Systems prediction of chronic lung allograft dysfunction: Results and perspectives from the Cohort of Lung Transplantation and Systems prediction of Chronic Lung Allograft Dysfunction cohorts
Authors: Pison Christophe , Tissot Adrien , Bernasconi Eric , Royer Pierre-Joseph , Roux Antoine , Koutsokera Angela , Coiffard Benjamin , Renaud-Picard Benjamin , Le Pavec Jérôme , Mordant Pierre , Demant Xavier , Villeneuve Thomas , Mornex Jean-Francois , Nemska Simona , Frossard Nelly , Brugière Olivier , Siroux Valérie , Marsland Benjamin J. , Foureau Aurore , Botturi Karine , Durand Eugenie , Pellet Johann , Danger Richard , Auffray Charles , Brouard Sophie , Nicod Laurent , Magnan Antoine ,   Members of the Cohort of Lung Transplantation and Systems prediction of Chronic Lung Allograft Dysfunction consortia
Published: March 2023

Background

Chronic lung allograft dysfunction (CLAD) is the leading cause of poor long-term survival after lung transplantation (LT). Systems prediction of Chronic Lung Allograft Dysfunction (SysCLAD) aimed to predict CLAD.

Methods

To predict CLAD, we investigated the clinicome of patients with LT; the exposome through assessment of airway microbiota in bronchoalveolar lavage cells and air pollution studies; the immunome with works on activation of dendritic cells, the role of T cells to promote the secretion of matrix metalloproteinase-9, and subpopulations of T and B cells; genome polymorphisms; blood transcriptome; plasma proteome studies and assessment of MSK1 expression.

Results

Clinicome: the best multivariate logistic regression analysis model for early-onset CLAD in 422 LT eligible patients generated a ROC curve with an area under the curve of 0.77. Exposome: chronic exposure to air pollutants appears deleterious on lung function levels in LT recipients (LTRs), might be modified by macrolides, and increases mortality. Our findings established a link between the lung microbial ecosystem, human lung function, and clinical stability post-transplant. Immunome: a decreased expression of CLEC1A in human lung transplants is predictive of the development of chronic rejection and associated with a higher level of interleukin 17A; Immune cells support airway remodeling through the production of plasma MMP-9 levels, a potential predictive biomarker of CLAD. Blood CD9-expressing B cells appear to favor the maintenance of long-term stable graft function and are a potential new predictive biomarker of BOS-free survival. An early increase of blood CD4 + CD57 + ILT2+ T cells after LT may be associated with CLAD onset. Genome: Donor Club cell secretory protein G38A polymorphism is associated with a decreased risk of severe primary graft dysfunction after LT. Transcriptome: blood POU class 2 associating factor 1, T-cell leukemia/lymphoma domain, and B cell lymphocytes, were validated as predictive biomarkers of CLAD phenotypes more than 6 months before diagnosis. Proteome: blood A2MG is an independent predictor of CLAD, and MSK1 kinase overexpression is either a marker or a potential therapeutic target in CLAD.

Conclusion

Systems prediction of Chronic Lung Allograft Dysfunction generated multiple fingerprints that enabled the development of predictors of CLAD. These results open the way to the integration of these fingerprints into a predictive handprint.