title: Antiviral activity against CMV-infected fibroblasts in pediatric patients transplanted with CD34(+)-selected allografts from alternative donors.
abstract: Human cytomegalovirus (HCMV) remains a cause of serious infectious complications after allogeneic transplantation of hematopoietic stem cells, especially in recipients of T-cell-depleted grafts. Here we investigated the antiviral activity of natural killer (NK) cells from healthy donors (n = 8) as well as of mononuclear cells (MNC) from transplanted pediatric patients (n = 11) who had received CD34(+) selected (and thus T-cell-depleted) stem cells from unrelated and mismatched related donors. Allogeneic human fibroblasts infected with HCMV laboratory strain AD169 for 5 days were used as targets in a 2-h cytotoxicity assay. Downregulation of human leukocyte antigen class I and upregulation of the adhesion molecules CD54 (ICAM-1) and CD58 (LFA-3) were observed after infection. In this experimental setting, NK cells from healthy donors exerted no specific lysis. However, antibody-dependent cellular cytotoxicity (ADCC) mediated by human anti-CMV IgG (cytoglobin) as well as stimulation with low-dose interleukin-(IL)-2 or IL-15 enhanced lysis markedly. MNC from two thirds of the patients (7/11) were capable of lysing infected targets without stimulation. Here also, lytic activity was significantly increased by IL-2 or IL-15, used in combination with ADCC. In contrast, 4/11 patients exerted no lysis. The observed antiviral activity may contribute to the low incidence of CMV DNAemia (29% at day 100, detected by polymerase chain reaction) in the whole group of our patients who have been transplanted with CD34(+)-selected allografts since 1995. Furthermore, our data suggest a potential benefit of using low-dose IL-2 or IL-15, also combined with anti-CMV immunoglobulinG, for immune modulation in CMV disease.
authors.affiliation: Children's University Hospital, Tuebingen, Germany. prlang@med.uni-tuebingen.de
authors.forename: P
authors.initials: P
authors.lastname: Lang
authors.forename: A
authors.initials: A
authors.lastname: Griesinger
authors.forename: K
authors.initials: K
authors.lastname: Hamprecht
authors.forename: T
authors.initials: T
authors.lastname: Feuchtinger
authors.forename: M
authors.initials: M
authors.lastname: Schumm
authors.forename: F
authors.initials: F
authors.lastname: Neuhäuser
authors.forename: J
authors.initials: J
authors.lastname: Greil
authors.forename: D
authors.initials: D
authors.lastname: Martin
authors.forename: R
authors.initials: R
authors.lastname: Handgretinger
authors.forename: D
authors.initials: D
authors.lastname: Niethammer
mesh_terms: D000293:Adolescent; D000920:Antibody-Dependent Cell Cytotoxicity / Q000276:immunology; D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34 / Q000276:immunology*; D019002:CD56 Antigen / Q000032:analysis; D018968:CD58 Antigens / Q000378:metabolism; D002648:Child; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000175:diagnosis; D003601:Cytotoxicity Tests, Immunologic; D003602:Cytotoxicity, Immunologic / Q000276:immunology*; D004279:DNA, Viral / Q000032:analysis; D005347:Fibroblasts / Q000737:chemistry / Q000276:immunology / Q000821:virology*; D005434:Flow Cytometry; D018380:Hematopoietic Stem Cell Transplantation; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D019409:Interleukin-15 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000276:immunology; D014019:Tissue Donors; D014184:Transplantation, Homologous
chemical_list: D015703:Antigens, CD; D018952:Antigens, CD34; D019002:CD56 Antigen; D018968:CD58 Antigens; D004279:DNA, Viral; D015395:Histocompatibility Antigens Class I; D019409:Interleukin-15; D007376:Interleukin-2; D018799:Intercellular Adhesion Molecule-1