title: Rejection, herpesvirus infection, and Ki-67 expression in endomyocardial biopsy specimens from heart transplant recipients.
abstract: We examined 164 endomyocardial biopsy specimens from 29 patients who received an orthotopic heart transplant since 1984. Rejection was graded according to the Hannover classification. Non-isotopic in situ DNA hybridization was conducted on cryostat sections with biotinylated probes for herpes simplex virus, Epstein-Barr virus, and cytomegalovirus. Serial sections of 126 biopsies were investigated immunohistochemically for the presence of activated T lymphocytes and proliferating cells, with monoclonal antibodies against interleukin 2 receptors (CD 25) and Ki-67 antigen. Relations between rejection grades, presence of proliferating cells, and presence of herpesvirus DNA were determined for the total number of biopsies. For some patients correlation of these parameters was studied over time. Herpesviral nucleic acids were detected in 25% of all biopsies: 37% of biopsies with relevant rejection (grades A 2 or A 3; 39% of all biopsies) compared to 18% of biopsies graded A 0, A 1, or A 5 (61% of all samples) (P less than 0.01). 56% of the biopsies with infection showed relevant rejection as compared with only 33% of the uninfected. Ki-67 expression was found in 41% of all biopsies, mainly in infiltrating cells: 69% of biopsies with relevant rejection compared with 23% of cases of minor/no rejection (P much less than 0.001). Ki-67 expression was also associated with herpesvirus infection: 66% of infected biopsies contained Ki-67 positive cells compared with 33% of uninfected biopsies (P less than 0.001). Herpesvirus infection was usually observed within the interstitial cell population, which, in many cases, displayed a considerable Ki-67 expression, too. In few cases only, hybridization was unequivocally found in vascular wall cells or myocytes. Viral myocarditis does not only mimic graft rejection morphologically, but it may also affect the course of rejection, via induction of antigenic changes or direct injury of cardiac tissues. Virus infections may also elicit or aggravate obliterative coronary artery disease, and thus contribute to accelerated graft atherosclerosis.
authors.affiliation: Institute of Pathology, University of Hamburg, FRG.
authors.forename: K T
authors.initials: KT
authors.lastname: Jäkel
authors.forename: T
authors.initials: T
authors.lastname: Löning
authors.forename: R
authors.initials: R
authors.lastname: Arndt
authors.forename: W
authors.initials: W
authors.lastname: Rödiger
mesh_terms: D000328:Adult; D000469:Alkaline Phosphatase / Q000032:analysis; D001706:Biopsy / Q000379:methods; D002455:Cell Division / Q000502:physiology; D002461:Cell Line, Transformed; D003587:Cytomegalovirus / Q000302:isolation & purification; D015342:DNA Probes; D004273:DNA, Neoplasm / Q000235:genetics; D005260:Female; D006084:Graft Rejection / Q000502:physiology*; D016027:Heart Transplantation / Q000473:pathology*; D006561:Herpes Simplex / Q000150:complications / Q000473:pathology*; D004854:Herpesvirus 4, Human / Q000302:isolation & purification; D006801:Humans; D019394:Ki-67 Antigen; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000302:isolation & purification*; D015375:Receptors, Interleukin-2 / Q000276:immunology; D018139:Simplexvirus / Q000302:isolation & purification; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D015342:DNA Probes; D004273:DNA, Neoplasm; D019394:Ki-67 Antigen; D009687:Nuclear Proteins; D015375:Receptors, Interleukin-2; D000469:Alkaline Phosphatase