title: Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation.
abstract: Because of the expression of inhibitory receptors (KIR) for major histocompatibility complex (MHC) class I allotypes, a person's natural killer (NK) cells will not recognize and will, therefore, kill cells from individuals lacking his/her KIR epitopes. This study investigated the role of NK cell alloreactivity in human HLA haplotype-mismatched hematopoietic stem cell transplantation and, specifically, the role of the three major NK specificities, ie, those for HLA-C group 1, HLA-C group 2, and HLA-Bw4 alleles. In 20 of 60 donor-recipient pairs, KIR epitope incompatibility and functional analyses of donor NK cell clones predicted donor NK cells could cause graft-versus-host (GVH)/graft-versus-leukemia (GVL) reactions. NK cell clones of donor origin were obtained from transplanted recipients and tested for lysis of recipient's cryopreserved pretransplant lymphocytes. Despite the absence of GVH disease, we detected high frequencies of NK clones which killed recipient's target cells. Lysis followed the rules of NK cell alloreactivity, being blocked only by the MHC class I KIR epitope which was missing in the recipient. The alloreactive NK clones also killed the allogeneic leukemia. Transplants from these KIR epitope incompatible donors had higher engraftment rates. Therefore, a GVL effector and engraftment facilitating mechanism, which is independent of T-cell-mediated GVH reactions, may be operational in HLA mismatched hematopoietic cell transplants.
authors.affiliation: Division of Hematology and Clinical Immunology, the Department of Clinical and Experimental Medicine, University of Perugia, Perugia, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Ruggeri
authors.forename: M
authors.initials: M
authors.lastname: Capanni
authors.forename: M
authors.initials: M
authors.lastname: Casucci
authors.forename: I
authors.initials: I
authors.lastname: Volpi
authors.forename: A
authors.initials: A
authors.lastname: Tosti
authors.forename: K
authors.initials: K
authors.lastname: Perruccio
authors.forename: E
authors.initials: E
authors.lastname: Urbani
authors.forename: R S
authors.initials: RS
authors.lastname: Negrin
authors.forename: M F
authors.initials: MF
authors.lastname: Martelli
authors.forename: A
authors.initials: A
authors.lastname: Velardi
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D003602:Cytotoxicity, Immunologic; D020350:Graft vs Tumor Effect / Q000276:immunology*; D006680:HLA Antigens; D018380:Hematopoietic Stem Cell Transplantation; D006650:Histocompatibility Testing; D006801:Humans; D007519:Isoantigens / Q000276:immunology; D007694:Killer Cells, Natural / Q000276:immunology*; D007938:Leukemia / Q000628:therapy*; D008875:Middle Aged; D014181:Transplantation Immunology; D014184:Transplantation, Homologous
chemical_list: D006680:HLA Antigens; D007519:Isoantigens