title: Maintenance therapy with histamine plus IL-2 induces a striking expansion of two CD56bright NK cell subpopulations in patients with acute myeloid leukemia and supports their activation.
abstract: Histamine dihydrochloride (HDC) plus IL-2 has been proposed as a novel maintenance-immunotherapy in acute myeloid leukemia (AML). We analyzed the immunophenotype and function of natural killer (NK) cells in blood of AML patients treated after chemotherapy with HDC plus IL-2. The treatment caused a striking expansion of CD56brightCD16neg and CD56brightCD16low NK cell subpopulations. A reduced NK cell fraction recovered and high proportions of cells expressed the activating receptors NKG2D, NKp30, and NKp46. Concomitantly, KIR-expressing NK cells were reduced and NK cells with inhibitory NKG2A/CD94 receptors increased beyond normal levels. In addition, the immunotherapy-induced NK cells exhibited high capacity to produce IFN-γ and to degranulate. Furthermore, we provide evidence from subsequent in vitro studies that this is caused in part by direct effects of IL-2 on the CD56bright cells. IL-2 specifically induced proliferation of both CD56bright subpopulations, but not of CD56dim cells. It further preserved the expression of activating receptors and the capacity to produce IFN-γ and to degranulate. These data suggest that therapy with HDC plus IL-2 supports the reconstitution of a deficient NK cell fraction through the specific amplification of CD56bright NK cells giving rise to a functional NK cell compartment with high potential to combat leukemic disease.
authors.affiliation: Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Angélica
authors.initials: A
authors.lastname: Cuapio
authors.affiliation: Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Mirte
authors.initials: M
authors.lastname: Post
authors.affiliation: Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria.|Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.
authors.forename: Sabine
authors.initials: S
authors.lastname: Cerny-Reiterer
authors.affiliation: Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria.|Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.
authors.forename: Karoline V
authors.initials: KV
authors.lastname: Gleixner
authors.affiliation: Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Stefanzl
authors.affiliation: Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Jose
authors.initials: J
authors.lastname: Basilio
authors.affiliation: Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria.|Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.
authors.forename: Susanne
authors.initials: S
authors.lastname: Herndlhofer
authors.affiliation: Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria.|Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.
authors.forename: Wolfgang R
authors.initials: WR
authors.lastname: Sperr
authors.affiliation: National Core Facility Cytometry, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg.
authors.forename: Nicolaas H C
authors.initials: NH
authors.lastname: Brons
authors.affiliation: Ludwig Boltzmann Institute of Cancer Research, Vienna, Austria.|Institute of Pharmacology, Center of Physiology and Pharmacology, Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
authors.forename: Emilio
authors.initials: E
authors.lastname: Casanova
authors.affiliation: Department of Infection and Immunity, Luxembourg Institute of Health, Esch-sur-Alzette, Luxembourg.
authors.forename: Jacques
authors.initials: J
authors.lastname: Zimmer
authors.affiliation: Department of Internal Medicine I, Division of Hematology & Hemostaseology, Medical University of Vienna, Vienna, Austria.|Ludwig Boltzmann Cluster Oncology, Medical University of Vienna, Vienna, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Valent
authors.affiliation: Department of Vascular Biology and Thrombosis Research, Medical University of Vienna, Vienna, Austria.
authors.forename: Erhard
authors.initials: E
authors.lastname: Hofer
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D006632:Histamine / Q000008:administration & dosage*; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D007376:Interleukin-2 / Q000008:administration & dosage*; D007694:Killer Cells, Natural / Q000187:drug effects; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000276:immunology; D016131:Lymphocyte Subsets / Q000187:drug effects; D060046:Maintenance Chemotherapy / Q000379:methods; D011994:Recombinant Proteins / Q000008:administration & dosage
chemical_list: D007376:Interleukin-2; D011994:Recombinant Proteins; D006632:Histamine
keywords: CD56bright; CD56dim; IL-2; histamine; natural killer cells