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1.
Nat Commun ; 12(1): 5314, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493727

RESUMO

Adoptive T cell therapy (ACT) requires lymphodepletion preconditioning to eliminate immune-suppressive elements and enable efficient engraftment of adoptively transferred tumor-reactive T cells. As anti-CD4 monoclonal antibody depletes CD4+ immune-suppressive cells, the combination of anti-CD4 treatment and ACT has synergistic potential in cancer therapy. Here, we demonstrate a post-ACT conditioning regimen that involves transient anti-CD4 treatment (CD4post). Using murine melanoma, the combined effect of cyclophosphamide preconditioning (CTXpre), CD4post, and ex vivo primed tumor-reactive CD8+ T-cell infusion is presented. CTXpre/CD4post increases tumor suppression and host survival by accelerating the proliferation and differentiation of ex vivo primed CD8+ T cells and endogenous CD8+ T cells. Endogenous CD8+ T cells enhance effector profile and tumor-reactivity, indicating skewing of the TCR repertoire. Notably, enrichment of polyfunctional IL-18Rαhi CD8+ T cell subset is the key event in CTXpre/CD4post-induced tumor suppression. Mechanistically, the anti-tumor effect of IL-18Rαhi subset is mediated by IL-18 signaling and TCR-MHC I interaction. This study highlights the clinical relevance of CD4post in ACT and provides insights regarding the immunological nature of anti-CD4 treatment, which enhances anti-tumor response of CD8+ T cells.


Assuntos
Anticorpos Monoclonais/farmacologia , Antineoplásicos Alquilantes/farmacologia , Linfócitos T CD4-Positivos/efeitos dos fármacos , Ciclofosfamida/farmacologia , Subunidade alfa de Receptor de Interleucina-18/genética , Melanoma Experimental/terapia , Neoplasias Cutâneas/terapia , Linfócitos T Citotóxicos/imunologia , Transferência Adotiva , Animais , Antígenos CD/genética , Antígenos CD/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD4-Positivos/patologia , Feminino , Regulação Neoplásica da Expressão Gênica , Imunoterapia Adotiva/métodos , Interleucina-18/genética , Interleucina-18/imunologia , Subunidade alfa de Receptor de Interleucina-18/agonistas , Subunidade alfa de Receptor de Interleucina-18/imunologia , Ativação Linfocitária , Melanoma Experimental/genética , Melanoma Experimental/imunologia , Melanoma Experimental/mortalidade , Camundongos , Camundongos Endogâmicos C57BL , Receptores CCR4/genética , Receptores CCR4/imunologia , Receptores CCR8/genética , Receptores CCR8/imunologia , Receptores Histamínicos H4/genética , Receptores Histamínicos H4/imunologia , Transdução de Sinais , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/mortalidade , Análise de Sobrevida , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/transplante , Carga Tumoral/efeitos dos fármacos
2.
Front Immunol ; 12: 719544, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34367188

RESUMO

Background: Hyperinflammation with dysregulated production of galectins and cytokines may develop in COVID-19 or adult-onset Still's disease (AOSD). Given the similar clinical features in both diseases, it is necessary to identify biomarkers that can differentiate COVID-19 from AOSD. However, the related data remain scarce currently. Methods: In this cross-sectional study, plasma levels of galectin-3, galectin-9, and soluble TIM-3 (sTIM-3) were determined by ELISA in 55 COVID-19 patients (31 non-severe and 24 severe), 23 active AOSD patients, and 31 healthy controls (HC). The seropositivity for SARS-CoV-2 was examined using an immunochromatographic assay, and cytokine profiles were determined with the MULTIPLEX platform. Results: Significantly higher levels of galectin-3, galectin-9, IL-1ß, IL-1Ra, IL-10, IFN-α2, IL-6, IL-18, and TNF-α were observed in severe COVID-19 and active AOSD patients compared with HC (all p<0.001). AOSD, but not COVID-19, showed significantly higher IFN-γ and IL-17A compared with HC (both p<0.01). Moreover, active AOSD patients had 68-fold higher IL-18 levels and 5-fold higher ferritin levels than severe COVID-19 patients (both p<0.001). IL-18 levels at the cut-off value 190.5pg/mL had the highest discriminative power for active AOSD and severe COVID-19, with AUC 0.948, sensitivity 91.3%, specificity 95.8%, and accuracy of 91.5% (p<0.005). Multivariate regression analysis revealed IL-18 as a significant predictor of active AOSD (p<0.05). Conclusion: Active AOSD patients share features of hyperinflammation and cytokine storm with severe COVID-19 patients but possess a distinct cytokine profile, including elevated IL-18, IL-6, IFN-γ, and IL-17A. IL-18 is a potential discriminator between AOSD and COVID-19 and may significantly predict active AOSD.


Assuntos
COVID-19 , Interleucina-18 , SARS-CoV-2 , Doença de Still de Início Tardio , Adulto , Biomarcadores/sangue , COVID-19/sangue , COVID-19/imunologia , Estudos Transversais , Feminino , Humanos , Interleucina-18/sangue , Interleucina-18/imunologia , Masculino , SARS-CoV-2/imunologia , SARS-CoV-2/metabolismo , Doença de Still de Início Tardio/sangue , Doença de Still de Início Tardio/imunologia
3.
Nature ; 595(7865): 101-106, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34108686

