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

JCI insight 4:123971 (2019)
Publishers Version Research data DOI PMC
Open Access Green as soon as Postprint is submitted to ZB.
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 mu MT-/- 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.
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Publication type Article: Journal article
Document type Scientific Article
Keywords B Cells ; Pulmonology ; Transplantation; Obliterative Airway Disease; Indirect Allorecognition; Allograft Dysfunction; Chronic Rejection; Natural-killer; Alpha-3 Domain; Ebi2; Antibody; Model; Induction
Reviewing status