A DOSE-DEPENDENT INHIBITORY EFFECT OF CYCLOSPORINE-A ON OBLITERATIVE BRONCHIOLITIS OF RAT TRACHEAL ALLOGRAFTS

Inbred DA and WF rats were used as donors and recipients of heterotopi c tracheal allografts. To investigate cellular and molecular mechanism s as well as inhibitory effects of differently acting immunosuppressiv e drugs on the development of obliterative bronchiolitis (OB), the rec ipient rats received either cyclosporine A (CsA; 1, 2, or 5 mg/kg/d), 15-deoxyspergualin (DSC; 1 or 2 mg/kg/d), or mycophenolate mofetil (MM F; 20 or 40 mg/kg/d), or were left without immunosuppression. The graf ts were removed at various time points for histology and immunohistoch emistry. In tracheal allografts removed from nonimmunosuppressed anima ls, respiratory epithelium was replaced by cuboidal or squamous cell e pithelium, with markedly enhanced expression of epithelial major histo compatibility class (MHC) Class II antigens at 3 d after transplantati on. This was associated with a pronounced inflammatory episode and pro liferation of T cells and macrophages, with the prominence of lymphoid activation markers, MHC Class II antigens and interleukin-2R (IL-2R). Later, total epithelial necrosis developed and intense proliferation of granulation tissue occluded the airway lumen producing a condition resembling OB in humans. In syngeneic tracheal grafts, no such changes could be observed. CsA decreased the development of OB in a dose-depe ndent fashion, in association with downregulation of epithelial MHC Cl ass II antigen expression, IL-2 R expression, and the infiltration of T cells. The new immunosuppressive drugs DSC (suppression of the monoc yte/macrophage action and lymphocyte proliferation) and MMF (blocking of the de novo pathway of purine synthesis), in the dose range tested, showed no significant effect on the development of OB. These results suggest that an acute alloimmune response to airway targets, perhaps t o epithelium, is the primary cause of OB, since CsA, with a nearly exc lusive effect on the transcription of immune cytokines, entirely inhib ited the generation of OB, and that preventive intervention for OB mus t occur early in the T-cell activation pathway.