Development of a Multivariate Prediction Model for Early-Onset Bronchiolitis Obliterans Syndrome and Restrictive Allograft Syndrome in Lung Transplantation.

Chronic lung allograft dysfunction and its main phenotypes, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), are major causes of mortality after lung transplantation (LT). RAS and early-onset BOS, developing within 3 years after LT, are associated with particularly inferior clinical outcomes. Prediction models for early-onset BOS and RAS have not been previously described. LT recipients of the French and Swiss transplant cohorts were eligible for inclusion in the SysCLAD cohort if they were alive with at least 2 years of follow-up but less than 3 years, or if they died or were retransplanted at any time less than 3 years. These patients were assessed for early-onset BOS, RAS, or stable allograft function by an adjudication committee. Baseline characteristics, data on surgery, immunosuppression, and year-1 follow-up were collected. Prediction models for BOS and RAS were developed using multivariate logistic regression and multivariate multinomial analysis. Among patients fulfilling the eligibility criteria, we identified 149 stable, 51 BOS, and 30 RAS subjects. The best prediction model for early-onset BOS and RAS included the underlying diagnosis, induction treatment, immunosuppression, and year-1 class II donor-specific antibodies (DSAs). Within this model, class II DSAs were associated with BOS and RAS, whereas pre-LT diagnoses of interstitial lung disease and chronic obstructive pulmonary disease were associated with RAS. Although these findings need further validation, results indicate that specific baseline and year-1 parameters may serve as predictors of BOS or RAS by 3 years post-LT. Their identification may allow intervention or guide risk stratification, aiming for an individualized patient management approach

Modulation de l'activation lymphocytaire T dans l'asthme et le rejet chronique de transplantation pulmonaire

L activation des lymphocytes T (LT) est un évènement majeur de la réaction inflammatoire de la pathologie bronchique. Notre travail a porté sur l étude de l activation des LT dans l asthme et la bronchiolite oblitérante (BO) des transplantés pulmonaires. Dans l asthme, nos résultats montrent une activation Th1 de base (IFN-g+ augmentés), associée à un déficit en LT régulateurs (Treg) (CD4+CD25+Foxp3+ et CTLA-4+ diminués). Dans l allergie, c est la stimulation spécifique qui induit une activation Th2 (CD28+, IL-4+ et IL-13+ accrus) et un déficit en Treg (CD4+CD25+Foxp3+, CTLA-4+, IL-10+ diminués). Par l utilisation d anticorps anti-corécepteurs nous avons pu démontrer que la production d IL 4 dépend de l engagement d ICOS et CD28, alors que celle d IL-13 passe en plus par CTLA-4. Dans l allergie, l étude de l expression des récepteurs à l histamine HR1 et HR2 et l utilisation d un agoniste inverse de HR1, a permis de mettre en évidence le rôle de ce récepteur dans l activation Th2. Chez les transplantés pulmonaires, nous avons étudié plus particulièrement l interaction cellule dendritiques (DC)/LT et analysé le phénotype de ces cellules en présence d antigène bactérien ou d anticorps anti-corécepteur. Les DC des sujets sains sont immatures par rapport à celles des BO (CD80+ et CD83+ diminuées, IDO+ accrue) et induisent les Treg (CD4+CD25+Foxp3+, IL-10+, CTLA-4+ augmentés et LT IL-13+, IL-4+ et ICOS+ abaissés). Ce résultat, qui est conservé après stimulation bactérienne, dépend de l engagement de CTLA-4.T cell activation is a major event of the inflammatory reaction in bronchial pathology. The aim of our work was to study T cell activation in asthma and bronchiolitis obliterans syndrome (BOS) in lung transplant recipients (LTR). In asthma, our results show a basal Th1 activation (up-regulation of IFN-g+), associated with a deficit in T regulatory cells (Treg) (decreased CD4+CD25+Foxp3+ and CTLA-4+). In allergy, the allergen-specific stimulation induced a Th2 activation (increased CD28+, IL-4+ and IL-13+) and a deficit in Treg cells (decreased CD4+CD25+Foxp3+, CTLA-4+, IL 10+). The use of anticoreceptors antibodies leads us to demonstrate that IL-4 production was dependant on ICOS and CD28 engagement, whereas IL-13 production also depends on CTLA-4. In allergy, the study of histamine receptor 1 (H1R) and H2R expression as well as the use of H1R inverse agonist, also demonstrated the role of H1R in Th2 activation. In LTR, we studied the dendritic cells (DC)/T cell interactions and analysed the cell phenotype in the presence of bacterial compounds or anti-coreceptors antibodies. DC from healthy LTR are immature when compared to those from BOS (decreased CD80+ and CD83+, increased IDO+) et induced a tolerant phenotype of T cells (CD4+CD25+Foxp3+, IL-10+, CTLA-4+ increase and IL-13+, IL-4+, ICOS+ decrease). This result, which is conserved after bacterial stimulation, is dependant on CTLA-4.AIX-MARSEILLE2-BU Méd/Odontol. (130552103) / SudocSudocFranceF

