IL-15 Superagonist-Mediated Immunotoxicity: Role of NK Cells and IFN-γ.

Guo Y, Luan L, Rabacal W, Bohannon JK, Fensterheim BA, Hernandez A, Sherwood ER
J Immunol. 2015 195 (5): 2353-64

PMID: 26216888 · PMCID: PMC4543906 · DOI:10.4049/jimmunol.1500300

IL-15 is currently undergoing clinical trials to assess its efficacy for treatment of advanced cancers. The combination of IL-15 with soluble IL-15Rα generates a complex termed IL-15 superagonist (IL-15 SA) that possesses greater biological activity than IL-15 alone. IL-15 SA is considered an attractive antitumor and antiviral agent because of its ability to selectively expand NK and memory CD8(+) T (mCD8(+) T) lymphocytes. However, the adverse consequences of IL-15 SA treatment have not been defined. In this study, the effect of IL-15 SA on physiologic and immunologic functions of mice was evaluated. IL-15 SA caused dose- and time-dependent hypothermia, weight loss, liver injury, and mortality. NK (especially the proinflammatory NK subset), NKT, and mCD8(+) T cells were preferentially expanded in spleen and liver upon IL-15 SA treatment. IL-15 SA caused NK cell activation as indicated by increased CD69 expression and IFN-γ, perforin, and granzyme B production, whereas NKT and mCD8(+) T cells showed minimal, if any, activation. Cell depletion and adoptive transfer studies showed that the systemic toxicity of IL-15 SA was mediated by hyperproliferation of activated NK cells. Production of the proinflammatory cytokine IFN-γ, but not TNF-α or perforin, was essential to IL-15 SA-induced immunotoxicity. The toxicity and immunological alterations shown in this study are comparable to those reported in recent clinical trials of IL-15 in patients with refractory cancers and advance current knowledge by providing mechanistic insights into IL-15 SA-mediated immunotoxicity.

Copyright © 2015 by The American Association of Immunologists, Inc.

MeSH Terms (22)

Animals Antigens, CD Antigens, Differentiation, T-Lymphocyte Body Temperature CD8-Positive T-Lymphocytes Cell Proliferation Cytotoxicity, Immunologic Dose-Response Relationship, Drug Female Flow Cytometry Granzymes Humans Interferon-gamma Interleukin-15 Interleukin-15 Receptor alpha Subunit Killer Cells, Natural Lectins, C-Type Lymphocyte Activation Mice, Inbred C57BL Mice, Knockout Multiprotein Complexes Perforin

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