Humoral immune responses mediate the development of a restrictive phenotype of chronic lung allograft dysfunction
Keizo Misumi, David S. Wheeler, Yoshiro Aoki, Michael P. Combs, Russell R. Braeuer, Ryuji Higashikubo, Wenjun Li, Daniel Kreisel, Ragini Vittal, Jeffrey Myers, Amir Lagstein, Natalie M. Walker, Carol F. Farver, Vibha N. Lama
Keizo Misumi, David S. Wheeler, Yoshiro Aoki, Michael P. Combs, Russell R. Braeuer, Ryuji Higashikubo, Wenjun Li, Daniel Kreisel, Ragini Vittal, Jeffrey Myers, Amir Lagstein, Natalie M. Walker, Carol F. Farver, Vibha N. Lama
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Research Article Pulmonology Transplantation

Humoral immune responses mediate the development of a restrictive phenotype of chronic lung allograft dysfunction

Abstract

Understanding the distinct pathogenic mechanisms that culminate in allograft fibrosis and chronic graft failure is key in improving outcomes after solid organ transplantation. Here, we describe an F1 → parent orthotopic lung transplant model of restrictive allograft syndrome (RAS), a particularly fulminant form of chronic lung allograft dysfunction (CLAD), and identify a requisite pathogenic role for humoral immune responses in development of RAS. B6D2F1/J (H2-b/d) donor lungs transplanted into the parent C57BL/6J (H2-b) recipients demonstrated a spectrum of histopathologic changes, ranging from lymphocytic infiltration, fibrinous exudates, and endothelialitis to peribronchial and pleuroparenchymal fibrosis, similar to those noted in the human RAS lungs. Gene expression profiling revealed differential humoral immune cell activation as a key feature of the RAS murine model, with significant B cell and plasma cell infiltration noted in the RAS lung allografts. B6D2F1/J lung allografts transplanted into μMt–/– (mature B cell deficient) or activation-induced cytidine deaminase (AID)/secretory μ-chain (μs) double-KO (AID−/−μs−/−) C57BL/6J mice demonstrated significantly decreased allograft fibrosis, indicating a key role for antibody secretion by B cells in mediating RAS pathology. Our study suggests that skewing of immune responses determines the diverse allograft remodeling patterns and highlights the need to develop targeted therapies for specific CLAD phenotypes.

Authors

Keizo Misumi, David S. Wheeler, Yoshiro Aoki, Michael P. Combs, Russell R. Braeuer, Ryuji Higashikubo, Wenjun Li, Daniel Kreisel, Ragini Vittal, Jeffrey Myers, Amir Lagstein, Natalie M. Walker, Carol F. Farver, Vibha N. Lama

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Figure 2

B6D2F1/J → C57BL/6J transplant lungs demonstrate a spectrum of histopathological characteristics of RAS.

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B6D2F1/J → C57BL/6J transplant lungs demonstrate a spectrum of histopath...
(A) Summary of the histologic characteristics on allograft lungs examined on posttransplant days 7, 14, 28, and 40. Mononuclear cell infiltration of the vessels (acute rejection), airways (lymphocytic bronchiolitis), and pleura (pleuritis) was noted at day 7. Day 14 allografts demonstrated further increase in pleural thickness with plasma cell infiltration and evolving fibrosis. Another prominent feature was development of patches of intraalveolar fibrinous exudates. Fibrosis along the bronchovascular bundles and pleura with occasional fibroblastic plugs in the airway lumen was a key feature at day 28. Alveolar spaces were marked by presence of foamy macrophages. Endothelialitis with evidence of plasma cell infiltration was noted beginning at day 28, and plasmacytic vasculitis marked day 40 allografts. Other findings at this time point included severe pleural fibrosis, along with interlobular septal thickening and fibrosis. Pleuroparenchymal fibroelastosis (PPFE) was noted in some allografts. Bronchovascular bundles demonstrated persistent rejection with epithelial injury. Photomicrographs represent 6–9 mice in each group and were validated by a board-certified pathologist. Lung explants marked for histology at 28 and day 40 overlap with samples shown in Figure 1. New transplants were performed for day 7 and 14 after transplant. Scale bar: 80 μm (original magnification, 200×). (B) Photomicrograph of the entire RAS allograft lung with Masson’s trichrome collagen staining (in blue) is shown at day 40. Fibrosis is seen emanating from the pleura and along the bronchovascular bundles. Concomitant histology features included intraalveolar fibrinous exudates and acute rejection. BVBF, bronchovascular bundle fibrosis; PPFE, pleuroparenchymal fibroelastosis; PF, pleural fibrosis. (C) Quantitative representation of the histologic characteristics and pathology scores over time after transplant. Average score divided by the highest score at each time point, is presented as a fold-change of 0–1.0 in the heatmap (n = 3–9 in each group).