RESUMO
Neurotrophins such as nerve growth factor and brain-derived neurotrophic factor have been described to be involved in the pathogenesis of asthma. Neurturin (NTN), another neurotrophin from the glial cell line-derived neurotrophic factor family, was shown to be produced by human immune cells: monocytes, B cells, and T cells. Furthermore, it was previously described that the secretion of inflammatory cytokines was dramatically stimulated in NTN knockout (NTN(-/-)) mice. NTN is structurally similar to TGF-ß, a protective cytokine in airway inflammation. This study investigates the implication of NTN in a model of allergic airway inflammation using NTN(-/-) mice. The bronchial inflammatory response of OVA-sensitized NTN(-/-) mice was compared with wild-type mice. Airway inflammation, Th2 cytokines, and airway hyperresponsiveness (AHR) were examined. NTN(-/-) mice showed an increase of OVA-specific serum IgE and a pronounced worsening of inflammatory features. Eosinophil number and IL-4 and IL-5 concentration in the bronchoalveolar lavage fluid and lung tissue were increased. In parallel, Th2 cytokine secretion of lung draining lymph node cells was also augmented when stimulated by OVA in vitro. Furthermore, AHR was markedly enhanced in NTN(-/-) mice after sensitization and challenge when compared with wild-type mice. Administration of NTN before challenge with OVA partially rescues the phenotype of NTN(-/-) mice. These findings provide evidence for a dampening role of NTN on allergic inflammation and AHR in a murine model of asthma.
Assuntos
Asma/imunologia , Hiper-Reatividade Brônquica/imunologia , Citocinas/imunologia , Neurturina/imunologia , Células Th2/imunologia , Animais , Anticorpos/sangue , Anticorpos/imunologia , Asma/metabolismo , Hiper-Reatividade Brônquica/metabolismo , Líquido da Lavagem Broncoalveolar/química , Líquido da Lavagem Broncoalveolar/citologia , Líquido da Lavagem Broncoalveolar/imunologia , Citocinas/metabolismo , Eosinófilos/imunologia , Eosinófilos/metabolismo , Citometria de Fluxo , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/imunologia , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Pulmão/patologia , Linfonodos/imunologia , Linfonodos/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurturina/deficiência , Neurturina/genética , Ovalbumina/imunologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Células Th2/metabolismoRESUMO
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused a pandemic of respiratory and cardiovascular diseases, known as coronavirus disease 2019 (COVID-19). SARS-CoV-2 encodes the structural proteins spike (S), envelope (E), membrane (M), and nucleocapsid (N). The receptor-binding domain on the surface subunit S1 is responsible for attachment of the virus to angiotensin (Ang)-converting enzyme 2 (ACE2), which is highly expressed in host cells. The cytokine storm observed in patients with COVID-19 contributes to the endothelial vascular dysfunction, which can lead to acute respiratory distress syndrome, multiorgan failure, alteration in iron homeostasis, and death. Growth and differentiation factor 15 (GDF15), which belongs to the transforming growth factor-ß (TGF-ß) superfamily of proteins, has a pivotal role in the development and progression of diseases because of its role as a metabolic regulator. In COVID-19, GDF15 activity increases in response to tissue damage. GDF15 appears to be a strong predictor of poor outcomes in patients critically ill with COVID-19 and acts as an 'inflammation-induced central mediator of tissue tolerance' via its metabolic properties. In this review, we examine the potential properties of GDF15 as an emerging modulator of immunity in COVID-19 in association with iron metabolism. The virus life cycle in host cell provides potential targets for drug therapy.
Assuntos
COVID-19/imunologia , Síndrome da Liberação de Citocina/imunologia , Endotélio Vascular/imunologia , Fator 15 de Diferenciação de Crescimento/imunologia , Ferro/metabolismo , Apoptose/imunologia , COVID-19/metabolismo , Síndrome da Liberação de Citocina/metabolismo , Endotélio Vascular/metabolismo , Endotélio Vascular/fisiopatologia , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/imunologia , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/metabolismo , Fator 15 de Diferenciação de Crescimento/metabolismo , Humanos , Fatores Imunológicos/uso terapêutico , Estresse Oxidativo/imunologia , Prognóstico , Piroptose/imunologia , SARS-CoV-2 , Tratamento Farmacológico da COVID-19RESUMO
Luminal A (hormone receptor-positive) breast cancer constitutes 70% of total breast cancer patients. In an attempt to develop a targeted therapeutic for this cancer indication, we have identified and characterized Glial cell line-Derived Neurotrophic Factor (GDNF) Family Receptor Alpha 1 (GFRA1) antibody-drug conjugates (ADC) using a cleavable valine-citrulline-MMAE (vcMMAE) linker-payload. RNAseq and IHC analysis confirmed the abundant expression of GFRA1 in luminal A breast cancer tissues, whereas minimal or no expression was observed in most normal tissues. Anti-GFRA-vcMMAE ADC internalized to the lysosomes and exhibited target-dependent killing of GFRA1-expressing cells both in vitro and in vivo The ADCs using humanized anti-GFRA1 antibodies displayed robust therapeutic activity in clinically relevant cell line-derived (MCF7 and KPL-1) tumor xenograft models. The lead anti-GFRA1 ADC cross-reacts with rodent and cynomolgus monkey GFRA1 antigen and showed optimal pharmacokinetic properties in both species. These properties subsequently enabled a target-dependent toxicity study in rats. Anti-GFRA1 ADC is well tolerated in rats, as seen with other vcMMAE linker-payload based ADCs. Overall, these data suggest that anti-GFRA1-vcMMAE ADC may provide a targeted therapeutic opportunity for luminal A breast cancer patients. Mol Cancer Ther; 17(3); 638-49. ©2017 AACR.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/antagonistas & inibidores , Imunoconjugados/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Anticorpos/química , Anticorpos/imunologia , Anticorpos/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Sobrevivência Celular/genética , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/genética , Receptores de Fator Neurotrófico Derivado de Linhagem de Célula Glial/imunologia , Células HEK293 , Humanos , Imunoconjugados/imunologia , Imunoconjugados/farmacocinética , Células MCF-7 , Macaca fascicularis , Camundongos Nus , Camundongos SCID , Ratos Sprague-Dawley , Receptores de Esteroides/metabolismo , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/genéticaRESUMO
Label-free biosensors are often used in the discovery of therapeutic antibodies to characterize the epitope binding regions of a panel of monoclonal antibodies that target a specific antigen, thus facilitating their organization into epitope groups or "bins". When tested in a pairwise combinatorial manner, two antibodies that compete with one another for binding to a specific antigen may be grouped into the same epitope bin - that is, they recognize similar or overlapping epitopes - whereas two antibodies that bind simultaneously to the antigen are placed into different epitope bins. However, depending on the assay format used, results from such experiments can sometimes contradict one another. Here, we provide two examples that illustrate how antigen heterogeneity, either inherent in an antigen sample, or induced by the assay conditions, can confound the interpretation of epitope binning results and, in some cases, lead to erroneous conclusions. We highlight why assays that employ solution antigen are often more reliable than those that employ immobilized antigen and, by corroborating our binning results with assays that utilize native antigen, we determine which subpopulations of our heterogeneous antigen samples are biologically relevant and thus improve the correlation between epitope bins and functional activity. Furthermore, we provide recommendations for performing definitive binning assays and a diagnostic assay procedure that can be followed when antigen heterogeneity is suspected.