RESUMO

T cell immunoglobulin and mucin-containing molecule 3 (TIM-3), first identified as a molecule expressed on interferon-γ producing T cells1, is emerging as an important immune-checkpoint molecule, with therapeutic blockade of TIM-3 being investigated in multiple human malignancies. Expression of TIM-3 on CD8+ T cells in the tumour microenvironment is considered a cardinal sign of T cell dysfunction; however, TIM-3 is also expressed on several other types of immune cell, confounding interpretation of results following blockade using anti-TIM-3 monoclonal antibodies. Here, using conditional knockouts of TIM-3 together with single-cell RNA sequencing, we demonstrate the singular importance of TIM-3 on dendritic cells (DCs), whereby loss of TIM-3 on DCs-but not on CD4+ or CD8+ T cells-promotes strong anti-tumour immunity. Loss of TIM-3 prevented DCs from expressing a regulatory program and facilitated the maintenance of CD8+ effector and stem-like T cells. Conditional deletion of TIM-3 in DCs led to increased accumulation of reactive oxygen species resulting in NLRP3 inflammasome activation. Inhibition of inflammasome activation, or downstream effector cytokines interleukin-1ß (IL-1ß) and IL-18, completely abrogated the protective anti-tumour immunity observed with TIM-3 deletion in DCs. Together, our findings reveal an important role for TIM-3 in regulating DC function and underscore the potential of TIM-3 blockade in promoting anti-tumour immunity by regulating inflammasome activation.


Assuntos
Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Inflamassomos/metabolismo , Neoplasias/imunologia , Neoplasias/metabolismo , Animais , Células Dendríticas , Feminino , Receptor Celular 2 do Vírus da Hepatite A/deficiência , Receptor Celular 2 do Vírus da Hepatite A/genética , Interleucina-18/imunologia , Interleucina-1beta/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Neoplasias/patologia , Linfócitos T/imunologia , Linfócitos T/metabolismo
4.
Front Immunol ; 12: 644862, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34093533

RESUMO

NLRP3 inflammasome has emerged as a crucial regulator of inflammatory bowel disease (IBD) characterized by a chronic inflammatory disease of the gastrointestinal tract. The expression of MCT4 is significantly increased in intestinal mucosal tissue of IBD, which has been identified to regulate intestinal barrier function. However, the function of MCT4 in cell pyroptosis remained unknown. In this study, we have established a stable cell line with MCT4 overexpression in HT-29 and CaCO2 cells, respectively. Functional analysis revealed that ectopic expression of MCT4 in CaCO2 cells contributed to cell pyroptosis as evidenced by LDH assay, which is largely attributed to Caspase-1-mediated canonical pyroptosis, but not Caspase-4 and Caspase-5, leading to cleave pro-IL-1ß and IL-18 into mature form and release mediated by cleaved GSDMD. Mechanically, MCT4 overexpression in HT-29 and CaCO2 cell triggered the phosphorylation of ERK1/2 and NF-κB p65, while inhibition of MCT4 by MCT inhibitor α-Cyano-4-hydroxycinnamic acid (α-CHCA) in HT-29 and CaCO2 cells led to a significant downregulation of ERK1/2 and NF-κB activity. What's more, blockade of ERK1/2-NF-κB pathway could reverse the promotion effect of MCT4 on IL-1ß expression. Importantly, both MCT4 and Caspase-1, GSDMD were significantly increased in patients with IBD, and a positive clinical correlation between MCT4 and Caspase-1 expression was observed (p < 0.001). Taken together, these findings suggested that MCT4 promoted Caspase-1-mediated canonical cell pyroptosis to aggravate intestinal inflammation in intestinal epithelial cells (IECs) through the ERK1/2-NF-κB pathway.


Assuntos
Doenças Inflamatórias Intestinais/imunologia , Sistema de Sinalização das MAP Quinases/imunologia , Transportadores de Ácidos Monocarboxílicos/imunologia , Proteínas Musculares/imunologia , Piroptose/imunologia , Células CACO-2 , Caspases/imunologia , Células HT29 , Humanos , Inflamação/imunologia , Inflamação/patologia , Doenças Inflamatórias Intestinais/patologia , Interleucina-18/imunologia , Interleucina-1beta/imunologia , Proteína Quinase 1 Ativada por Mitógeno/imunologia , Proteína Quinase 3 Ativada por Mitógeno/imunologia , Fator de Transcrição RelA/imunologia
5.
J Biol Chem ; 296: 100630, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33823154

RESUMO

Unchecked inflammation can result in severe diseases with high mortality, such as macrophage activation syndrome (MAS). MAS and associated cytokine storms have been observed in COVID-19 patients exhibiting systemic hyperinflammation. Interleukin-18 (IL-18), a proinflammatory cytokine belonging to the IL-1 family, is elevated in both MAS and COVID-19 patients, and its level is known to correlate with the severity of COVID-19 symptoms. IL-18 binds its specific receptor IL-1 receptor 5 (IL-1R5, also known as IL-18 receptor alpha chain), leading to the recruitment of the coreceptor, IL-1 receptor 7 (IL-1R7, also known as IL-18 receptor beta chain). This heterotrimeric complex then initiates downstream signaling, resulting in systemic and local inflammation. Here, we developed a novel humanized monoclonal anti-IL-1R7 antibody to specifically block the activity of IL-18 and its inflammatory signaling. We characterized the function of this antibody in human cell lines, in freshly obtained peripheral blood mononuclear cells (PBMCs) and in human whole blood cultures. We found that the anti-IL-1R7 antibody significantly suppressed IL-18-mediated NFκB activation, reduced IL-18-stimulated IFNγ and IL-6 production in human cell lines, and reduced IL-18-induced IFNγ, IL-6, and TNFα production in PBMCs. Moreover, the anti-IL-1R7 antibody significantly inhibited LPS- and Candida albicans-induced IFNγ production in PBMCs, as well as LPS-induced IFNγ production in whole blood cultures. Our data suggest that blocking IL-1R7 could represent a potential therapeutic strategy to specifically modulate IL-18 signaling and may warrant further investigation into its clinical potential for treating IL-18-mediated diseases, including MAS and COVID-19.


