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

Smirnova NF, Conlon TM, Morrone C, Dorfmuller P, Humbert M, Stathopoulos G, Umkehrer S, Pfeiffer F, Yildirim AO, Eickelberg O (2019)

Publication Type: Journal article

Publication year: 2019

Journal

JCI Insight American Society for Clinical Investigation

Book Volume: 4

Article Number: Y

Journal Issue: 3

DOI: 10.1172/jci.insight.123971

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.

Involved external institutions

Ludwig-Maximilians-Universität (LMU) DE Germany (DE) University of Paris 11 - Paris-Sud / Université Paris XI Paris-Sud FR France (FR) Technische Universität München (TUM) DE Germany (DE)

How to cite

APA:

Smirnova, N.F., Conlon, T.M., Morrone, C., Dorfmuller, P., Humbert, M., Stathopoulos, G.,... Eickelberg, O. (2019). Inhibition of B cell–dependent lymphoid follicle formation prevents lymphocytic bronchiolitis after lung transplantation. JCI Insight, 4(3). https://doi.org/10.1172/jci.insight.123971

MLA:

Smirnova, Natalia F., et al. "Inhibition of B cell–dependent lymphoid follicle formation prevents lymphocytic bronchiolitis after lung transplantation." JCI Insight 4.3 (2019).

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