Immune Cells in a Mouse Airway Model of Obliterative Bronchiolitis

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Abstract
Obliterative bronchiolitis (OB), a form of chronic lung rejection, affects 50% of all lung-transplant recipients and is a major cause of morbidity and mortality. We used the mouse tracheal allograft model of OB to quantitate inflammatory cells during disease progression to evaluate the pathogenesis of this disorder. Tracheas of BALB/c mice were implanted into C57BL/6, severe combined immunodeficiency (SCID), and BALB/c mice. Cyclosporin was administered at 25 mg/kg/d. Grafts were harvested at 2, 6, 10, and 15 wk, and analyzed immunohistochemically. Tracheal allografts developed epithelial injury and cellular infiltrates at 2 wk, epithelial denudation and complete luminal obliteration at 6 wk, and dense collagenous scarring by 15 wk. SCID allografts and isografts demonstrated intact epithelium throughout, although a mononuclear infiltrate was initially present at 2 wk in the SCID allografts. Immunohistochemical staining, using antibodies to mouse CD4(+) (T-helper lymphocyte), CD8(+) (T-cytotoxic/suppressor lymphocyte), and B lymphocytes, macrophages, and myofibroblasts, revealed large numbers of macrophages and CD4(+) and CD8(+) lymphocytes in allografts at 2 wk, compared with isografts. The allograft CD4(+)/CD8(+) ratio was 0.75 at 2 wk. Allografts demonstrated macrophage, myofibroblast, and CD4(+) predominance at 6 and 10 wk (CD4(+)/CD8(+) = 2/1), but by 15 wk had minimal cellularity and were densely scarred. SCID allografts demonstrated a macrophage-predominant infiltrate at 2 wk, with minimal cellularity at later time points. These results indicate that: (1) OB is predominantly an immunologic airway injury; and (2) CD4(+) and CD8(+) lymphocytes and macrophages play an important role in the evolution of airway inflammation and fibrosis. Additionally, this model suggests that chronic airway fibrosis follows a period of intense airway-directed, cell-mediated rejection.