Enhancement of cytomegalovirus infection and acute rejection after allogeneic lung transplantation in the rat: virus-induced expression of major histocompatibility complex class II antigens.
BACKGROUND
Cytomegalovirus infection is considered a major complication after lung and heart-lung transplantation because it can trigger acute and chronic rejection. The potential mechanisms of lung transplant rejection induced by viral infection include the upregulation of expression of major histocompatibility complex antigens. To address this question, a model of rat cytomegalovirus infection and acute lung transplant rejection was established.


METHODS
Lewis inbred strain rats received syngeneic (n = 25) or allogeneic (Brown-Norway inbred rat strain, n = 38) orthotopic left-side lung transplants. Triple-drug immunosuppression with cyclosporin A, methylprednisolone, and azathioprine was given from postoperative days 1 through 10. Rat cytomegalovirus was inoculated intraperitoneally on postoperative day 3. Two control groups, those infected with cytomegalovirus (n = 15) and those without rat cytomegalovirus infection (n = 6) were treated with identical immunosuppressive regimens. Animals were sacrificed on postoperative days 11, 15, 18, 20, and 25. The salivary glands and both lungs were removed for pathologic and immunohistochemical investigations.


RESULTS
All animals inoculated with rat cytomegalovirus developed systemic viral infection on or after postoperative day 11, as confirmed by an assay of plaque-forming units and immunohistologic examination. Cytomegalovirus-induced expression of major histocompatibility complex class II antigens on vascular endothelial cells was seen in the nontransplanted lungs of rats, but no major histocompatibility complex class II antigens were detected on noninfected, nontransplanted lungs. Cytomegalovirus infection also was found to enhance major histocompatibility complex class II antigen expression on pneumocytes and leukocytes in rats. Acute rejection occurred in allogeneic transplants from postoperative days 15 through 25. The expression of class II antigens on endothelial cells, pneumocytes, and leukocytes was further enhanced during the course of allograft rejection in the cytomegalovirus-infected rats compared with the noninfected controls. In cytomegalovirus-positive rats, the rejection grade was higher than that in cytomegalovirus-negative rats on postoperative days 15 through 18.


CONCLUSIONS
Our results indicate that cytomegalovirus induces and enhances the expression of major histocompatibility complex class II antigens on endothelial cells, pneumocytes and leukocytes. Upregulation by cytomegalovirus infection may trigger or promote acute rejection by alloantigenic T-lymphocyte stimulation after lung transplantation. By this mechanism it may strongly influence the long-term course of lung transplant rejection.
You
X M
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Department of Thoracic and Cardiovascular Surgery, Hannover Medical School, Germany.
Steinmüller
C
C
Wagner
T O
TO
Bruggeman
C A
CA
Haverich
A
A
Steinhoff
G
G
D000208:Acute Disease; D000818:Animals; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000473:pathology; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D000949:Histocompatibility Antigens Class II / Q000378:metabolism*; D007150:Immunohistochemistry; D007165:Immunosuppression Therapy; D016040:Lung Transplantation / Q000276:immunology* / Q000473:pathology; D008285:Major Histocompatibility Complex / Q000276:immunology*; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D013997:Time Factors; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D000949:Histocompatibility Antigens Class II