Adulto , Feminino , Rinossinusite
11.
N Engl J Med ; 388(12): 1080-1091, 2023 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-36920778

RESUMO

BACKGROUND: Lebrikizumab, a high-affinity IgG4 monoclonal antibody targeting interleukin-13, prevents the formation of the interleukin-4Rα-interleukin-13Rα1 heterodimer receptor signaling complex. METHODS: We conducted two identically designed, 52-week, randomized, double-blind, placebo-controlled, phase 3 trials; both trials included a 16-week induction period and a 36-week maintenance period. Eligible patients with moderate-to-severe atopic dermatitis (adults [≥18 years of age] and adolescents [12 to <18 years of age, weighing ≥40 kg]) were randomly assigned in a 2:1 ratio to receive either lebrikizumab at a dose of 250 mg (loading dose of 500 mg at baseline and week 2) or placebo, administered subcutaneously every 2 weeks. Outcomes for the induction period were assessed up to 16 weeks and are included in this report. The primary outcome was an Investigator's Global Assessment (IGA) score of 0 or 1 (indicating clear or almost clear skin; range, 0 to 4 [severe disease]) with a reduction (indicating improvement) of at least 2 points from baseline at week 16. Secondary outcomes included a 75% improvement in the Eczema Area and Severity Index score (EASI-75 response) and assessments of itch and of itch interference with sleep. Safety was also assessed. RESULTS: In trial 1, the primary outcome was met in 43.1% of 283 patients in the lebrikizumab group and in 12.7% of 141 patients in the placebo group (P<0.001); an EASI-75 response occurred in 58.8% and 16.2%, respectively (P<0.001). In trial 2, the primary outcome was met in 33.2% of 281 patients in the lebrikizumab group and in 10.8% of 146 patients in the placebo group (P<0.001); an EASI-75 response occurred in 52.1% and 18.1%, respectively (P<0.001). Measures of itch and itch interference with sleep indicated improvement with lebrikizumab therapy. The incidence of conjunctivitis was higher among patients who received lebrikizumab than among those who received placebo. Most adverse events during the induction period were mild or moderate in severity and did not lead to trial discontinuation. CONCLUSIONS: In the induction period of two phase 3 trials, 16 weeks of treatment with lebrikizumab was effective in adolescents and adults with moderate-to-severe atopic dermatitis. (Funded by Dermira; ADvocate1 and ADvocate2 ClinicalTrials.gov numbers, NCT04146363 and NCT04178967, respectively.).


Assuntos
Anticorpos Monoclonais , Dermatite Atópica , Adolescente , Adulto , Humanos , Lactente , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Dermatite Atópica/complicações , Dermatite Atópica/tratamento farmacológico , Dermatite Atópica/imunologia , Método Duplo-Cego , Interleucina-13/antagonistas & inibidores , Interleucina-13/imunologia , Prurido/tratamento farmacológico , Prurido/etiologia , Prurido/imunologia , Índice de Gravidade de Doença , Resultado do Tratamento , Imunoglobulina G/imunologia , Pele/efeitos dos fármacos , Pele/imunologia
12.
Allergol. immunopatol ; 50(6): 71-75, 01 nov. 2022. ilus, graf
Artigo em Inglês | IBECS | ID: ibc-211508

RESUMO

Allergic rhinitis and asthma are the main airway diseases with a higher prevalence. Eosinophilic inflammation, airway hyperresponsiveness, mucus hypersecretion, and reversible airflow obstruction are immunopathogenesis symptoms of rhinitis and asthma. Crotonic acid has bio-activity on the inflammation, and gluconic acid as chelator may protect crotonic acid activity in airway and together may control allergic rhinitis and asthma. Allergic rhinitis and asthma mice models were treated with crotonic and gluconic acids. The total IgE, histamine, IL-4, IL-5, and IL-13 levels were measured. In lung tissues, goblet cell hyperplasia, mucus hypersecretion, and inflammation were evaluated. The level of IL-5, goblet cell hyperplasia, and perivascular and peribronchial inflammation were controlled by crotonic acid in asthma and allergic rhinitis groups. But, total IgE, hista-mine, IL-4, and IL-13 levels, and mucus hypersecretion had no significant changes between treated and nontreated asthma and rhinitis groups. Crotonic acid can control eosinophilic inflammation via harnessing IL-5 and preventing goblet cell hyperplasia. When used with gluconic acid, it had a strong effect on the control of allergic rhinitis and asthma immunopathologies (AU)


