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Simultaneous LFA-1 and CD40 Ligand Antagonism Prevents Airway Remodeling in Orthotopic Airway Transplantation: Implications for the Role of Respiratory Epithelium as a Modulator of Fibrosis¹

Tomohiro Murakawa^*, Michelle M. Kerklo, Martin R. Zamora, Yi Wei, Ronald G. Gill, Peter M. Henson^¶, Frederick L. Grover^* and Mark R. Nicolls^2,

^* Department of Surgery, Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, and Department of Immunology, University of Colorado Health Sciences Center, Denver, CO 80262; Regeneron Pharmaceuticals, Tarrytown, NY 10591; and ^¶ Program in Cell Biology, Department of Pediatrics, National Jewish Medical and Research Center, Denver, CO 80206

Airway remodeling is a prominent feature of certain immune-mediated lung diseases such as asthma and chronic lung transplant rejection. Under conditions of airway inflammation, the respiratory epithelium may serve an important role in this remodeling process. Given the proposed role of respiratory epithelium in nonspecific injury models, we investigated the respiratory epithelium in an immune-specific orthotopic airway transplant model. MHC-mismatched tracheal transplants in mice were used to generate alloimmune-mediated airway lesions. Attenuation of this immune injury and alteration of antidonor reactivity were achieved by the administration of combined anti-LFA-1/anti-CD40L mAbs. By contrast, without immunotherapy, transplanted airways remodeled with a flattening of respiratory epithelium and significant subepithelial fibrosis. Unopposed alloimmune injury for 10 days was associated with subsequent epithelial transformation and subepithelial fibrosis that could not be reversed with immunotherapy. The relining of donor airways with recipient-derived epithelium was delayed with immunotherapy resulting in partially chimeric airways by 28 days. Partial epithelial cell chimerism was sufficient to prevent luminal fibrosis. However, epithelial chimerism was also associated with airway remodeling. Therefore, there appears to be an intimate relationship between the morphology and level of chimerism of the respiratory epithelium and the degree of airway remodeling following alloimmune injury.

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