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Smirnova, N.F. ; Conlon, T.M. ; Morrone, C. ; Dorfmuller, P.* ; Humbert, M.* ; Stathopoulos, G.T. ; Umkehrer, S.* ; Pfeiffer, F.* ; Yildirim, A.Ö. ; Eickelberg, O.*

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

JCI insight 4:123971 (2019)
Verlagsversion Forschungsdaten DOI PMC
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.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter B Cells ; Pulmonology ; Transplantation; Obliterative Airway Disease; Indirect Allorecognition; Allograft Dysfunction; Chronic Rejection; Natural-killer; Alpha-3 Domain; Ebi2; Antibody; Model; Induction
ISSN (print) / ISBN 2379-3708
e-ISSN 2379-3708
Zeitschrift JCI insight
Quellenangaben Band: 4, Heft: 3, Seiten: , Artikelnummer: 123971 Supplement: ,
Verlag Clarivate
Verlagsort Ann Arbor, Michigan
Begutachtungsstatus