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A New Murine Model for Bronchiolitis Obliterans Post–Bone Marrow Transplant

¹ Division of Hematology/Oncology, Department of Pediatrics, Blood and Marrow Transplant Program, Cancer Center, and ² Division of Pulmonary, Allergy and Critical Care Medicine, University of Minnesota, Minneapolis, Minnesota

Correspondence and requests for reprints should be addressed to Angela Panoskaltsis-Mortari, Ph.D., University of Minnesota, Department of Pediatrics, Mayo Mail Code 366, 420 Delaware Street SE, Minneapolis, MN 55455. E-mail: panos001{at}umn.edu.

Rationale: Bronchiolitis obliterans (BO) is a major problem in lung transplantation and is also part of the spectrum of late-onset pulmonary complications that can occur after hematopoietic stem cell transplant. Better mouse models are needed to study the onset of this disease so that therapeutic interventions can be developed.

Objectives: Our goal was to develop a BO mouse model.

Methods: Recipients were lethally conditioned and given a rescue dose of T-cell–depleted, allogeneic bone marrow (BM) supplemented with a sublethal dose of allogeneic T cells.

Measurements and Main Results: At 2 months post–BM transplant, the lungs had extensive perivascular and peribronchiolar inflammation consisting of CD4⁺ T cells, CD8⁺ T cells, B cells, macrophages, neutrophils, and fibroblasts. In contrast to the acute model, histology showed airway obstruction consistent with BO. Epithelial cells of airways in the early stages of occlusion exhibited changes in expression of cytokeratins. Although the lung had severe allogeneic BM transplant–mediated disease, there was only mild to moderate graft-versus-host disease in liver, colon, skin, and spleen. High wet/dry weight ratios and elevated hydroxyproline were seen, consistent with pulmonary edema and fibrosis. Mice with BO exhibited high airway resistance and low compliance. Increases in many inflammatory mediators in the lungs of mice that develop BO were seen early post-transplant and not later at the time of BO.

Conclusions: This new mouse model will be useful for the study of BO associated with late post–hematopoietic stem cell transplant onset and chronic graft-versus-host disease, which also leads to poor outcome in the lung transplant setting.

Key Words: bronchiolitis obliterans • mouse models • transplantation

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject The formation of bronchiolitis obliterans lesions is generally believed to have two major components, airway epithelial injury due to a directed alloimmune response followed by fibroproliferation. The cause of the heterogeneity seen in this disease is unknown. What This Study Adds to the Field We describe a new mouse model of bronchiolitis obliterans amenable to intervention strategies.

 

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