Tissue remodelling in chronic bronchial diseases: from the epithelial to mesenchymal phenotype

International audienceAirway remodelling is a critical feature of chronic bronchial diseases, characterised by aberrant repair of the epithelium and accumulation of fibroblasts, which contribute to extracellular matrix (ECM) deposition resulting in fixed bronchial obstruction. Recently, epithelial-mesenchymal transition (EMT) has been identified as a new source of fibroblasts that could contribute to the remodelling of the airways. This phenomenon consists of the loss of the epithelial phenotype by bronchial epithelial cells and the acquisition of a mesenchymal phenotype. These cells are then able to migrate and secrete ECM molecules. Herein, we review the different types of EMT. We will then focus on the signalling pathways that are involved, such as transforming growth factor-b and Wnt, as well as the more recently described Sonic Hedgehog pathway. Finally, we will highlight the implication of EMT in airway remodelling in specific chronic bronchial pathologies, such as asthma, chronic obstructive pulmonary disease and bronchiolitis obliterans following lung transplantation. Despite the limitations of in vitro models, future studies of EMT in vivo are warranted to shed new light on the pathomechanisms of bronchial obstruction

Evaluation of the safety and efficacy of XAV-19 in patients with COVID-19-induced moderate pneumonia: study protocol for a randomized, double-blinded, placebo-controlled phase 2 (2a and 2b) trial

International audienceBackground: Early inhibition of entry and replication of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a very promising therapeutic approach. Polyclonal neutralizing antibodies offers many advantages such as providing immediate immunity, consequently blunting an early pro-inflammatory pathogenic endogenous antibody response and lack of drug-drug interactions. By providing immediate immunity and inhibiting entry into cells, neutralizing antibody treatment is of interest for patient with COVID-19-induced moderate pneumonia. Convalescent plasma to treat infected patients is therefore a relevant therapeutic option currently under assessment (CORIMUNO-PLASM NCT04324047). However, the difficulties of collecting plasma on the long term are not adapted to a broad use across all populations. New polyclonal humanized anti-SARS-CoV2 antibodies (XAV-19) developed by Xenothera and administered intravenous. XAV-19 is a heterologous swine glyco-humanized polyclonal antibody (GH-pAb) raised against the spike protein of SARS-CoV-2, blocking infection of ACE-2-positive human cells with SARS-CoV-2.Methods: Pharmacokinetic and pharmacodynamic studies have been performed in preclinical models including primates. A first human study with another fully representative GH-pAb from Xenothera is ongoing in recipients of a kidney graft. These studies indicated that 5 consecutive administrations of GH-pAbs can be safely performed in humans. The objectives of this 2-step phase 2 randomized double-blinded, placebo-controlled study are to define the safety and the optimal XAV-19 dose to administrate to patients with SARS-CoV-2 induced moderate pneumonia, and to assess the clinical benefits of a selected dose of XAV-19 in this population.Discussion: This study will determine the clinical benefits of XAV-19 when administered to patients with SARS-CoV-2-induced moderate pneumonia. As a prerequisite, a first step of the study will define the safety and the dose of XAV-19 to be used. Such treatment might become a new therapeutic option to provide an effective treatment for COVID-19 patients (possibly in combination with anti-viral and immunotherapies). Further studies could later evaluate such passive immunotherapy as a potential post-exposure prophylaxis

