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American Journal of Pathology, Vol 144, 41-50, Copyright © 1994 by American Society for Investigative Pathology
REGULAR ARTICLES |
P Koskinen, K Lemstrom, C Bruggeman, I Lautenschlager and P Hayry
Transplantation Laboratory, University of Helsinki, Finland.
Clinical and experimental studies have established the accelerating role of cytomegalovirus (CMV) infection on cardiac allograft arteriosclerosis, ie, chronic rejection. We have investigated the mechanisms behind the interaction between CMV infection and chronic rejection. In the first part of the study, 762 endomyocardial biopsy specimens obtained from 47 heart allograft recipients were analyzed. Of these, 28 patients developed CMV infection during the first postoperative year. In 24 of 28 CMV patients, mononuclear inflammatory cells (endothelialitis) were seen in the subendothelium of small intramyocardial arterioles. In CMV-free recipients, only five of 19 had any subendothelial inflammation in the vascular structures P < 0.0001 when compared with CMV patients). The subendothelial inflammation demonstrated an intensive peak at the onset of CMV infection, subsiding slowly thereafter. Morphologically, the inflammatory cells in the subendothelium were small lymphocytes. Only few activated pyroninophilic lymphocytes were seen. Immunohistochemistry revealed that the lymphocytes were mostly T cells (UCHL1+). In the second part of the study, we investigated if a similar endothelialitis could be induced experimentally in allografted rats. We performed rat aortic allografts from the DA (AG-B4, RT1a) donors to the WF (AG-B2, RT1v) recipients and infected the recipients with 10(5) plaque-forming units of rat CMV Maastricht strain 1 day after transplantation. In rat CMV- infected aortic allografts, the frequency of subendothelial leukocyte common antigen (LCA, OX1) positive leukocytes, 1.7 +/- 0.1 (SEM) point score units, was significantly higher when compared to noninfected allografts, 0.8 +/- 0.1 point score units (P < 0.05), and they were most prominent in the intimal space during and following acute infection. During subsequent weeks, the LCA-positive leukocytes were replaced by alpha-actin-positive smooth muscle cells. Instead, most of the cells in intima of CMV-free grafted rats stained positively to alpha-actin from the beginning and were smooth muscle cells. Practically no leukocytes were seen. In rat CMV-infected aortic allografts most subendothelial inflammatory cells represented T cells (W3/25+) and cells of the monocyte/macrophage lineage (OX42+). In conclusion, acute CMV infection is associated with an subendothelial inflammation (endothelialitis) of allograft vascular structures both in human and in rat. Nonactivated T lymphocytes and monocytes predominate the inflammatory lesion in the subendothelium. The results suggest that the virus-linked vascular wall inflammation may play a role in the immune injury toward allograft vascular structures, particularly to endothelium, and thus contribute to allograft arteriosclerosis.
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