Assuntos
Anti-Inflamatórios/farmacologia , Anticorpos Monoclonais/farmacologia , Anticorpos Neutralizantes/farmacologia , Fatores Imunológicos/farmacologia , Interleucina-18/genética , Receptores de Interleucina-18/genética , Anti-Inflamatórios/metabolismo , Anticorpos Monoclonais/biossíntese , Anticorpos Neutralizantes/biossíntese , COVID-19/tratamento farmacológico , Candida albicans/crescimento & desenvolvimento , Candida albicans/patogenicidade , Regulação da Expressão Gênica , Células HEK293 , Humanos , Fatores Imunológicos/biossíntese , Inflamação , Interferon gama/genética , Interferon gama/imunologia , Interleucina-18/imunologia , Interleucina-6/genética , Interleucina-6/imunologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/microbiologia , Lipopolissacarídeos/antagonistas & inibidores , Lipopolissacarídeos/farmacologia , Síndrome de Ativação Macrofágica/tratamento farmacológico , NF-kappa B/genética , NF-kappa B/imunologia , Cultura Primária de Células , Receptores de Interleucina-18/antagonistas & inibidores , Receptores de Interleucina-18/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
6.
Front Immunol ; 12: 578548, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33815355

RESUMO

Objectives: To explore the potential role of CD3+CD8+CD161high TCRVα7.2+ mucosal-associated invariant T (MAIT) cells in the pathogenesis of primary biliary cholangitis (PBC). Methods: We enrolled 55 patients with PBC, 69 healthy controls (HCs), and 8 patients with hepatic hemangioma. Circulating MAIT cells and their chemokine receptor profiles and cytokine production were quantified using flow cytometry. Liver-resident MAIT cells were examined by immunofluorescence staining. CXCL12-mediated chemotaxis of MAIT cells was measured using a transwell migration assay. Plasma interleukin (IL)-18 was measured using ELISA, and cytokine production in IL-18-stimulated MAIT cells was detected using flow cytometry. Result: Peripheral MAIT cells were found to be significantly lower in patients with PBC (3.0 ± 3.2% vs. 9.4 ± 8.0%, p < 0.01) and negatively correlated with alkaline phosphatase (ALP) levels (r = -0.3209, p < 0.05). Liver immunofluorescence staining suggested that MAIT cells might accumulate in PBC liver. MAIT cells from patients with PBC expressed higher levels of CXCR4 (84.8 ± 18.0% vs. 58.7 ± 11.4%, p < 0.01), and the expression of CXCL12 was higher in PBC liver. CXCL12 promoted MAIT cell chemotaxis (70.4 ± 6.8% vs. 52.2 ± 3.5%, p < 0.01), which was attenuated by CXCR4 antagonist. MAIT cells from PBC produced significantly more interferon-γ (IFN-γ) (88.3 ± 4.2% vs. 64.2 ± 10.1%, p < 0.01), tumor necrosis factor-α (TNF-α) (93.0 ± 1.1% vs. 80.1 ± 5.3%, p < 0.01), Granzyme B (89.3 ± 3.3% vs. 72.1 ± 7.0%, p < 0.01), and perforin (46.8 ± 6.6% vs. 34.8 ± 7.7%, p < 0.05). MAIT cells from PBC expressed higher levels of IL18-Rα (83.8 ± 10.2% vs. 58.3 ± 8.7%, p < 0.01). Plasma IL-18 was more abundant in patients with PBC (286.8 ± 75.7 pg/ml vs. 132.9 ± 78.1 pg/ml, p < 0.01). IL-18 promoted IFN-γ production in MAIT cells (74.9 ± 6.6% vs. 54.7 ± 6.7%, p < 0.01), which was partially attenuated by blocking IL-18R (68.6 ± 8.3% vs. 43.5 ± 4.2%, p < 0.01). Conclusion: Mucosal-associated invariant T cells from patients with PBC accumulated in the liver via CXCL12-CXCR4-mediated chemotaxis, produced pro-inflammatory cytokines, and contributed to portal inflammation, which was potentially mediated by elevated IL-18. Targeting MAIT cells might be a therapeutic approach for PBC.


Assuntos
Quimiocina CXCL12/imunologia , Cirrose Hepática Biliar/imunologia , Fígado/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Receptores CXCR4/imunologia , Adulto , Fosfatase Alcalina/imunologia , Fosfatase Alcalina/metabolismo , Quimiocina CXCL12/metabolismo , Quimiotaxia/imunologia , Feminino , Granzimas/imunologia , Granzimas/metabolismo , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-18/imunologia , Interleucina-18/metabolismo , Fígado/metabolismo , Cirrose Hepática Biliar/sangue , Cirrose Hepática Biliar/metabolismo , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Células T Invariantes Associadas à Mucosa/metabolismo , Perforina/imunologia , Perforina/metabolismo , Receptores CXCR4/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo
7.
Cells ; 10(5)2021 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-33919154

