ACUTE CYTOMEGALOVIRUS-INFECTION INDUCES A SUBENDOTHELIAL INFLAMMATION(ENDOTHELIALITIS) IN THE ALLOGRAFT VASCULAR WALL - A POSSIBLE LINKAGEWITH ENHANCED ALLOGRAFT ARTERIOSCLEROSIS

Clinical and experimental studies have established the accelerating ro le of cytomegalovirus (CMV) infection on cardiac allograft arterioscle rosis, ie, chronic rejection. We have investigated the mechanisms behi nd the interaction between CMV infection and chronic rejection. In the first part of the study, 762 endomyocardial biopsy specimens obtained front 47 heart allograft recipients were analyzed Of these, 28 patien ts developed CMV infection during the first postoperative year. In 24 of 28 CMV patients, mononuclear inflammatory cells (endothelialitis) w ere seen in the subendothelium of small intramyocardial arterioles. In CMV;free recipients, only five of 19 had any subendothelial inflammat ion in the vascular structures P < 0.0001 when compared with CMV patie nts). The subendothelial inflammation demonstrated an intensive peak a t the onset of CMV infection, subsiding slowly thereafter. Morphologic ally, the inflammatory cells in the subendothelium were small lymphocy tes. Only few activated pyroninophilic lymphocytes were seen. Immunohi stochemistry revealed that the lymphocytes were mostly T cells (UCHL1 +). In the second part of the study, we investigated if a similar endo thelialitis could be induced experimentally in allografted rats. We pe rformed rat aortic allografts from the DA (AG-B4, RT1(a)) donors to th e WF(AG-B2, RT1(v)) recipients and infected the recipients with 10(5) plaque-forming units of rat CMV Maastricht strain I day after transpla ntation In rat CMV-infected aortic allografts, the frequency of subend othelial leukocyte common antigen (LCA, OX1) positive leukocytes, 1.7 +/- 0.1 (SEM) point score units, was significantly higher when compare d to noninfected allografts, 0.8 +/- 0.1 point score units (P < 0.05), and they were most prominent in the intililal space during and follow ing acute infection. During subsequent weeks, the LCA-positive leukocy tes were replaced by alpha-actin-positive smooth muscle cells. Instead most of the cells is intima of CMV-free grafted rats stained positive ly to alpha-actin from the beginning and were smooth muscle cells. Pra ctically no leukocytes were seen lit rat CMV-infected aortic allograft s 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 inflammatio n (endothelialitis) of at allograft vascular structures both in human and in rat. Nonactivated T lymphocytes and monocytes predominate the i nflammatory 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 endotheli um, and thus contribute to allograft arteriosclerosis.