Assuntos
Animais , Masculino , Camundongos , Rinite Alérgica/tratamento farmacológico , Crotonatos/uso terapêutico , Amidas/uso terapêutico , Asma/tratamento farmacológico , Asma/patologia , Modelos Animais de Doenças , Camundongos Endogâmicos BALB C , Anti-Inflamatórios/uso terapêutico , Lavagem Broncoalveolar , Citocinas/imunologia , Hipersensibilidade Imediata/imunologia , Inflamação , Interleucina-4/imunologia , Interleucina-5/imunologia , Interleucina-13/imunologia
13.
Eur J Immunol ; 52(12): 1972-1979, 2022 12.
Artigo em Inglês | MEDLINE | ID: mdl-36271745

RESUMO

After recovery, mild and severe COVID-19 diseases are associated with long-term effects on the host immune system, such as prolonged T-cell activation or accumulation of autoantibodies. In this study, we show that mild SARS-CoV-2 infections, but not SARS-CoV-2 spike mRNA vaccinations, cause durable atopic risk factors such as a systemic Th2- and Th17-type environment as well as activation of B cells responsive of IgE against aeroallergens from house dust mite and mold. At an average of 100 days post mild SARS-CoV-2 infections, anti-mold responses were associated with low IL-13 levels and increased pro-inflammatory IL-6 titers. Acutely severely ill COVID-19 patients instead showed no evidence of atopic reactions. Considering convalescents of mild COVID-19 courses and mRNA-vaccinated individuals together, IL-13 was the predominant significantly upregulated factor, likely shaping SARS-CoV-2 immunity. Application of multiple regression analysis revealed that the IL-13 levels of both groups were determined by the Th17-type cytokines IL-17A and IL-22. Taken together, these results implicate a critical role for IL-13 in the aftermath of SARS-CoV-2 mild infections and mRNA vaccinations, conferring protection against airway directed, atopic side reactions that occur in mildly experienced COVID-19.


Assuntos
Vacinas contra COVID-19 , COVID-19 , Hipersensibilidade Imediata , Imunoglobulina E , Interleucina-13 , Humanos , COVID-19/imunologia , COVID-19/prevenção & controle , Interleucina-13/imunologia , SARS-CoV-2 , Vacinação , Imunoglobulina E/imunologia , Vacinas contra COVID-19/imunologia , Vacinas de mRNA/imunologia
14.
Sci Immunol ; 7(71): eabl6543, 2022 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-35559665

RESUMO

The intestinal tract is a common site for various types of infections including viruses, bacteria, and helminths, each requiring specific modes of immune defense. The intestinal epithelium has a pivotal role in both immune initiation and effector stages, which are coordinated by lymphocyte cytokines such as IFNγ, IL-13, and IL-22. Here, we studied intestinal epithelial immune responses using organoid image analysis based on a convolutional neural network, transcriptomic analysis, and in vivo infection models. We found that IL-13 and IL-22 both induce genes associated with goblet cells, but the resulting goblet cell phenotypes are dichotomous. Moreover, only IL-13-driven goblet cells are associated with classical NOTCH signaling. We further showed that IL-13 induces the bone morphogenetic protein (BMP) pathway, which acts in a negative feedback loop on immune type 2-driven tuft cell hyperplasia. This is associated with inhibiting Sox4 expression to putatively limit the tuft cell progenitor population. Blocking ALK2, a BMP receptor, with the inhibitor dorsomorphin homolog 1 (DMH1) interrupted the feedback loop, resulting in greater tuft cell numbers both in vitro and in vivo after infection with Nippostrongylus brasiliensis. Together, this investigation of cytokine effector responses revealed an unexpected and critical role for the BMP pathway in regulating type 2 immunity, which can be exploited to tailor epithelial immune responses.