Systematic Analysis of Blood Cell Transcriptome in End-Stage Chronic Respiratory Diseases

International audienceBackgroundEnd-stage chronic respiratory diseases (CRD) have systemic consequences, such as weight loss and susceptibility to infection. However the mechanisms of such dysfunctions are as yet poorly explained. We hypothesized that the genes putatively involved in these mechanisms would emerge from a systematic analysis of blood mRNA profiles from pre-transplant patients with cystic fibrosis (CF), pulmonary hypertension (PAH), and chronic obstructive pulmonary disease (COPD).MethodsWhole blood was first collected from 13 patients with PAH, 23 patients with CF, and 28 Healthy Controls (HC). Microarray results were validated by quantitative PCR on a second and independent group (7PAH, 9CF, and 11HC). Twelve pre-transplant COPD patients were added to validate the common signature shared by patients with CRD for all causes. To further clarify a role for hypoxia in the candidate gene dysregulation, peripheral blood mononuclear cells from HC were analysed for their mRNA profile under hypoxia.ResultsUnsupervised hierarchical clustering allowed the identification of 3 gene signatures related to CRD. One was common to CF and PAH, another specific to CF, and the final one was specific to PAH. With the common signature, we validated T-Cell Factor 7 (TCF-7) and Interleukin 7 Receptor (IL-7R), two genes related to T lymphocyte activation, as being under-expressed. We showed a strong impact of the hypoxia on modulation of TCF-7 and IL-7R expression in PBMCs from HC under hypoxia or PBMCs from CRD. In addition, we identified and validated genes upregulated in PAH or CF, including Lectin Galactoside-binding Soluble 3 and Toll Like Receptor 4, respectively.ConclusionsSystematic analysis of blood cell transcriptome in CRD patients identified common and specific signatures relevant to the systemic pathologies. TCF-7 and IL-7R were downregulated whatever the cause of CRD and this could play a role in the higher susceptibility to infection of these patients

Proliferation and collagen synthesis of human anterior cruciate ligament cells in vitro: effects of ascorbate-2-phosphate, dexamethasone and oxygen tension.

Clinical and experimental studies demonstrate that injured anterior cruciate ligaments (ACL) do not usually heal and that autografts used to repair the ACL rapidly weaken in the early period and take a long time to regain strength. The aim of this study was to develop an in vitro culture system in which environmental and biochemical factors influencing the proliferation and matrix synthesis of cells derived from human anterior cruciate ligaments can be studied. Primary cultures of human ACL cells were obtained by outgrowth from explants of normal ACL obtained at knee replacement for osteoarthritis in Dulbecco's minimum essential medium (DMEM). The effects of the additives 100 microm L-ascorbic acid-2-phosphate (Asc-2-P) and 10 n m dexamethasone (dex) on proliferation and collagen synthesis were assessed after 4, 8 and 12 days in culture. Ligament cells were grown at 0, 5, 10 and 21%p O(2)in the presence of 100 microm asc-2-P and 10 n m dex. DNA content was assessed using the Hoechst dye method and collagen synthesis by the incorporation of 5 mCi/ml [(3)H]proline after 3, 6 and 12 days in culture. At 21%p O(2), the presence of asc-2-P and dex induced significantly greater (P< 0.01, ANOVA) cell proliferation than with either additives alone. Greatest percentage collagen to total protein synthesis was observed when cells were grown in the presence of asc-2-P only. Least proliferation and percentage collagen to total protein synthesis was seen when both additives were omitted. Greatest cell proliferation was seen when cells were grown in 10%p O(2)and 5%p O(2)was associated with increased collagen synthesis. These results suggest that it is possible to study the effects of environmental and biochemical factors on human ACL healing in vitro. Our data suggest oxygen can influence certain biosynthetic activities of ACL cells. Low oxygen tensions lead to an increase in collagen production by ACL cells. However early responses to injury require extensive cell proliferation which may be activated at higher p O(2). Variation of p O(2)in ligaments during healing may therefore be an important modulator of successful repair

