title: Homeostasis of human NK cells is not IL-15 dependent.
abstract: IL-15 is a proinflammatory cytokine that plays an important role in the development and activation of NK cells and is a potential target for inflammatory disease therapy. Studies conducted in IL-15- and IL-15R knockout mice identified IL-15 as an important cytokine for NK cell homeostasis. Consistent with this information derived from genetically modified mice, we demonstrated that neutralizing IL-15 with a mouse anti-mouse IL-15 mAb (M96) depletes C57BL/6 mouse NK cells. An mAb directed against macaque IL-15 (Hu714MuXHu) was manufactured and demonstrated to block IL-15-induced activation of nonhuman primate (NHP) NK cells in vitro. Neutralization of macaque IL-15 by parenteral administration of Hu714MuXHu reduces (>95%) circulating NK cell counts in NHPs. A blocking mAb directed against human IL-15 (huIL-15; AMG 714) was manufactured. Unexpectedly, when human subjects were treated with the blocking anti-IL-15 Ab AMG 714 in clinical trials, no reductions in circulating NK cell counts were observed despite achieving significantly higher exposures than the levels of Hu714MuXHu needed to cause NK cell count reductions in NHPs in vivo. Both AMG 714 and Hu714MuXHu are able to block huIL-15 activity in a human T cell blast proliferation and IFN-γ production assay. Both Abs block huIL-15-mediated Stat5 activation and CD69 expression in human NK cells. Collectively, these results demonstrate that NK cell homeostasis is obligatorily dependent upon IL-15 in both mice and NHPs, but that IL-15 is dispensable for maintenance of circulating human NK cells.
authors.affiliation: Toxicology Sciences Department, Amgen, Inc., Seattle, WA 98119;
authors.forename: Herve
authors.initials: H
authors.lastname: Lebrec
authors.forename: Michelle J
authors.initials: MJ
authors.lastname: Horner
authors.forename: Kevin S
authors.initials: KS
authors.lastname: Gorski
authors.forename: Wayne
authors.initials: W
authors.lastname: Tsuji
authors.forename: Dong
authors.initials: D
authors.lastname: Xia
authors.forename: Wei-Jian
authors.initials: WJ
authors.lastname: Pan
authors.forename: Gary
authors.initials: G
authors.lastname: Means
authors.forename: Greg
authors.initials: G
authors.lastname: Pietz
authors.forename: Nianyu
authors.initials: N
authors.lastname: Li
authors.forename: Marc
authors.initials: M
authors.lastname: Retter
authors.forename: Kathy
authors.initials: K
authors.lastname: Shaffer
authors.forename: Neha
authors.initials: N
authors.lastname: Patel
authors.forename: Padma K
authors.initials: PK
authors.lastname: Narayanan
authors.forename: Eric A
authors.initials: EA
authors.lastname: Butz
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D002986:Clinical Trials as Topic; D006706:Homeostasis / Q000187:drug effects; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D008251:Macaca; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D019138:Antibodies, Blocking; D019409:Interleukin-15; D050799:STAT5 Transcription Factor; D007371:Interferon-gamma