Assuntos
Proteínas Morfogenéticas Ósseas , Hiperplasia , Interleucina-13 , Mucosa Intestinal , Proteínas Morfogenéticas Ósseas/metabolismo , Retroalimentação , Humanos , Hiperplasia/imunologia , Interleucina-13/imunologia , Fatores de Transcrição SOXC/metabolismo , Infecções por Strongylida
15.
Front Immunol ; 13: 824110, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35140724

RESUMO

Background: Bullous pemphigoid (BP) is a senile chronic autoimmune bullous skin disease with a high relapse rate, which significantly impairs patients' quality of life and contributes to disease mortality. This observational case-control study explores the gene polymorphisms of cytokines and their clinical significance in Chinese patients with BP. Methods: IL-1α (rs1800587), IL-1ß (rs16944, rs1143627, rs1143634), IL-4 (rs2243250), IL-6 (rs1800795), IL-10 (rs1800896, rs1800871, rs1800872), IL-13 (rs1800925, rs20541), TNF-α (rs1799964, rs1800630, rs1799724, rs361525), IFN-γ (rs1799964, rs1800630, rs361525, rs1800629, rs4248160, rs1800750), and TGF-ß1 (rs2317130, rs1800469, rs4803457) genes were genotyped in the healthy controls and BP patients, respectively. Expression of these cytokines in serum was measured. Medical profiles of patients, including baseline characteristics and prognosis, were statistically analyzed. Results: We found that IL-1 ß and IL-13 concentrations were higher in the BP patients' sera compared to those in the controls. For IL-13, significant differences were found in the nucleotide ratio/genotype/haploid frequency/haplotype, respectively. IL-13 (rs20541, rs1800925) is related to gender, and the IL-13 genotype was significantly associated with recurrence. Conclusions: BP is associated with IL-13 gene polymorphism and IL-13 concentration is elevated in blood circulation in patients with BP. Our results support that IL-13 is relevant in the pathogenesis of BP, suggesting that IL-13 could potentially represent a promising target for BP therapy and a prognostic marker.


Assuntos
Interleucina-13/genética , Interleucina-13/imunologia , Penfigoide Bolhoso/genética , Penfigoide Bolhoso/imunologia , Polimorfismo de Nucleotídeo Único , Adulto , Idoso , Idoso de 80 Anos ou mais , Povo Asiático , Biomarcadores , Estudos de Casos e Controles , Feminino , Predisposição Genética para Doença , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Penfigoide Bolhoso/patologia , Prognóstico
16.
J Biol Chem ; 298(2): 101533, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34973336

RESUMO

Therapeutic antibody development requires discovery of an antibody molecule with desired specificities and drug-like properties. For toxicological studies, a therapeutic antibody must bind the ortholog antigen with a similar affinity to the human target to enable relevant dosing regimens, and antibodies falling short of this affinity design goal may not progress as therapeutic leads. Herein, we report the novel use of mammalian recombination signal sequence (RSS)-directed recombination for complementarity-determining region-targeted protein engineering combined with mammalian display to close the species affinity gap of human interleukin (IL)-13 antibody 731. This fully human antibody has not progressed as a therapeutic in part because of a 400-fold species affinity gap. Using this nonhypothesis-driven affinity maturation method, we generated multiple antibody variants with improved IL-13 affinity, including the highest affinity antibody reported to date (34 fM). Resolution of a cocrystal structure of the optimized antibody with the cynomolgus monkey (or nonhuman primate) IL-13 protein revealed that the RSS-derived mutations introduced multiple successive amino-acid substitutions resulting in a de novo formation of a π-π stacking-based protein-protein interaction between the affinity-matured antibody heavy chain and helix C on IL-13, as well as an introduction of an interface-distant residue, which enhanced the light chain-binding affinity to target. These mutations synergized binding of heavy and light chains to the target protein, resulting in a remarkably tight interaction, and providing a proof of concept for a new method of protein engineering, based on synergizing a mammalian display platform with novel RSS-mediated library generation.


