Lymphotoxin driven chronic lung allograft dysfunction (CLAD) after lung transplantation (LoxCLAD)

• Applicants: Professor Nikolaus Kneidinger, Ph.D.; Professor Ali Önder Yildirim, Ph.D.
• Subject Area: Pneumology, Thoracic Surgery
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 511333489

Chronic lung allograft dysfunction (CLAD) is the leading cause of long-term mortality after lung transplantation. CLAD is an umbrella term to describe the clinical manifestations of a range of pathologic processes in the airway and parenchymal compartments of the lung allograft that lead to a significant and persistent deterioration in lung function. The most common manifestation of CLAD is the development of airflow limitation, caused by obliterative bronchiolitis (OB), which is termed bronchiolitis obliterans syndrome (BOS). Another manifestation of CLAD is characterized by a fibrotic pattern. The restrictive allograft syndrome (RAS) is less frequent but is associated with worse outcome. Currently, when the diagnosis of CLAD is established a significant amount of lung function is already irreversibly lost. Progression of CLAD is a matter of time, which leads to respiratory failure and death in the majority of affected patients. Associated with CLAD development is the presence of tertiary lymphoid structures called inducible bronchus-associated lymphoid tissue (iBALT) in the lung. Many of the pathways responsible for the development and maintenance of iBALTs, mirror those responsible for lymphoid organogenesis, which can be reactivated during chronic inflammation. In this case the interaction between the lymphotoxin-β receptor (LTβR) on stromal organizer cells and membrane bound lymphotoxin, heterotrimeric complexes of the TNF superfamily members LTα and LTβ expressed on the surface of lymphoid tissue inducer (LTi) cells is crucial. In chronic inflammation lymphocytes are capable of fulfilling the role of LTi cells, which activate lymphotoxin signaling and that triggers the expression of a cascade of downstream molecules and subsequent iBALT formation. Blocking lymphotoxin signaling has been shown to alleviate several chronic inflammatory diseases. Furthermore, the treatment LTβR-Ig lead to a significant reduction of iBLAT formation resulting in reversing experimental COPD. We hypothesize that iBALT formation is an early contributor in the development of CLAD. Furthermore, we hypothesize that activation of lymphotoxin signaling may be used as biomarker for CLAD before the clinical onset and that blocking lymphotoxin signaling can be used as approach to prevent and treat CLAD. Therefore, we aim to elucidate the contribution of specific lymphoid cell subtypes as the primary source of LTβR ligand in orchestrating iBALT formation and CLAD development in the chronically rejecting lung following transplantation and to delineate their potential as CLAD biomarkers in patient PBMCs or bronchoalveolar lavage to improve an early diagnosis. To refine the phenotypes associated with differential prognosis and to identify early biological processes that lead to CLAD to enable an early intervention that could modify the inevitable damage of respiratory function is of enormous medical need.

• DFG Programme: Research Grants