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Inhibition of B cell–dependent lymphoid follicle formation prevents lymphocytic bronchiolitis after lung transplantation
Natalia F. Smirnova, … , Ali Ö. Yildirim, Oliver Eickelberg
Natalia F. Smirnova, … , Ali Ö. Yildirim, Oliver Eickelberg
Published February 7, 2019
Citation Information: JCI Insight. 2019;4(3):e123971. https://doi.org/10.1172/jci.insight.123971.
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Research Article Pulmonology Transplantation

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

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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.

Authors

Natalia F. Smirnova, Thomas M. Conlon, Carmela Morrone, Peter Dorfmuller, Marc Humbert, Georgios T. Stathopoulos, Stephan Umkehrer, Franz Pfeiffer, Ali Ö. Yildirim, Oliver Eickelberg

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Figure 1

HLA-A2–knockin lung allografts are chronically rejected in a mouse model of orthotopic lung transplantation and present human-like signs of lymphocytic bronchiolitis.

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HLA-A2–knockin lung allografts are chronically rejected in a mouse model...
Left lungs from C57BL/6J (B6) and HLA-A2–knockin (HLA) mice on a B6 background (HLA) were orthotopically transplanted into B6 recipients and analyzed 1 month (B6→B6, n = 4, HLA→B6, n = 4) and 2 months (B6→B6, n = 4, HLA→B6, n = 5) later. (A) Heart-lung blocks from the indicated mice. The arrows show the grafts. (B) Lungs acquired with the x-ray dark-field imaging technique. The arrows show the grafts. (C) Quantification of the left lung graft scattering. Data are expressed as mean ± SEM and were analyzed with a 2-way ANOVA with a Bonferroni post-test; **P < 0.01. (D) Scans (original magnification, ×2; scale bars: 1000 μm) and zoomed bronchi (original magnification, ×20; scale bars: 100 μm) from indicated transplanted mice stained with Masson’s trichrome. (E) Scans of Masson’s trichrome–stained explants from healthy and transplanted human lungs with bronchiolitis obliterans syndrome (BOS), with magnifications of bronchioles (LB, lymphocytic bronchiolitis; OB, obliterative bronchiolitis). (F) Quantification of the epithelial and peribronchial areas of the indicated mice. Data are expressed as mean ± SEM of all the quantified bronchi and analyzed with a 2-way ANOVA with a Bonferroni post-test; ***P < 0.001. (G) Double immunofluorescence and quantification of the CC10+ club cells and AcTUB+ ciliated cells. Scale bars: 100 μm (top); 200 μm (bottom). Data are expressed as mean ± SEM of all the quantified bronchi and were analyzed with a Mann-Whitney test. (H) Immunofluorescence from bronchioles of human explants stained with anti-CC10 (83) and counterstained with DAPI (blue). Scale bars: 100 μm. BOS, Bronchiolitis obliterans syndrome; LB, lymphocytic bronchiolitis; OB, obliterative bronchiolitis. (I) Flow cytometry of anti–HLA-A2 anti-donor antibody titers in the transplanted mice plasma, 2 months after LTx, and semiquantitative assessment of the anti-HLA Ab levels expressed as mean fluorescence intensity. Data are expressed as mean ± SEM and were analyzed with a Mann-Whitney test; *P < 0.05.

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