Assuntos
Anticorpos , Interleucina-13 , Sinais Direcionadores de Proteínas , Sequência de Aminoácidos , Animais , Anticorpos/genética , Anticorpos/imunologia , Afinidade de Anticorpos , Humanos , Interleucina-13/genética , Interleucina-13/imunologia , Macaca fascicularis , Mamíferos , Recombinação Genética
17.
Int J Mol Sci ; 22(21)2021 Oct 28.
Artigo em Inglês | MEDLINE | ID: mdl-34769080

RESUMO

The chemokine CCL18 is produced in cells of the myelomonocytic lineage and represents one of the most highly expressed chemokines in lesional skin and serum of atopic dermatitis patients. We investigated the role of histamine in CCL18 production in human monocyte-derived M2 macrophages differentiated in the presence of M-CSF and activated with IL-4, IL-13 or with IL-10. Since expression and regulation of histamine H1 receptor (H1R), H2R and H4R by IL-4 and IL-13 on human M2 macrophages were described, we analyzed expression of the histamine receptors in response to IL-10 stimulation by quantitative RT-PCR. IL-10 upregulated H2R and downregulated H4R mRNA expression by trend in M2 macrophages. IL-10, but in a more pronounced manner, IL-4 and IL-13, also upregulated CCL18. Histamine increased the cytokine-induced upregulation of CCL18 mRNA expression by stimulating the H2R. This effect was stronger in IL-10-stimulated M2 macrophages where the upregulation of CCL18 was confirmed at the protein level by ELISA using selective histamine receptor agonist and antagonists. The histamine-induced CCL18 upregulation in IL-10-activated M2 macrophages was almost similar in cells obtained from atopic dermatitis patients compared to cells from healthy control persons. In summary, our data stress a new function of histamine showing upregulation of the Th2 cells attracting chemokine CCL18 in human, activated M2 macrophages. This may have an impact on the course of atopic dermatitis and for the development of new therapeutic interventions.


Assuntos
Quimiocinas CC/genética , Histamina/imunologia , Macrófagos/imunologia , Células Cultivadas , Quimiocinas CC/imunologia , Dermatite Atópica/genética , Dermatite Atópica/imunologia , Humanos , Inflamação/imunologia , Interleucina-10/imunologia , Interleucina-13/imunologia , Interleucina-4/imunologia , Ativação de Macrófagos , Macrófagos/citologia , Células Th2/imunologia , Regulação para Cima
18.
Theranostics ; 11(20): 9805-9820, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34815787

RESUMO

Background: Microglia and macrophages adopt a pro-inflammatory phenotype after spinal cord injury (SCI), what is thought to contribute to secondary tissue degeneration. We previously reported that this is due, in part, to the low levels of anti-inflammatory cytokines, such as IL-4. Since IL-13 and IL-4 share receptors and both cytokines drive microglia and macrophages towards an anti-inflammatory phenotype in vitro, here we studied whether administration of IL-13 and IL-4 after SCI leads to beneficial effects. Methods: We injected mice with recombinant IL-13 or IL-4 at 48 h after SCI and assessed their effects on microglia and macrophage phenotype and functional outcomes. We also performed RNA sequencing analysis of macrophages and microglia sorted from the injured spinal cords of mice treated with IL-13 or IL-4 and evaluated the metabolic state of these cells by using Seahorse technology. Results: We observed that IL-13 induced the expression of anti-inflammatory markers in microglia and macrophages after SCI but, in contrast to IL-4, it failed to mediate functional recovery. We found that these two cytokines induced different gene signatures in microglia and macrophages after SCI and that IL-4, in contrast to IL-13, shifted microglia and macrophage metabolism from glycolytic to oxidative phosphorylation. These findings were further confirmed by measuring the metabolic profile of these cells. Importantly, we also revealed that macrophages stimulated with IL-4 or IL-13 are not deleterious to neurons, but they become cytotoxic when oxidative metabolism is blocked. This suggests that the metabolic shift, from glycolysis to oxidative phosphorylation, is required to minimize the cytotoxic responses of microglia and macrophages. Conclusions: These results reveal that the metabolic fitness of microglia and macrophages after SCI contributes to secondary damage and that strategies aimed at boosting oxidative phosphorylation might be a novel approach to minimize the deleterious actions of microglia and macrophages in neurotrauma.