RESUMO

Interleukin-18 receptor accessory protein (IL18RAP) is an indispensable subunit for the IL-18 receptor (IL-18R) complex's ability to mediate high-affinity IL-18 binding and signalling transduction. Interest in IL-18 in systemic lupus erythematosus (SLE) has been mostly focused on its role as a type 1 T helper cell-driving cytokine. The functional significance of IL18RAP in mediating the IL-18-driven response in myeloid cells in SLE remains largely unexplored. This study aimed to investigate the expression and function significance of IL18RAP in neutrophils of SLE patients. By qRT-PCR and Western blot analyses, elevated expressions of IL18RAP mRNA and protein were observed in neutrophils from SLE patients-particularly those with a history of nephritis. IL18RAP expression correlated negatively with complement 3 level and positively with disease activity, with higher expression in patients exhibiting renal and immunological manifestations. The increased IL18RAP expression in SLE neutrophils could be attributed to elevated type I interferon level in sera. Functionally, neutrophils from SLE patients showed higher IL-18-mediated enhancement in reactive oxygen species (ROS) generation, which showed positive correlation with IL18RAP expression and could be neutralized by anti-IL18RAP blocking antibodies. Taken together, our findings suggest that IL-18 could contribute to SLE pathogenesis through mediation of neutrophil dysfunction via the upregulation of IL18RAP expression.


Assuntos
Subunidade beta de Receptor de Interleucina-18/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Neutrófilos/imunologia , Espécies Reativas de Oxigênio/imunologia , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Interferon Tipo I/imunologia , Interleucina-18/imunologia , Masculino , Pessoa de Meia-Idade , Neutrófilos/citologia
8.
Int Immunopharmacol ; 94: 107503, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33647825

RESUMO

Our previous studies have implicated Caspase-1 signaling in driving the proinflammatory state of acute graft versus host disease (aGVHD). Therefore, we aimed to elucidate the mechanism of Caspase-1 in in murine models of aGVHD through specific inhibition of its activity with the decoy peptide Ac-YVAD-CMK. We transplanted bone marrow from donor C57BL/6 (H-2b) mice into recipient BALB/c (H-2Kd) mice and randomized the recipients into the following treatment cohorts: (1) allogeneic hematopoietic stem cell transplantation and splenic cell infusion control (PBS group); (2) low dose Ac-YVAD-CMK (AC low group); (3) and high dose Ac-YVAD-CMK (AC high group). Indeed, we observed that Caspase-1 inhibition by Ac-YVAD-CMK ameliorated pathological damage and inflammation in the liver, lungs, and colon elicited by aGVHD. This was associated with reduced mortality secondary to aGVHD. Mechanistically, we found that Caspase-1 inhibition modulated donor T cell expansion, restored the balance of Th1/Th17/Treg subsets, and markedly decreased serum levels and aGVHD target organ mRNA expression of IL-1ß, IL-18, and HMGB1. Thus, we demonstrate that inhibition of Caspase-1 by Ac-YVAD-CMK mitigates murine aGVHD by regulating Th1/Th17/Treg balance and attenuating its characteristic proinflammatory state.


Assuntos
Clorometilcetonas de Aminoácidos/uso terapêutico , Caspase 1/imunologia , Doença Enxerto-Hospedeiro/tratamento farmacológico , Clorometilcetonas de Aminoácidos/farmacologia , Animais , Colo/efeitos dos fármacos , Colo/imunologia , Doença Enxerto-Hospedeiro/sangue , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/imunologia , Proteína HMGB1/sangue , Proteína HMGB1/genética , Proteína HMGB1/imunologia , Interleucina-18/sangue , Interleucina-18/genética , Interleucina-18/imunologia , Interleucina-1beta/sangue , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Fígado/efeitos dos fármacos , Fígado/imunologia , Pulmão/efeitos dos fármacos , Pulmão/imunologia , Masculino , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia
9.
Proc Natl Acad Sci U S A ; 118(10)2021 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-33674380

RESUMO

Interleukin (IL)-37, an antiinflammatory IL-1 family cytokine, is a key suppressor of innate immunity. IL-37 signaling requires the heterodimeric IL-18R1 and IL-1R8 receptor, which is abundantly expressed in the gastrointestinal tract. Here we report a 4-mo-old male from a consanguineous family with a homozygous loss-of-function IL37 mutation. The patient presented with persistent diarrhea and was found to have infantile inflammatory bowel disease (I-IBD). Patient cells showed increased intracellular IL-37 expression and increased proinflammatory cytokine production. In cell lines, mutant IL-37 was not stably expressed or properly secreted and was thus unable to functionally suppress proinflammatory cytokine expression. Furthermore, induced pluripotent stem cell-derived macrophages from the patient revealed an activated macrophage phenotype, which is more prone to lipopolysaccharide and IL-1ß stimulation, resulting in hyperinflammatory tumor necrosis factor production. Insights from this patient will not only shed light on monogenic contributions of I-IBD but may also reveal the significance of the IL-18 and IL-37 axis in colonic homeostasis.


Assuntos
Regulação da Expressão Gênica/imunologia , Doenças Inflamatórias Intestinais , Interleucina-1 , Mutação com Perda de Função , Ativação de Macrófagos/imunologia , Macrófagos/imunologia , Pré-Escolar , Feminino , Humanos , Células-Tronco Pluripotentes Induzidas/imunologia , Doenças Inflamatórias Intestinais/genética , Doenças Inflamatórias Intestinais/imunologia , Interleucina-1/genética , Interleucina-1/imunologia , Interleucina-18/genética , Interleucina-18/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Ativação de Macrófagos/genética , Masculino
10.
Front Immunol ; 12: 641562, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33679805

