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1.
J Allergy Clin Immunol ; 151(2): 526-538.e8, 2023 02.
Artigo em Inglês | MEDLINE | ID: mdl-35963455

RESUMO

BACKGROUND: Neutrophilic asthma is associated with disease severity and corticosteroid insensitivity. Novel therapies are required to manage this life-threatening asthma phenotype. Programmed cell death protein-1 (PD-1) is a key homeostatic modulator of the immune response for T-cell effector functions. OBJECTIVE: We sought to investigate the role of PD-1 in the regulation of acute neutrophilic inflammation in a murine model of airway hyperreactivity (AHR). METHODS: House dust mite was used to induce and compare neutrophilic AHR in wild-type and PD-1 knockout mice. Then, the therapeutic potential of a human PD-1 agonist was tested in a humanized mouse model in which the PD-1 extracellular domain is entirely humanized. Single-cell RNA sequencing and flow cytometry were mainly used to investigate molecular and cellular mechanisms. RESULTS: PD-1 was highly induced on pulmonary T cells in our inflammatory model. PD-1 deficiency was associated with an increased neutrophilic AHR and high recruitment of inflammatory cells to the lungs. Consistently, PD-1 agonist treatment dampened AHR, decreased neutrophil recruitment, and modulated cytokine production in a humanized PD-1 mouse model. Mechanistically, we demonstrated at the transcriptional and protein levels that the inhibitory effect of PD-1 agonist is associated with the reprogramming of pulmonary effector T cells that showed decreased number and activation. CONCLUSIONS: PD-1 agonist treatment is efficient in dampening neutrophilic AHR and lung inflammation in a preclinical humanized mouse model.


Assuntos
Asma , Receptor de Morte Celular Programada 1 , Humanos , Animais , Camundongos , Receptor de Morte Celular Programada 1/metabolismo , Pulmão , Células Th2 , Modelos Animais de Doenças
2.
Front Immunol ; 12: 733136, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34531874

RESUMO

While pulmonary ILC2s represent one of the major tissue-resident innate lymphoid cell populations at steady state and are key drivers of cytokine secretion in their occupational niche, their role in pulmonary cancer progression remains unclear. As the programmed cell death protein-1 (PD-1) plays a major role in cancer immunotherapy and immunoregulatory properties, here we investigate the specific effect of PD-1 inhibition on ILC2s during pulmonary B16 melanoma cancer metastasis. We demonstrate that PD-1 inhibition on ILC2s suppresses B16 tumor growth. Further, PD-1 inhibition upregulates pulmonary ILC2-derived TNF-α production, a cytotoxic cytokine that directly induces cell death in B16 cells, independent of adaptive immunity. Together, these results highlight the importance of ILC2s and their anti-tumor role in pulmonary B16 cancer progression during PD-1 inhibitory immunotherapy.


Assuntos
Inibidores de Checkpoint Imunológico/farmacologia , Neoplasias Pulmonares/tratamento farmacológico , Linfócitos/efeitos dos fármacos , Melanoma Experimental/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Neoplasias Cutâneas/tratamento farmacológico , Microambiente Tumoral , Fator de Necrose Tumoral alfa/metabolismo , Animais , Linhagem Celular Tumoral , Progressão da Doença , Humanos , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/secundário , Linfócitos/imunologia , Linfócitos/metabolismo , Melanoma Experimental/imunologia , Melanoma Experimental/metabolismo , Melanoma Experimental/secundário , Camundongos Endogâmicos BALB C , Camundongos Knockout , Receptor de Morte Celular Programada 1/metabolismo , Neoplasias Cutâneas/imunologia , Neoplasias Cutâneas/metabolismo , Neoplasias Cutâneas/patologia , Carga Tumoral
3.
Mucosal Immunol ; 14(4): 899-911, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33731828

RESUMO

Allergic asthma is a chronic inflammatory disorder associated with airway hyperreactivity (AHR) whose global prevalence is increasing at an alarming rate. Group 2 innate lymphoid cells (ILC2s) and T helper 2 (TH2) cells are producers of type 2 cytokines, which may contribute to development of AHR. In this study, we explore the potential of CD52-targeted depletion of type 2 immune cells for treating allergic AHR. Here we show that anti-CD52 therapy can prevent and remarkably reverse established IL-33-induced AHR by reducing airway resistance and alleviating lung inflammation. We further show that CD52 depletion prevents and treats allergic AHR induced by clinically relevant allergens such as Alternaria alternata and house dust mite. Importantly, we leverage various humanized mice models of AHR to show new therapeutic applications for Alemtuzumab, an anti-CD52 depleting antibody that is currently FDA approved for treatment of multiple sclerosis. Our results demonstrate that CD52 depletion is a viable therapeutic option for reduction of pulmonary inflammation, abrogation of eosinophilia, improvement of lung function, and thus treatment of allergic AHR. Taken together, our data suggest that anti-CD52 depleting monoclonal antibodies, such as Alemtuzumab, can serve as viable therapeutic drugs for amelioration of TH2- and ILC2-dependent AHR.


Assuntos
Alemtuzumab/farmacologia , Anti-Inflamatórios/farmacologia , Antineoplásicos Imunológicos/farmacologia , Asma/etiologia , Antígeno CD52/antagonistas & inibidores , Pneumonia/etiologia , Imunidade Adaptativa/imunologia , Alérgenos/imunologia , Animais , Asma/tratamento farmacológico , Asma/metabolismo , Asma/patologia , Proteínas de Ligação a DNA/deficiência , Modelos Animais de Doenças , Suscetibilidade a Doenças , Humanos , Imunidade Inata , Subpopulações de Linfócitos , Camundongos , Camundongos Knockout , Pneumonia/tratamento farmacológico , Pneumonia/metabolismo , Pneumonia/patologia , Pyroglyphidae/imunologia , Células Th2/imunologia , Células Th2/metabolismo
4.
Nat Commun ; 10(1): 5681, 2019 12 12.
Artigo em Inglês | MEDLINE | ID: mdl-31831743

RESUMO

Aberrant autophagy is a major risk factor for inflammatory diseases and cancer. However, the genetic basis and underlying mechanisms are less established. UVRAG is a tumor suppressor candidate involved in autophagy, which is truncated in cancers by a frameshift (FS) mutation and expressed as a shortened UVRAGFS. To investigate the role of UVRAGFS in vivo, we generated mutant mice that inducibly express UVRAGFS (iUVRAGFS). These mice are normal in basal autophagy but deficient in starvation- and LPS-induced autophagy by disruption of the UVRAG-autophagy complex. iUVRAGFS mice display increased inflammatory response in sepsis, intestinal colitis, and colitis-associated cancer development through NLRP3-inflammasome hyperactivation. Moreover, iUVRAGFS mice show enhanced spontaneous tumorigenesis related to age-related autophagy suppression, resultant ß-catenin stabilization, and centrosome amplification. Thus, UVRAG is a crucial autophagy regulator in vivo, and autophagy promotion may help prevent/treat inflammatory disease and cancer in susceptible individuals.


Assuntos
Autofagia/genética , Carcinogênese/genética , Inflamação/genética , Mutação , Proteínas Supressoras de Tumor/genética , Animais , Carcinogênese/patologia , Proliferação de Células , Centrossomo , Colite , Neoplasias do Colo/patologia , Neoplasias Colorretais/genética , Feminino , Mutação da Fase de Leitura , Inflamassomos , Lipopolissacarídeos/efeitos adversos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína 3 que Contém Domínio de Pirina da Família NLR , Sepse , Inanição , Receptor 4 Toll-Like/metabolismo
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