title: The cytotoxic potential of interleukin-15-stimulated cytokine-induced killer cells against leukemia cells.
abstract: OBJECTIVE
  Cytokine-induced killer (CIK) cells may serve as an alternative approach to adoptive donor lymphocyte infusions (DLI) for patients with acute leukemia relapsing after haplo-identical hematopoietic stem cell transplantation (HSCT). We investigated the feasibility of enhancing CIK cell-mediated cytotoxicity by interleukin (IL)-15 against acute myeloid and lymphoblastic leukemia/lymphoma cells.
  
  
  METHODS
  CIK cells were activated using IL-2 (CIK(IL-2)) or IL-15 (CIK(IL-15)) and phenotypically analyzed by fluorescence-activated cell sorting (FACS). Cytotoxic potential was measured by europium release assay.
  
  
  RESULTS
  CIK(IL-2) cells showed potent cytotoxicity against the T-lymphoma cell line H9, T-cell acute lymphoblastic leukemia (T-ALL) cell line MOLT-4 and subtype M4 acute myeloid leukemia (AML) cell line THP-1, but low cytotoxicity against the precursor B (pB)-cell ALL cell line Tanoue. IL-15 stimulation resulted in a significant enhancement of CIK cell-mediated cytotoxicity against acute lymphoblastic leukemia/lymphoma cell lines as well as against primary acute myeloid and defined lymphoblastic leukemia cells. However, the alloreactive potential of CIK(IL-15) cells remained low. Further analysis of CIK(IL-15) cells demonstrated that the NKG2D receptor is apparently involved in the recognition of target cells whereas killer-cell immunoglobulin-like receptor (KIR)-HLA mismatches contributed to a lesser extent to the CIK(IL-15) cell-mediated cytotoxicity. In this context, CD3 (+) CD8 (+) CD25 (+) CD56(-) CIK(IL-15) cell subpopulations were more effective in the lysis of AML cells, in contrast with CD56 (+) CIK(IL-15) cells, which showed the highest cytotoxic potential against ALL cells.
  
  
  CONCLUSIONS
  This study provides the first evidence that CIK(IL-15) cells may offer a therapeutic option for patients with refractory or relapsed leukemia following haplo-identical HSCT.
authors.affiliation: University Children's Hospital of Frankfurt/Main and Department of Pediatric Hematology, Oncology and Hemostaseology, Goethe-University Frankfurt/Main, Frankfurt/Main, Germany. eva.rettinger@kgu.de
authors.forename: Eva
authors.initials: E
authors.lastname: Rettinger
authors.forename: Selim
authors.initials: S
authors.lastname: Kuçi
authors.forename: Ivonne
authors.initials: I
authors.lastname: Naumann
authors.forename: Petra
authors.initials: P
authors.lastname: Becker
authors.forename: Hermann
authors.initials: H
authors.lastname: Kreyenberg
authors.forename: Martina
authors.initials: M
authors.lastname: Anzaghe
authors.forename: Andre
authors.initials: A
authors.lastname: Willasch
authors.forename: Ulrike
authors.initials: U
authors.lastname: Koehl
authors.forename: Gesine
authors.initials: G
authors.lastname: Bug
authors.forename: Martin
authors.initials: M
authors.lastname: Ruthardt
authors.forename: Thomas
authors.initials: T
authors.lastname: Klingebiel
authors.forename: Simone
authors.initials: S
authors.lastname: Fulda
authors.forename: Peter
authors.initials: P
authors.lastname: Bader
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000951:Antigens, Neoplasm / Q000276:immunology; D045744:Cell Line, Tumor; D000075202:Contraindications; D003602:Cytotoxicity, Immunologic; D005240:Feasibility Studies; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007111:Immunity, Cellular; D016219:Immunotherapy, Adoptive; D019409:Interleukin-15 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D017708:Leukocyte Transfusion; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011110:Polymorphism, Genetic; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D012008:Recurrence; D014184:Transplantation, Homologous
chemical_list: D000276:Adjuvants, Immunologic; D000951:Antigens, Neoplasm; D019409:Interleukin-15; D055655:NK Cell Lectin-Like Receptor Subfamily K