title: Potential mechanisms of human natural killer cell expansion in vivo during low-dose IL-2 therapy.
abstract: The continuous, in vivo infusion of low-dose IL-2 selectively expands the absolute number of human natural killer (NK) cells after 4-6 weeks of therapy. The mechanism responsible for this expansion is unknown and was examined in this study. NK cells cultured at low concentrations of IL-2, comparable to those found during in vivo therapy, proliferate for 6 days and then exit the cell cycle. However, NK cells in vivo did not traverse the S/G(2)/M phase of the cell cycle during low-dose IL-2 therapy. Low concentrations of IL-2 delay programmed cell death of NK cells but have the same effect on resting T cells that do not expand in vivo. When CD34(+) bone marrow hematopoietic progenitor cells are cultured for 21 days with low concentrations of IL-2, they differentiate into CD56(+)CD3(-) NK cells, not T cells. Thus, the selective expansion of human NK cells during continuous in vivo infusion of low-dose IL-2 likely results from enhanced NK-cell differentiation from bone marrow progenitors, combined with an IL-2-dependent delay in NK-cell death, rather than proliferation of mature NK cells in the periphery.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology. Division of Medicine, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Fehniger
authors.forename: E M
authors.initials: EM
authors.lastname: Bluman
authors.forename: M M
authors.initials: MM
authors.lastname: Porter
authors.forename: E
authors.initials: E
authors.lastname: Mrózek
authors.forename: M A
authors.initials: MA
authors.lastname: Cooper
authors.forename: J B
authors.initials: JB
authors.lastname: VanDeusen
authors.forename: S R
authors.initials: SR
authors.lastname: Frankel
authors.forename: W
authors.initials: W
authors.lastname: Stock
authors.forename: M A
authors.initials: MA
authors.lastname: Caligiuri
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000032:analysis; D019002:CD56 Antigen / Q000032:analysis; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology* / Q000627:therapeutic use; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000502:physiology; D008213:Lymphocyte Activation / Q000187:drug effects; D011817:Rabbits; D011994:Recombinant Proteins / Q000494:pharmacology
chemical_list: D018952:Antigens, CD34; D019002:CD56 Antigen; D007376:Interleukin-2; D011994:Recombinant Proteins