Chronic ThromboEmbolic Pulmonary Hypertension (CTEPH) is a rare but severe complication of pulmonary embolism (PE). CTEPH is evoked in patients with persistent dyspnea. According to international guidelines, symptomatic patients with perfusion defects on lung scan and Pulmonary Hypertension (PH)-likely transthoracic echo (TTE) must be evaluated in Pulmonary Hypertension (PH)-centers with right heart catheterism, to confirm or rule out the presence of precapillary Pulmonary Hypertension (PH), and precise the group of Pulmonary Hypertension (PH). However, persistent dyspnea and perfusion defects are frequent after pulmonary embolism (PE), and the accuracy of transthoracic echo (TTE) is not great for precapillary Pulmonary Hypertension (PH). This study proposed to seek for a specific proteomic pattern in patients admitted for a suspicion of Chronic ThromboEmbolic Pulmonary Hypertension (CTEPH).

Project Leader : Pr. Laurent Bertoletti

PI involved :  Pr. Xavier Delavenne

ITA involved: Sophie Hodin

Student involved : TBA

Extracellular vesicles (EVs) are active biological entities that participate in a wide range of cellular processes and functions, including intercellular communication, angiogenesis, coagulation and cell survival. Immune effector Cell-Associated Neurotoxicity (ICANS) is a new toxicity mainly described with immunotherapies as CAR-T cell. ICANS affects approximately a third of patients who receive this treatment. The ICANS mechanism has not yet been well understood. Autopsy studies showed endothelial activation markers and multifocal vascular abnormalities. It is hypothesized that activation of endothelial cells by systemic inflammation occurs when the release of pro-inflammatory cytokines at the time of CAR-T treatment increases the permeability of the blood-brain barrier (BBB). Indeed, it was shown in vitro that after exposure of brain endothelial cells to pro-inflammatory cytokines, these cells emitted EVs capable of modulating several functions and cellular partners (expression of junction zone proteins, resistance of endothelial cells brain, of the transcriptome modulation (pericytes), or increased adhesion of T lymphocytes to endothelial cells). In vivo, it has been demonstrated that endothelial EVs of cerebral origin are increased in the plasma of patients with other neuroinflammatory disorders such as multiple sclerosis during exacerbations of the disease. In patients treated with CAR T cells, only one team has published to date on the analysis of EVs. They showed an increase in CAR T EVs in the plasma of patients with ICANS and a higher proportion of senescent CD8+ T cells and M-MDSCs correlated with early signs of neuroaxonal damage before receiving CAR T cells, suggesting that ICANS could be the final event of a process that begins before infusion. However, no study analysed EVs of endothelial origin in these patients. Thus, we conduct a prospective study with the aim of characterizing the EVs secreted in patients treated with CAR-T cells, in particular EVs of endothelial origin, their presence and their possible role of EVs in the appearance of ICANS type neurological complications. Through this study, we combine three analysis methods to refine the phenotype of EVs : analysis using Nano Tracking Analysis, flow cytometry and electron microscopy. The cytokine profile and its kinetics during treatment and in the event of ICANS occurrence will be correlated to the analyzes of EVs. Patients carry out neuropsychological assessment and brain MRI to analyze the BBB permeability. This study, ultimately, could facilitate the detection, prevention and treatment of ICANS.

Project Leader : Dr. Emilie Chalayer

PI involved :

Dr Fouillet Ludovic, Clinical Haematology, CHU St Etienne

Dr. Duchez Anne Claire

Pr. Roche Fréderic

Pr. Perek Nathalie, SAINBIOSE DVH, groupe apnée du sommeil

Dr. Fabien SCHNEIDER, Radiology TAPE EA7423

Dr. Nora Mallouk-Forges, Centre de Microscopie Electronique Stéphanois

Student involved : Sébastien Charles