RESUMO

Natural killer-like B (NKB) cells, which are newly identified immune subsets, reveal a critical immunoregulatory property in the eradication of microbial infection via the secretion of interleukin (IL)-18. For the first time, this study investigated the role of NKB cells in secreting IL-18 in the pathogenesis of periodontitis. In this study, NKB cells' percentage and IL-18 concentration in peripheral blood and periodontium in periodontitis patients was measured using flow cytometry and ELISA. The role of IL-18 in regulating periodontal inflammation was examined in a Porphyromonas gingivalis (P. gingivalis)-induced periodontitis murine model. Peripheral and periodontal-infiltrating CD3-CD19+NKp46+ NKB cells, which were the main source of IL-18, were elevated and correlated with attachment loss in periodontitis patients. In vitro IL-18 stimulation promoted proinflammatory cytokine production in periodontal ligament cells. P. gingivalis infection induced elevation of IL-18 receptor in periodontium in a periodontitis murine model. IL-18 neutralization not only suppressed P. gingivalis-induced alveolar bone resorption, but also inhibited recruitment of antigen-non-specific inflammatory cells into the periodontium, probably via dampening expressions of cytokines, chemokines, and matrix metalloproteinases. NKB cells secreting IL-18 appeared to be an important mediator in the inflammatory response following intraoral P. gingivalis infection. These findings might be relevant to the development of immunotherapies for periodontitis.


Assuntos
Subpopulações de Linfócitos B/imunologia , Interleucina-18/imunologia , Periodontite/imunologia , Adulto , Animais , Infecções por Bacteroidaceae/imunologia , Feminino , Humanos , Inflamação/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Porphyromonas gingivalis
11.
Nat Immunol ; 22(3): 322-335, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33531712

RESUMO

Immune system dysfunction is paramount in coronavirus disease 2019 (COVID-19) severity and fatality rate. Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in mucosal immunity and protection against viral infections. Here, we studied the immune cell landscape, with emphasis on MAIT cells, in cohorts totaling 208 patients with various stages of disease. MAIT cell frequency is strongly reduced in blood. They display a strong activated and cytotoxic phenotype that is more pronounced in lungs. Blood MAIT cell alterations positively correlate with the activation of other innate cells, proinflammatory cytokines, notably interleukin (IL)-18, and with the severity and mortality of severe acute respiratory syndrome coronavirus 2 infection. We also identified a monocyte/macrophage interferon (IFN)-α-IL-18 cytokine shift and the ability of infected macrophages to induce the cytotoxicity of MAIT cells in an MR1-dependent manner. Together, our results suggest that altered MAIT cell functions due to IFN-α-IL-18 imbalance contribute to disease severity, and their therapeutic manipulation may prevent deleterious inflammation in COVID-19 aggravation.


Assuntos
COVID-19/imunologia , Interferon-alfa/imunologia , Interleucina-18/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Células T Invariantes Associadas à Mucosa/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Lavagem Broncoalveolar , Estudos de Casos e Controles , Chlorocebus aethiops , Estudos de Coortes , Feminino , França , Humanos , Imunofenotipagem , Interleucina-10/imunologia , Interleucina-15/imunologia , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Interleucina-8/imunologia , Masculino , Pessoa de Meia-Idade , RNA-Seq , SARS-CoV-2 , Índice de Gravidade de Doença , Análise de Célula Única , Células Vero , Adulto Jovem
12.
Res Vet Sci ; 136: 89-96, 2021 May.
Artigo em Inglês | MEDLINE | ID: mdl-33592449

RESUMO

Although the immunogenicity of DNA vaccines is nonideal, they are still considered as potential alternative vaccine candidates to conventional vaccines. Various DNA delivery systems, including nanoparticles, have been extensively explored and validated to further enhance the immunogenicity of DNA vaccines. DNA vaccines are considered as alternative vaccine candidates. Various DNA delivery systems, including nanoparticles, have been extensively explored to enhance the immunogenicity of DNA vaccines. In this study, positively charged Poly (D, l-lactide-co-glycolic acid) (PLGA) nanoparticles were generated and characterized as a delivery system for O-serotype foot-and-mouth DNA vaccine. A recombinant plasmid encoding swine interleukin (IL)-18, IL-2, or granulocyte-macrophage colony-stimulating factor (GM-CSF) gene was introduced into the DNA vaccine to further improve its immunogenicity, which was evaluated in a guinea pig model. PLGA-pVAX-VP013/IL-18 elicited significantly (P = 0.0149) higher FMDV-specific antibody levels than naked DNA before the challenge. The level of neutralizing antibodies induced by PLGA-pVAX-VP013/IL-18, PLGA-pVAX-VP013/IL-2, and PLGA-pVAX-VP013/GM-CSF significantly increased compared with that induced by naked DNA (P < 0.0001). The lymphocyte proliferation assay showed that cellular immunity induced by PLGA-pVAX-VP013/IL-18 and PLGA-pVAX-VP013/GM-CSF was dramatically enhanced compared with that induced by the inactivated vaccine. The protection by PLGA-pVAX-VP013/IL-18 was consistent with that by the inactivated vaccine post-challenge and was followed by PLGA-pVAX-VP013/GM-CSF. Therefore, cationic PLGA nanoparticles can deliver DNA vaccines and induce humoral and cellular immune responses. The co-administration of FMD DNA vaccine with IL-18 formulated with PLGA nanoparticles was the optimal strategy to improve the immunogenicity of FMD DNA vaccines.


