title: Prevention of cytomegalovirus infection-enhanced experimental obliterative bronchiolitis by antiviral prophylaxis or immunosuppression in rat tracheal allografts.
abstract: In this study, the prevention of rat cytomegalovirus (RCMV) infection-enhanced experimental obliterative bronchiolitis in rat tracheal allografts was investigated. RCMV infection markedly enhanced cell proliferation and histological changes of obliterative bronchiolitis, a form of chronic rejection after lung transplantation. These alterations were linked to increased interleukin (IL)-2 and tumor necrosis factor-alpha (TNF-alpha) immunoreactivity, and reduction of IL-10 expression. In recipient rats with acute RCMV infection, prophylaxis with either ganciclovir (DHPG) or hyperimmune serum (HIS) totally prevented RCMV infection-enhanced tracheal occlusion. DHPG treatment initiated during acute RCMV infection also reduced lesion development but markedly less than DHPG prophylaxis. Treatment of acute RCMV infection with HIS alone or in combination with DHPG had no significant effect on tracheal occlusion. Inhibition of the transcription of cytokines by high doses of cyclosporine A significantly reduced RCMV infection-enhanced tracheal obliteration. In rats with chronic RCMV infection, obliterative alterations were prevented by DHPG prophylaxis initiated at the time of transplantation. Prophylaxis either with DHPG or HIS did not affect the amount of infectious RCMV recovered from host salivary glands, nor were there differences seen in RCMV major immediate early DNA expression in tracheal allografts between different antiviral drug regimens. Immunohistochemical analysis of allografts revealed that inhibition of tracheal occlusion by antiviral prophylaxis was associated with a reduction in the number of ED1(+) macrophages and cells staining for Th1 cytokines and TNF-alpha, while immune modulation by cyclosporine A up-regulated IL-10 production. In conclusion, the results of the present study suggest that the CMV infection-enhanced chronic rejection develops independently of viral load but requires both immune activation and simultaneous CMV gene expression beyond immediate early genes.
authors.affiliation: Cardiopulmonary Research Group of the Transplantation Laboratory, University of Helsinki and Helsinki University Central Hospital, Helsinki, Finland. jussi.tikkanen@helsinki.fi
authors.forename: J M
authors.initials: JM
authors.lastname: Tikkanen
authors.forename: E A
authors.initials: EA
authors.lastname: Kallio
authors.forename: C A
authors.initials: CA
authors.lastname: Bruggeman
authors.forename: P K
authors.initials: PK
authors.lastname: Koskinen
authors.forename: K B
authors.initials: KB
authors.lastname: Lemström
mesh_terms: D000208:Acute Disease; D000818:Animals; D000998:Antiviral Agents / Q000627:therapeutic use*; D001989:Bronchiolitis Obliterans / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control* / Q000821:virology*; D002908:Chronic Disease; D003587:Cytomegalovirus / Q000235:genetics; D003586:Cytomegalovirus Infections / Q000150:complications*; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D015774:Ganciclovir / Q000627:therapeutic use*; D015967:Gene Expression Regulation, Viral; D006084:Graft Rejection / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control* / Q000821:virology*; D007106:Immune Sera / Q000008:administration & dosage*; D007150:Immunohistochemistry; D016040:Lung Transplantation / Q000009:adverse effects*; D016676:Macrophages, Alveolar / Q000648:ultrastructure; D008297:Male; D011292:Premedication / Q000379:methods*; D051381:Rats; D011919:Rats, Inbred Strains; D018417:Th1 Cells / Q000648:ultrastructure; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000648:ultrastructure; D019562:Viral Load
chemical_list: D000998:Antiviral Agents; D007106:Immune Sera; D014409:Tumor Necrosis Factor-alpha; D015774:Ganciclovir