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Inhibition of B cell-dependent lymphoid follicle formation prevents lymphocytic bronchiolitis after lung transplantation.

ABSTRACT: Lung transplantation (LTx) is the only therapeutic option for many patients with chronic lung disease. However, long-term survival after LTx is severely compromised by chronic rejection (chronic lung allograft dysfunction [CLAD]), which affects 50% of recipients after 5 years. The underlying mechanisms for CLAD are poorly understood, largely due to a lack of clinically relevant animal models, but lymphocytic bronchiolitis is an early sign of CLAD. Here, we report that lymphocytic bronchiolitis occurs early in a long-term murine orthotopic LTx model, based on a single mismatch (grafts from HLA-A2:B6-knockin donors transplanted into B6 recipients). Lymphocytic bronchiolitis is followed by formation of B cell-dependent lymphoid follicles that induce adjacent bronchial epithelial cell dysfunction in a spatiotemporal fashion. B cell deficiency using recipient μMT-/- mice prevented intrapulmonary lymphoid follicle formation and lymphocytic bronchiolitis. Importantly, selective inhibition of the follicle-organizing receptor EBI2, using genetic deletion or pharmacologic inhibition, prevented functional and histological deterioration of mismatched lung grafts. In sum, we provided what we believe to be a mouse model of chronic rejection and lymphocytic bronchiolitis after LTx and identified intrapulmonary lymphoid follicle formation as a target for pharmacological intervention of long-term allograft dysfunction after LTx.

SUBMITTER: Smirnova NF

PROVIDER: S-EPMC6413786 | biostudies-literature | 2019 Feb

REPOSITORIES: biostudies-literature

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Inhibition of B cell-dependent lymphoid follicle formation prevents lymphocytic bronchiolitis after lung transplantation.

Smirnova Natalia F NF Conlon Thomas M TM Morrone Carmela C Dorfmuller Peter P Humbert Marc M Stathopoulos Georgios T GT Umkehrer Stephan S Pfeiffer Franz F Yildirim Ali Ö AÖ Eickelberg Oliver O

JCI insight 20190207 3

Lung transplantation (LTx) is the only therapeutic option for many patients with chronic lung disease. However, long-term survival after LTx is severely compromised by chronic rejection (chronic lung allograft dysfunction [CLAD]), which affects 50% of recipients after 5 years. The underlying mechanisms for CLAD are poorly understood, largely due to a lack of clinically relevant animal models, but lymphocytic bronchiolitis is an early sign of CLAD. Here, we report that lymphocytic bronchiolitis o ...[more]

PMID: 30728330

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Project description:BackgroundBronchiolitis obliterans (BO) is one of the most common late non-infectious pulmonary complications after hematopoietic stem cell transplantation (HSCT). Lung transplantation (LT) is the only cure for patients with end-stage BO, but the overall efficacy is rarely reported. Our study aims to conclude and elucidate the clinical experience of our single center and provide a reference for the current selection of treatment.MethodsWe retrospectively analyzed the medical records of six patients with post-HSCT BO who received LT in our center from 2015 to 2019. The collected information included demographic data, surgery-related conditions, and postoperative follow-up data, which covered blood tests, infection status assessment, lung function assessment, anesthesia assessment, function assessment of other organs and so on. All patients were regularly followed up after discharge, which in the first year, was performed every 3 months. Over the next 2 years, patients were assessed every 6 months, and after 3 years, the frequency was once annually.ResultsThe mean age of patients at LT time was 28±13 years, with an interval of 72±48 months from HSCT. All patients developed hypercapnia with an average carbon dioxide partial pressure (pCO2) of 71.1±20.8 mmHg. Preoperative pulmonary function tests showed the mean actual forced expiratory volume in 1 second (FEV1) was 16.7%±5.9% of the predicted value in four patients. After assessment, four patients adopted sequential bilateral LT and two adopted right-sided LT. Due to hemodynamic instability, five patients adopted intraoperative assistance of extracorporeal membrane oxygenation (ECMO). One patient died of septic shock 9 days after surgery, and the other five survived healthy for 53±23 months. The actual value of FEV1 at 3 months postoperatively accounted for 57.9%±15.3% of the predicted value. No patients had recurrence of BO.ConclusionsLT may be a treatment worthy of consideration in patients with post-HSCT end-stage BO because it can improve lung function, quality of life and prolong survival of these selected patients.

