IMMUNE CELLS IN A MOUSE AIRWAY MODEL OF OBLITERATIVE BRONCHIOLITIS

Obliterative bronchiolitis (OB), a form of chronic lung rejection, aff ects 50% of all lung-transplant recipients and is a major cause of mor bidity and mortality. We used the mouse tracheal allograft model of OB to quantitate inflammatory cells during disease progression to evalua te the pathogenesis of this disorder. Tracheas of BALB/c mice were imp lanted into C57BL/6, severe combined immunodeficiency (SCID), and BALB /c mice. Cyclosporin was administered at 25 mg/kg/d. Grafts were harve sted at 2, 6, 10, and 15 wk, and analyzed immunohistochemically. Trach eal 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 isograf ts demonstrated intact epithelium throughout, although a mononuclear i nfiltrate was initially present at 2 wk in the SCID allografts. Immuno histochemical staining, using antibodies to mouse CD4(+) (T-helper lym phocyte), CD8(+) (T-cytotoxic/suppressor lymphocyte), and B lymphocyte s, macrophages, and myofibroblasts, revealed large numbers of macropha ges and CD4(+) and CD8(+) lymphocytes in allografts at 2 wk, compared with isografts. The allograft CD4(+)/CD8(+) ratio was 0.75 at 2 wk. Al lografts demonstrated macrophage, myofibroblast, and CD4(+) predominan ce at 6 and 10 wk (CD4(+)/CD8(+) = 2/1), but by 15 wk had minimal cell ularity and were densely scarred. SCID allografts demonstrated a macro phage-predominant infiltrate at 2 wk, with minimal cellularity at late r 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 inflamma tion and fibrosis. Additionally, this model suggests that chronic airw ay fibrosis follows a period of intense airway-directed, cell-mediated rejection.