Assuntos
Vírus da Febre Aftosa/imunologia , Imunogenicidade da Vacina , Nanopartículas , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/imunologia , Vacinas de DNA/imunologia , Vacinas Virais/imunologia , Animais , Febre Aftosa/imunologia , Febre Aftosa/prevenção & controle , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Cobaias , Interleucina-18/imunologia , Interleucina-2/imunologia , Nanopartículas/administração & dosagem , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/administração & dosagem , Sorogrupo
13.
Int J Mol Sci ; 22(3)2021 Jan 28.
Artigo em Inglês | MEDLINE | ID: mdl-33525345

RESUMO

Chronic inflammation contributes to the development and progression of various tumors. Especially where the inflammation is mediated by cells of the innate immune system, the NLRP3 inflammasome plays an important role, as it senses and responds to a variety of exogenous and endogenous pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). The NLRP3 inflammasome is responsible for the maturation and secretion of the proinflammatory cytokines interleukin-1ß (IL-1ß) and IL-18 and for the induction of a type of inflammatory cell death known as pyroptosis. Overactivation of the NLRP3 inflammasome can be a driver of various diseases. Since leukemia is known to be an inflammation-driven cancer and IL-1ß is produced in elevated levels by leukemic cells, research on NLRP3 in the context of leukemia has increased in recent years. In this review, we summarize the current knowledge on leukemia-promoting inflammation and, in particular, the role of the NLRP3 inflammasome in different types of leukemia. Furthermore, we examine a connection between NLRP3, autophagy and leukemia.


Assuntos
Carcinogênese/imunologia , Inflamassomos/imunologia , Inflamação/imunologia , Leucemia/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Alarminas/genética , Alarminas/imunologia , Animais , Autofagia/genética , Autofagia/imunologia , Carcinogênese/genética , Carcinogênese/patologia , Progressão da Doença , Regulação Leucêmica da Expressão Gênica , Humanos , Imunidade Inata , Inflamassomos/genética , Inflamação/complicações , Inflamação/genética , Inflamação/patologia , Interleucina-18/genética , Interleucina-18/imunologia , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Leucemia/etiologia , Leucemia/genética , Leucemia/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Padrões Moleculares Associados a Patógenos/imunologia , Padrões Moleculares Associados a Patógenos/metabolismo , Piroptose/genética , Piroptose/imunologia , Transdução de Sinais
14.
Rheumatology (Oxford) ; 60(8): 3888-3895, 2021 08 02.
Artigo em Inglês | MEDLINE | ID: mdl-33550379

RESUMO

OBJECTIVES: Elevation of serum IL-18 in adult-onset Still's disease (AOSD) and systemic JIA (sJIA) suggests the role of the inflammasome in these diseases. Gasdermin D is a pore-forming protein playing central roles in inflammasome-mediated inflammation, but its role in rheumatic disease is unknown. We aimed to elucidate the auto-inflammatory mechanisms in AOSD and sJIA. METHODS: Patients with AOSD, sJIA, hemophagocytic lymphohistiocytosis (HLH) and Behçet's disease followed at Yokohama City University (YCU), or US National Institutes of Health (NIH) were included in the study. Disease activity was evaluated by the modified Pouchot score. Ferritin and N-terminal gasdermin D levels in serum and culture supernatant were measured by ELISA. Primary monocytes (Mo) were stimulated with GM-CSF or M-CSF and differentiated into M1 macrophages (Mφ) or M2Mφ, respectively. The number of Mo/Mφ and their viability were monitored over time. RESULTS: Patients with active AOSD and sJIA had increased levels of serum gasdermin D N-terminal, which correlated with serum ferritin and IL-18 levels. Mo-derived Mφ from active AOSD patients showed reduced cell viability and increased cell death. The number of cultured Mφ cells on day nine was negatively correlated with the serum ferritin and gasdermin D levels. Higher ferritin and gasdermin D levels were observed in the M1Mφ culture supernatant of active AOSD patients. Gasdermin D inhibitors reduced the pyroptosis-mediated ferritin release in Mo. CONCLUSION: Elevation of serum gasdermin D N-terminal provides evidence for inflammasome activation triggering gasdermin D-mediated Mo and Mφ pyroptosis in AOSD and possibly sJIA.


Assuntos
Artrite Juvenil/imunologia , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Macrófagos/imunologia , Monócitos/imunologia , Proteínas de Ligação a Fosfato/imunologia , Piroptose/imunologia , Doença de Still de Início Tardio/imunologia , Adolescente , Adulto , Síndrome de Behçet/imunologia , Diferenciação Celular , Criança , Pré-Escolar , Feminino , Ferritinas/sangue , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Humanos , Inflamassomos/imunologia , Interleucina-18/imunologia , Linfo-Histiocitose Hemofagocítica/imunologia , Fator Estimulador de Colônias de Macrófagos , Masculino , Pessoa de Meia-Idade
15.
Methods Mol Biol ; 2240: 13-29, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33423223

RESUMO

Contact allergy is of considerable importance to the toxicologist, and regulatory authorities worldwide require testing for skin sensitization potential and appropriate hazard labeling to enable management of the risk to human health. Although traditionally the identification of skin-sensitizing chemicals has been carried out using animal models, in Europe legislative changes have promoted, and now require, the use of non-animal methods (i.e., Cosmetic Directive, REACH). Several in vitro alternatives for hazard identification have now been validated, but do not provide information on the potency of a skin sensitizer. Here, we describe an animal model, the local lymph node assay (LLNA), and an in vitro model, the RhE IL-18 potency assay, in the context of the identification and potency classification of skin sensitizers. These two assays have been chosen among the different available tests as representative of an alternative in vivo model (the LLNA) and a promising in vitro method with the potential of both hazard identification and potency classification.


