Specific immune responses against airway epithelial cells in a transgenic mouse-trachea transplantation model for obliterative airway disease

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Abstract
Immune injury to airway epithelium is suggested to play a central role in the pathogenesis of obliterative bronchiolitis (OB) after clinical lung transplantation. In several studies, a rejection model of murine trachea transplants is used, resulting in obliterative airway disease (OAD) with similarities to human OB. To focus on the role of an immune response specifically against airway epithelium, we transplanted tracheas from transgenic mice expressing human epithelial glycoprotein (hEGP) on epithelial cells. We hypothesized that the immune response against the hEGP-2 antigen would result in OAD in the trachea transplants. Tracheas from hEGP-2 transgenic and control nontransgenic FVB/N mice were heterotopically transplanted into FVB/N mice and harvested at week 1, 3, 6, and 9. Anti-hEGP-2 antibodies were determined in the recipient blood. The trachea grafts were analyzed for cellular infiltration, epithelial cell injury, and luminal obliteration. Recipients of transgenic tracheal grafts gradually developed anti-hEGP-2 antibodies. In the transgenic grafts, the submucosa was infiltrated predominantly by CD4+ T cells. Epithelial cells remained present but showed progressive abnormality. The tracheal lumen showed a mild degree of obliteration. All these changes were absent in nontransgenic FVB/N trachea transplants. The hEGP-2 antigen on the epithelial cells of transgenic trachea transplants induces specific humoral and cellular immune responses, leading to a mild form of OAD. It provides a suitable model for further investigation of the role of epithelial cells in the development of OAD in animals and OB in human-lung transplantation.