Correlation between systemic allergen desensitisation and long-term asthma protection in mice following intravenous administration of the live tuberculosis vaccine MTBVAC.

BACKGROUND: MTBVAC is a live attenuated tuberculosis vaccine, currently undergoing phase III evaluation for tuberculosis prevention. In previous preclinical studies, we found that local pulmonary administration of MTBVAC via the intranasal route had a strong therapeutic effect against asthma. This effect correlated with the abrogation of allergen-specific Th2 response in the lungs. METHODS: Using different mouse models of asthma, we investigated the effect of MTBVAC administered by intravenous (IV) route and its potential as immunotherapeutic agent to induce desensitisation of allergen-specific responses at a systemic level. We explored the effects of this process in the efficacy against airway hyperresponsiveness (AHR) induced by exposure to different allergens. FINDINGS: IV MTBVAC was highly efficient at reducing AHR induced by different allergens. Additionally, IV MTBVAC was found to be well-tolerated, being progressively eliminated from the different organs analysed. From a mechanistic standpoint, we observed that MTBVAC intravenous, but not intranasal, impaired allergen-specific Th2 response in both lungs and spleen. This reduction at a systemic level correlated with long-term therapeutic protection against allergen exposure. Our results also revealed differential immunological mechanisms governing systemic and local pulmonary allergen desensitisation processes. Notably, in a cohort of patients with asthma sensitive to house dust mite (HDM), in vitro incubation of peripheral blood mononuclear cells (PBMCs) with MTBVAC prevented allergen-specific production of Th2 cytokines IL-4 and IL-5. INTERPRETATION: Altogether, our results suggest that intravenous MTBVAC could be a plausible allergen desensitising approach for treatment of asthma, and could provide long-term protection against allergen exposure. FUNDING: MCIN/AEI/10.13039/501100011033 [grants number RTI2018-097625-B-I00 and PID2022-138624OB-I00]; Consorcio Centro de Investigación Biomédica en Red- (Groups CB06/06/0020 and CB06/06/0013), Instituto de Salud Carlos III.

Serum microRNAs as Tool to Predict Early Response to Benralizumab in Severe Eosinophilic Asthma.

Severe eosinophilic asthma poses a serious health and economic problem, so new therapy approaches have been developed to control it, including biological drugs such as benralizumab, which is a monoclonal antibody that binds to IL-5 receptor alpha subunit and depletes peripheral blood eosinophils rapidly. Biomarkers that predict the response to this drug are needed so that microRNAs (miRNAs) can be useful tools. This study was performed with fifteen severe eosinophilic asthmatic patients treated with benralizumab, and serum miRNAs were evaluated before and after treatment by semi-quantitative PCR (qPCR). Patients showed a clinical improvement after benralizumab administration. Additionally, deregulation of miR-1246, miR-5100 and miR-338-3p was observed in severe asthmatic patients after eight weeks of therapy, and a correlation was found between miR-1246 and eosinophil counts, including a number of exacerbations per year in these severe asthmatics. In silico pathway analysis revealed that these three miRNAs are regulators of the MAPK signaling pathway, regulating target genes implicated in asthma such as NFKB2, NFATC3, DUSP1, DUSP2, DUSP5 and DUSP16. In this study, we observed an altered expression of miR-1246, miR-5100 and miR-338-3p after eight weeks of benralizumab administration, which could be used as early response markers.

Stability of asthma control implies no changes in microRNAs expression

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Eosinophilic COPD Patients Display a Distinctive Serum miRNA Profile From Asthma and Non-eosinophilic COPD / Los pacientes con EPOC eosinofílica presentan un perfil de miRNA en suero diferente a los asmáticos y EPOC no eosinofílicos

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are common chronic airway diseases that may overlap in some individuals. Asthma COPD overlap (ACO) is a heterogeneous conditions that includes smoking-asthma (SA) and COPD with eosinophilia (COPDe). MicroRNAs (miRNA) are regulators of gene expression with a great potential as biomarkers. OBJECTIVES: The objective of this study was to identify distinctive miRNA signatures in patients from the whole spectrum of chronic obstructive bronchial disease (SA, COPDe, non-smoking asthmatics (NSA), and COPD) that could serve as diagnostic biomarkers or describe differential molecular mechanisms with potential therapeutic implications. METHODS: From a previously characterized cohort of ACO, COPD and asthma patients, we selected a discovery group of 40 patients for miRNA expression profiling by means of microarray technology. Differential expression of miRNAs were validated by quantitative PCR in the complete cohort (n = 274). RESULTS: Thirty differentially expressed miRNAs (eBAYES p < 0.05, fold change ≥ 2) were found among the different groups of patients regarding COPDe: 19 COPD-vs-COPDe, 13 NSA-vs-COPDe, 11 SA-vs-COPDe. A characteristic down-regulated miRNA expression pattern was identified in COPDe patients. Differential expression of miR-619-5p and miR-4486 in COPDe patients were validated in the complete cohort (n = 274). Conclusions: We postulate that COPDe patients show a characteristic expression profile of miRNAs distinctive from asthma and COPD. Also that SA and COPDe patients, which have been typically clustered in the ACO group, display distinct molecular events

ANTECEDENTES: El asma y la enfermedad pulmonar obstructiva crónica (EPOC) son enfermedades crónicas comunes de la vía aérea y pueden solaparse en algunos individuos. El solapamiento de asma y EPOC (ACO, por sus siglas en inglés) es una enfermedad heterogénea que incluye el asma en fumadores (AF) y la EPOC con eosinofilia (EPOCe). Los microRNA (miRNA) son reguladores de la expresión de genes con gran potencial para su uso como biomarcadores. OBJETIVOS: El objetivo de este estudio fue identificar las firmas características de miRNA en pacientes del espectro de enfermedades pulmonares obstructivas crónicas al completo (AF, EPOCe, asmáticos no fumadores y EPOC) que pudieran servir como biomarcadores diagnósticos o describir mecanismos moleculares diferenciales con potenciales implicaciones terapéuticas. MÉTODOS: A partir de una cohorte previamente caracterizada de pacientes con ACO, EPOC y asma, seleccionamos un grupo de descubrimiento de 40 pacientes para realizar sus perfiles de expresión de miRNA mediante microarrays. La expresión diferencial de miRNA se validó mediante PCR cuantitativa en la cohorte completa (n = 274). RESULTADOS: Se encontraron 30 miRNA expresados diferencialmente (eBayes p < 0,05, fold change [cambio en incremento] ≥ 2) entre los diferentes grupos de pacientes en relación con la EPOCe: 19 EPOC comparado con EPOCe, 13 asmáticos no fumadores comparado con EPOCe, 11 AF comparado con EPOCe. Se identificó un patrón característico de expresión con regulación a la baja de miRNA. La expresión diferencial de miR-619-5p y miR-4486 en los pacientes con EPOCe se validó con la cohorte al completo (n = 274). CONCLUSIONES: Postulamos que los pacientes con EPOCe muestran un perfil de expresión de miRNA característico y diferente al del asma y la EPOC. También que los pacientes con AF y con EPOCe, que se han agrupado típicamente en el grupo de ACO, muestran eventos moleculares diferenciales