Assuntos
Dermatite Alérgica de Contato/etiologia , Interleucina-18/imunologia , Ensaio Local de Linfonodo , Testes de Irritação da Pele/métodos , Alérgenos/imunologia , Alérgenos/toxicidade , Animais , Células Cultivadas , Dermatite Alérgica de Contato/diagnóstico , Dermatite Alérgica de Contato/imunologia , Humanos , Irritantes/imunologia , Irritantes/toxicidade , Queratinócitos/efeitos dos fármacos , Queratinócitos/imunologia , Camundongos , Cultura Primária de Células/métodos
16.
Nat Commun ; 12(1): 653, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33510147

RESUMO

Only a subpopulation of non-small cell lung cancer (NSCLC) patients responds to immunotherapies, highlighting the urgent need to develop therapeutic strategies to improve patient outcome. We develop a chemical positive modulator (HEI3090) of the purinergic P2RX7 receptor that potentiates αPD-1 treatment to effectively control the growth of lung tumors in transplantable and oncogene-induced mouse models and triggers long lasting antitumor immune responses. Mechanistically, the molecule stimulates dendritic P2RX7-expressing cells to generate IL-18 which leads to the production of IFN-γ by Natural Killer and CD4+ T cells within tumors. Combined with immune checkpoint inhibitor, the molecule induces a complete tumor regression in 80% of LLC tumor-bearing mice. Cured mice are also protected against tumor re-challenge due to a CD8-dependent protective response. Hence, combination treatment of small-molecule P2RX7 activator followed by immune checkpoint inhibitor represents a strategy that may be active against NSCLC.


Assuntos
Carcinoma Pulmonar de Lewis/terapia , Inibidores de Checkpoint Imunológico/farmacologia , Imunoterapia/métodos , Receptores Purinérgicos P2X7/imunologia , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Carcinoma Pulmonar de Lewis/genética , Carcinoma Pulmonar de Lewis/imunologia , Linhagem Celular Tumoral , Terapia Combinada , Feminino , Células HEK293 , Humanos , Inibidores de Checkpoint Imunológico/imunologia , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-18/genética , Interleucina-18/imunologia , Interleucina-18/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Estrutura Molecular , Receptores Purinérgicos P2X7/genética , Receptores Purinérgicos P2X7/metabolismo , Bibliotecas de Moléculas Pequenas/química , Análise de Sobrevida , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/imunologia
17.
Arthritis Rheumatol ; 73(7): 1189-1199, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33452867

RESUMO

OBJECTIVE: We undertook this study to evaluate the activation and functional relevance of inflammasome pathways in ankylosing spondylitis (AS) patients and rodent models and their relationship to dysbiosis. METHODS: An inflammasome pathway was evaluated in the gut and peripheral blood from 40 AS patients using quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), immunohistochemistry (IHC), flow cytometry, and confocal microscopy, and was compared to that of 20 healthy controls and 10 patients with Crohn's disease. Bacteria was visualized using silver stain in human samples, and antibiotics were administered to HLA-B27-transgenic rats. The NLRP3 inhibitor MCC950 was administered to SKG mice, and ileal and joint tissues were assessed by IHC analysis and real-time qRT-PCR. The role of inflammasome in modulating the interleukin-23 (IL-23)/IL-17 axis was studied ex vivo. RESULTS: Expression levels of Nlrp3, Nlrc4, and Aim2 were increased in the gut of HLA-B27-transgenic rats and reduced by antibiotic treatment (P < 0.05). In curdlan-treated SKG mice, NLRP3 blockade prevented ileitis and delayed arthritis onset (P < 0.05). Compared to healthy controls, AS patients demonstrated overexpression of NLRP3 (fold induction 2.33 versus 22.2; P < 0.001), NLRC4 (fold induction 1.90 versus 6.47; P < 0.001), AIM2 (fold induction 2.40 versus 20.8; P < 0.001), CASP1 (fold induction 2.53 versus 24.8; P < 0.001), IL1B (fold induction 1.07 versus 10.93; P < 0.001), and IL18 (fold induction 2.56 versus 15.67; P < 0.001) in the ileum, and caspase 1 activity was increased (P < 0.01). The score of adherent and invasive mucosa-associated bacteria was higher in AS (P < 0.01) and correlated with the expression of inflammasome components in peripheral blood mononuclear cells (P < 0.001). NLRP3 expression was associated with disease activity (the Ankylosing Spondylitis Disease Activity Score using the C-reactive protein level) (r2 = 0.28, P < 0.01) and with IL23A expression (r2 = 0.34, P < 0.001). In vitro, inflammasome activation in AS monocytes was paralleled by increased serum levels of IL-1ß and IL-18. Induction of IL23A, IL17A, and IL22 was IL-1ß-dependent. CONCLUSION: Inflammasome activation occurs in rodent models of AS and in AS patients, is associated with dysbiosis, and is involved in triggering ileitis in SKG mice. Inflammasomes drive type III cytokine production with an IL-1ß-dependent mechanism in AS patients.


Assuntos
Doença de Crohn/imunologia , Disbiose/imunologia , Microbioma Gastrointestinal/imunologia , Íleo/imunologia , Inflamassomos/imunologia , Articulações/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Espondilite Anquilosante/imunologia , Adolescente , Adulto , Animais , Antibacterianos/farmacologia , Proteínas Adaptadoras de Sinalização CARD/imunologia , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Proteínas de Ligação ao Cálcio/imunologia , Proteínas de Ligação ao Cálcio/metabolismo , Estudos de Casos e Controles , Caspase 1/imunologia , Caspase 1/metabolismo , Doença de Crohn/microbiologia , Proteínas de Ligação a DNA/imunologia , Proteínas de Ligação a DNA/metabolismo , Feminino , Furanos/farmacologia , Antígeno HLA-B27/genética , Humanos , Ileíte/imunologia , Ileíte/metabolismo , Ileíte/patologia , Íleo/efeitos dos fármacos , Íleo/metabolismo , Íleo/patologia , Imuno-Histoquímica , Indenos/farmacologia , Interleucina-17/imunologia , Interleucina-18/imunologia , Interleucina-18/metabolismo , Interleucina-1beta/imunologia , Interleucina-1beta/metabolismo , Interleucina-23/imunologia , Articulações/efeitos dos fármacos , Articulações/metabolismo , Articulações/patologia , Masculino , Camundongos , Pessoa de Meia-Idade , Proteína 3 que Contém Domínio de Pirina da Família NLR/antagonistas & inibidores , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ratos , Ratos Transgênicos , Receptores de Superfície Celular/imunologia , Receptores de Superfície Celular/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Espondilite Anquilosante/microbiologia , Sulfonamidas/farmacologia , Adulto Jovem
18.
Arch Virol ; 166(1): 219-223, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33073324

