title: NK-cell purging of leukemia: superior antitumor effects of NK cells H2 allogeneic to the tumor and augmentation with inhibitory receptor blockade.
abstract: Natural killer (NK) cells are composed of subsets characterized by the expression of inhibitory or activating receptors, or both, specific for different major histocompatibility complex (MHC) class I determinants. We have previously shown that inhibitory receptor blockade of syngeneic NK cells was an effective means of ex vivo purging of leukemia-contaminated bone marrow and that the transplantation of mice with the purged bone marrow cells (BMCs) resulted in long-term, relapse-free survival. We have extended the investigation to assess the antitumor effects mediated by NK cells H2-allogeneic to tumor cells. We demonstrate that various tumor cell lines are more susceptible to lysis by H2-allogeneic NK cells than by syngeneic NK cells in vitro even though comparable percentages of Ly49 NK cells were present. Using allogeneic NK cells to purge leukemia-contaminating BMCs before transplantation resulted in a higher proportion of mice with long-term survival than using syngeneic NK cells. Allogeneic NK cells did not suppress hematopoietic reconstitution as measured by granulocyte/monocyte-colony-forming unit (CFU-GM), complete blood count (CBC), and donor chimerism at various days after transplantation. Inhibitory receptor blockade of allogeneic NK cells also significantly increased these antitumor effects at lower NK/tumor ratios compared with those of syngeneic NK cells. These results demonstrate that H2-allogeneic NK cells mediate more potent antitumor effects than syngeneic NK cells without adverse hematologic effects and thus may be useful in cancer therapy.
authors.affiliation: Department of Microbiology and Immunology, University of Nevada School of Medicine, Applied Research Facility, Bldg 344/MS 199, Reno, NV 89557, USA.
authors.forename: Crystal Y
authors.initials: CY
authors.lastname: Koh
authors.forename: John R
authors.initials: JR
authors.lastname: Ortaldo
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Michael
authors.initials: M
authors.lastname: Bennett
authors.forename: William J
authors.initials: WJ
authors.lastname: Murphy
mesh_terms: D000818:Animals; D016465:Bone Marrow Purging / Q000379:methods*; D016026:Bone Marrow Transplantation / Q000379:methods; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic; D020544:Graft vs Leukemia Effect; D006183:H-2 Antigens / Q000276:immunology; D016219:Immunotherapy, Adoptive; D007694:Killer Cells, Natural / Q000276:immunology* / Q000637:transplantation; D007938:Leukemia / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D011971:Receptors, Immunologic / Q000037:antagonists & inhibitors; D054340:Receptors, KIR; D015996:Survival Rate; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
chemical_list: D006183:H-2 Antigens; D011971:Receptors, Immunologic; D054340:Receptors, KIR