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 heterotopic tracheal allografts. To investigate cellular and molecular mechanisms as well as inhibitory effects of differently acting immunosuppressive drugs on the development of obliterative bronchiolitis (OB), the recipient rats received either cyclosporine A (CsA; 1, 2, or 5 mg/kg/d), 15-deoxyspergualin (DSG; 1 or 2 mg/kg/d), or mycophenolate mofetil (MMF; 20 or 40 mg/kg/d), or were left without immunosuppression. The grafts were removed at various time points for histology and immunohistochemistry. In tracheal allografts removed from nonimmunosuppressed animals, respiratory epithelium was replaced by cuboidal or squamous cell epithelium, with markedly enhanced expression of epithelial major histocompatibility class (MHC) Class II antigens at 3 d after transplantation. This was associated with a pronounced inflammatory episode and proliferation 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-dependent fashion, in association with downregulation of epithelial MHC Class II antigen expression, IL-2R expression, and the infiltration of T cells. The new immunosuppressive drugs DSG (suppression of the monocyte/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 to epithelium, is the primary cause of OB, since CsA, with a nearly exclusive effect on the transcription of immune cytokines, entirely inhibited the generation of OB, and that preventive intervention for OB must occur early in the T-cell activation pathway.
Koskinen
P K
PK
Transplantation Laboratory, University of Helsinki, Finland.
Kallio
E A
EA
Krebs
R
R
Lemström
K B
KB
D000818:Animals; D001989:Bronchiolitis Obliterans / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D016572:Cyclosporine / Q000008:administration & dosage*; D004305:Dose-Response Relationship, Drug; D004848:Epithelium / Q000473:pathology; D006146:Guanidines / Q000008:administration & dosage; D000949:Histocompatibility Antigens Class II / Q000032:analysis; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives; D011183:Postoperative Complications / Q000517:prevention & control*; D051381:Rats; D011919:Rats, Inbred Strains; D014132:Trachea / Q000473:pathology / Q000637:transplantation*; D014181:Transplantation Immunology; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D006146:Guanidines; D000949:Histocompatibility Antigens Class II; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; C037258:gusperimus