Project description:RationaleCytomegalovirus pneumonitis is one of the most prevalent opportunistic infections after lung transplantation. Early studies reported that cytomegalovirus pneumonitis was a risk factor for chronic allograft dysfunction. More recently, in the era of routine prophylaxis and ganciclovir treatment, the adverse impact of treated cytomegalovirus pneumonitis on bronchiolitis obliterans syndrome has been challenged.ObjectivesWe hypothesized that cytomegalovirus pneumonitis contributes to adverse outcomes in the current antiviral era. We sought to define the impact of treated cytomegalovirus pneumonitis on bronchiolitis obliterans syndrome and survival in a large single-center cohort (n = 231) of consecutive patients undergoing lung transplantation from 2000 to 2004, all receiving short-course ganciclovir prophylaxis.MethodsTransbronchial biopsies were performed at defined intervals with prospective cytomegalovirus immunostaining on every biopsy (n = 1,887). Cox proportional hazards models were used to assess the relationship between treated cytomegalovirus pneumonitis and clinical outcomes.Measurements and main resultsForty-nine (21%) recipients developed cytomegalovirus pneumonitis a median of 106 days after transplantation. Treated cytomegalovirus pneumonitis within the first 6 months after transplantation significantly increased the risk for bronchiolitis obliterans syndrome (P = 0.001; hazard ratio, 2.19; 95% confidence interval, 1.36-3.51) and post-transplantation death (P = 0.02; hazard ratio, 1.89; 95% confidence interval, 1.11-3.23). This risk persisted when cytomegalovirus pneumonitis was considered as a time-dependent predictor as well as in multivariable models controlling for other risk factors.ConclusionsCytomegalovirus pneumonitis affects more than 20% of lung transplant recipients. Despite treatment, it increases the risk for bronchiolitis obliterans syndrome and death. More effective preventive strategies for cytomegalovirus pneumonitis are needed to improve long-term outcomes after lung transplantation.

Project description:Bronchiolitis obliterans syndrome (BOS) remains the major problem which precludes long-term survival after lung transplantation. Previously, an open label pilot study from our group demonstrated a possible beneficial effect of montelukast in progressive BOS patients with low airway neutrophilia (<15%), and already on azithromycin treatment, in whom the further decline in pulmonary function was attenuated. This was, however, a non-randomized and non-placebo controlled trial. The study design is a single center, prospective, interventional, randomized, double blind, placebo-controlled trial, with a two arm parallel group design and an allocation ratio of 1:1. Randomization to additional montelukast (10 mg/day, n = 15) or placebo (n = 15) was performed from 2010 to 2014 at the University Hospitals Leuven (Leuven, Belgium) in all consecutive patients with late-onset (>2years posttransplant) BOS ≥1. Primary end-point was freedom from graft loss 1 year after randomization; secondary end-points were acute rejection, lymphocytic bronchiolitis, respiratory infection rate; and change in FEV1, airway and systemic inflammation during the study period. Graft loss at 1 y and 2y was similar in both groups (respectively p = 0. 981 and p = 0.230). Montelukast had no effect on lung function decline in the overall cohort. However, in a post-hoc subanalysis of BOS stage 1 patients, montelukast attenuated further decline of FEV1 during the study period, both in absolute (L) (p = 0.008) and % predicted value (p = 0.0180). A linear mixed model confirmed this association. Acute rejection, lymphocytic bronchiolitis, respiratory infections, systemic and airway inflammation were comparable between groups over the study period. This randomized controlled trial showed no additional survival benefit with montelukast compared to placebo, although the study was underpowered. The administration of montelukast was associated with an attenuation of the rate of FEV1 decline, however, only in recipients with late-onset BOS stage 1.

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Inhibition of B cell-dependent lymphoid follicle formation prevents lymphocytic bronchiolitis after lung transplantation.

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Inhibition of B cell-dependent lymphoid follicle formation prevents lymphocytic bronchiolitis after lung transplantation.

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