RESUMO

Chronic joint pain is the most common pathology found in chikungunya virus (CHIKV)-infected patients. Eight cytokines were compared in CHIKV patients with and without joint pain. IL-4 and IL-13 levels were significantly lower in patients with joint pain (p = 0.006 and p < 0.0001, respectively). IL-18 levels were higher in the group of patients with joint pain (p < 0.0001) and were significantly higher on days 3 and 4 after onset (p = 0.0012 and p = 0.003, respectively). Moreover, TNF-α levels were significantly higher in patients with joint pain on day 3 (p = 0.028). This study demonstrated that cytokines, particularly IL-18, may be candidates for immunomodulation.


Assuntos
Febre de Chikungunya/imunologia , Vírus Chikungunya/imunologia , Imunomodulação/imunologia , Interleucina-18/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Artralgia/imunologia , Artralgia/virologia , Febre de Chikungunya/virologia , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/imunologia , Adulto Jovem
19.
Clin Exp Immunol ; 203(2): 174-182, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33128796

RESUMO

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, hyperinflammatory disorder, characterized by multiorgan failure, fever and cytopenias. The diagnosis of HLH and its subtype Macrophage Activation Syndrome (MAS) remains a challenge. Interleukin 18 (IL-18) is emerging as a potential biomarker for HLH/MAS but is currently not a part of diagnostic criteria. This systematic review aimed to assess the potential role of IL-18 in the diagnosis and monitoring of HLH and MAS, and was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. PubMed and Embase were searched on 30 January 2020. Studies included all subtypes of HLH and a range of underlying disorders in both children and adults. A total of 14 studies were included. Generally, serum IL-18 was elevated in both primary and secondary HLH (> 1000 pg/ml) compared with other inflammatory conditions and with healthy individuals; thus, serum IL-18 may be able to discriminate between HLH and other inflammatory conditions. Significantly increased IL-18 (> 10 000 pg/ml) was also consistently described in MAS compared with other subtypes of HLH. The ability of IL-18 to distinguish MAS from systemic juvenile idiopathic arthritis (JIA) is less unambiguous, as IL-18 levels > 100 000 pg/ml were described in sJIA patients both with and without MAS. IL-18 may help to differentiate between HLH subtypes and other inflammatory conditions. As HLH and MAS are rare disorders, only few and relatively small studies exist on the subject. Larger, prospective multi-center studies are called for to assess the diagnostic precision of IL-18 for HLH and MAS.


Assuntos
Interleucina-18/imunologia , Linfo-Histiocitose Hemofagocítica/diagnóstico , Síndrome de Ativação Macrofágica/diagnóstico , Macrófagos/imunologia , Monitorização Imunológica/métodos , Animais , Diagnóstico Diferencial , Humanos , Linfo-Histiocitose Hemofagocítica/imunologia , Ativação de Macrófagos , Síndrome de Ativação Macrofágica/imunologia , Fenótipo
20.
J Gastrointest Cancer ; 52(1): 31-40, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32944849

RESUMO

PURPOSE: The correlation of IL-8 and IL-18 gene polymorphisms with colorectal cancer (CRC) was investigated by previous studies, though the results remained conflicting. Thus, the meta-analysis was performed to investigate the association of IL-8 -251T>A and IL-18 -607C>A polymorphisms with CRC risk. METHODS: A comprehensive search of the PubMed, Web of Science, CNKI, SciELO, and Wanfang databases was performed up to February 20, 2020. The strength of the associations was calculated with odds ratios (ORs) and their corresponding 95% of confidence intervals (CIs). RESULTS: A total of 16 case-control studies including 13 studies with 3908 cases and 5005 controls on IL-8 -251T>A polymorphism and three studies with 396 cases and 560 controls on IL-18 -607C>A polymorphism were selected. Pooled data revealed that the IL-8 -251T>A and IL-18 -607C>A polymorphisms were not significantly associated with an increased risk of CRC in global population. When stratified by ethnicity, source of controls, sample size, and Hardy-Weinberg equilibrium (HWE), there were still no significant association between IL-8 -251T>A polymorphism and risk of CRC. CONCLUSIONS: Our results revealed that the IL-8 -251T>A and IL-18 -607C>A polymorphisms were not associated with an increased susceptibility to CRC. We strongly call for further studies with larger sample sizes and different ethnicities to confirm our findings.


Assuntos
Neoplasias Colorretais/genética , Predisposição Genética para Doença , Interleucina-18/genética , Interleucina-8/genética , Estudos de Casos e Controles , Neoplasias Colorretais/epidemiologia , Neoplasias Colorretais/imunologia , Humanos , Interleucina-18/imunologia , Interleucina-8/imunologia , Razão de Chances , Polimorfismo de Nucleotídeo Único
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