Development of a Multivariate Prediction Model for Early-Onset Bronchiolitis Obliterans Syndrome and Restrictive Allograft Syndrome in Lung Transplantation

BACKGROUND: Chronic lung allograft dysfunction and its main phenotypes, bronchiolitis obliterans syndrome (BOS) and restrictive allograft syndrome (RAS), are major causes of mortality after lung transplantation (LT). RAS and early-onset BOS, developing within 3 years after LT, are associated with particularly inferior clinical outcomes. Prediction models for early-onset BOS and RAS have not been previously described. METHODS: LT recipients of the French and Swiss transplant cohorts were eligible for inclusion in the SysCLAD cohort if they were alive with at least 2 years of follow-up but less than 3 years, or if they died or were retransplanted at any time less than 3 years. These patients were assessed for early-onset BOS, RAS, or stable allograft function by an adjudication committee. Baseline characteristics, data on surgery, immunosuppression, and year-1 follow-up were collected. Prediction models for BOS and RAS were developed using multivariate logistic regression and multivariate multinomial analysis. RESULTS: Among patients fulfilling the eligibility criteria, we identified 149 stable, 51 BOS, and 30 RAS subjects. The best prediction model for early-onset BOS and RAS included the underlying diagnosis, induction treatment, immunosuppression, and year-1 class II donor-specific antibodies (DSAs). Within this model, class II DSAs were associated with BOS and RAS, whereas pre-LT diagnoses of interstitial lung disease and chronic obstructive pulmonary disease were associated with RAS. CONCLUSION: Although these findings need further validation, results indicate that specific baseline and year-1 parameters may serve as predictors of BOS or RAS by 3 years post-LT. Their identification may allow intervention or guide risk stratification, aiming for an individualized patient management approach.status: publishe

Fantasía, onirismo y muerte en las novelas de Espido Freire

Esta investigación pretende realizar un estudio semiótico aproximativo a las novelas de Laura Espido. Para ello hemos partido de las novelas Irlanda, Donde siempre es octubre, Melocotones helados, Diabulus in musica y Nos espera la noche. No hemos seleccionado para este análisis La última batalla de Vincavec, novela juvenil, así como tampoco los cuentos realizados por la escritora, puesto que son bastante numerosos y excedería los límites de este trabajo. Por otra parte, estas narraciones breves se hallan incluidas en periódicos, revistas, premios y algunos en internet que en estos momentos dificultaría su recopilación, pero pretendemos que vea la luz posteriormente

Characterization of under-expressed genes in the CRD signature.

<p>A) Tree analysis of the CRD signature. Identification of the most representative genes by Gominer, PAM, IPA analysis and validation of the candidate genes in the validation cohort by qPCR; B) Network generated by IPA on the most significant GO categories in the CRD signature. Solid lines indicate <i>direct</i> interactions and dashed lines represent <i>indirect</i> interactions. Under-expressed genes in CRD are in gray. C) PAM analysis based on the most representative GO categories of Cluster A and B. Green represents relatively low expression, and red indicates relatively high expression. D) List of 9 genes able to classify correctly CRD and HC. E) The PCA graph of the 9 genes identified by PAM analysis indicated a clear separation between HC and patients with CRD (CF and PAH).</p

Gominer Analysis based for over-expressed genes in CF signature versus HC.

<p>Only GO categories enriched in cluster D (A) and in cluster E (B) with FDR less than 1%, with enrichment superior to 2 and with more than 10 genes are displayed.</p><p>Gominer Analysis based for over-expressed genes in CF signature versus HC.</p