Assuntos
Interleucina-13/metabolismo , Interleucina-4/metabolismo , Traumatismos da Medula Espinal/metabolismo , Animais , Anti-Inflamatórios/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Interleucina-13/imunologia , Interleucina-13/farmacologia , Interleucina-4/imunologia , Interleucina-4/farmacologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Microglia/metabolismo , Recuperação de Função Fisiológica/fisiologia , Medula Espinal/metabolismo , Traumatismos da Medula Espinal/imunologia , Traumatismos da Medula Espinal/fisiopatologia , Resultado do Tratamento
19.
Front Immunol ; 12: 704836, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34650552

RESUMO

Intestinal ischemia/reperfusion (I/R) injury is a grave condition with high morbidity and mortality. We previously confirmed that intestinal I/R induces intestinal flora disorders and changes in metabolites, but the role of different metabolites in intestinal I/R injury is currently unclear. Based on targeted metabolic sequencing, pravastatin (PA) was determined to be a metabolite of the gut microbiota. Further, intestinal I/R model mice were established through superior mesenteric artery obstruction. In addition, a co-culture model of small intestinal organoids and type II innate lymphoid cells (ILC2s) was subjected to hypoxia/reoxygenation (H/R) to simulate an intestinal I/R model. Moreover, correlation analysis between the PA level in preoperative feces of patients undergoing cardiopulmonary bypass and the indices of postoperative intestinal I/R injury was carried out. IL-33-deficient mice, ILC2-deleted mice, and anti-IL-13 neutralizing antibodies were also used to explore the potential mechanism through which PA attenuates intestinal I/R injury. We demonstrated that PA levels in the preoperative stool of patients undergoing cardiopulmonary bypass were negatively correlated with the indices of postoperative intestinal I/R injury. Furthermore, PA alleviated intestinal I/R injury and improved the survival of mice. We further showed that PA promotes IL-13 release from ILC2s by activating IL-33/ST2 signaling to attenuate intestinal I/R injury. In addition, IL-13 promoted the self-renewal of intestinal stem cells by activating Notch1 and Wnt signals. Overall, results indicated that the gut microbial metabolite PA can attenuate intestinal I/R injury by promoting the release of IL-13 from ILC2s via IL-33/ST2 signaling, revealing a novel mechanism of and therapeutic strategy for intestinal I/R injury.


Assuntos
Microbioma Gastrointestinal/imunologia , Imunidade Inata , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Interleucina-13/imunologia , Interleucina-33/imunologia , Enteropatias/imunologia , Linfócitos/imunologia , Pravastatina/imunologia , Animais , Modelos Animais de Doenças , Humanos , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Interleucina-13/genética , Interleucina-33/genética , Enteropatias/genética , Masculino , Camundongos , Camundongos Knockout , Traumatismo por Reperfusão
20.
J Immunol ; 207(10): 2608-2620, 2021 11 15.
Artigo em Inglês | MEDLINE | ID: mdl-34645688

RESUMO

IL-13 is a pleiotropic cytokine mainly secreted by Th2 cells. It reacts with many different types of cells involved in allergy, inflammation, and fibrosis, e.g., mastocytes, B cells, and fibroblasts. The role of IL-13 in conditions involving one or several of these phenotypes has therefore been extensively investigated. The inhibition of this cytokine in animal models for various pathologies yielded highly promising results. However, most human trials relying on anti-IL-13 conventional mAbs have failed to achieve a significant improvement of the envisaged disorders. Where some studies might have suffered from several weaknesses, the strategies themselves, such as targeting only IL-13 using conventional mAbs or employing a systemic administration, could be questioned. Nanobodies are recombinant Ag-binding fragments derived from the variable part of H chain-only Abs occurring in Camelidae. Thanks to their single-domain structure, small size (≈15 kDa), good stability, and solubility, they can be engineered into multispecific constructs for combined therapies or for use in new strategies such as formulations for local administration, e.g., pulmonary administration. In this study, we describe the generation of 38 nanobodies that can be subdivided into five CDR3 families. Nine nanobodies were found to have a good affinity profile (KD = 1-200 nM), but none were able to strongly inhibit IL-13 biological activity in vitro (IC50 > 50 µM: HEK-Blue IL-13/IL-4 cells). Multimeric constructs were therefore designed from these inhibitors and resulted in an up to 36-fold improvement in affinity and up to 300-fold enhancement of the biological activity while conserving a high specificity toward IL-13.


Assuntos
Anticorpos Neutralizantes/imunologia , Afinidade de Anticorpos/imunologia , Interleucina-13/antagonistas & inibidores , Interleucina-13/imunologia , Anticorpos de Domínio Único/imunologia , Humanos
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