title: IL-15 Superagonist-Mediated Immunotoxicity: Role of NK Cells and IFN-γ.
abstract: 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.
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; and Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Yin
authors.initials: Y
authors.lastname: Guo
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Liming
authors.initials: L
authors.lastname: Luan
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; and.
authors.forename: Whitney
authors.initials: W
authors.lastname: Rabacal
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Julia K
authors.initials: JK
authors.lastname: Bohannon
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; and.
authors.forename: Benjamin A
authors.initials: BA
authors.lastname: Fensterheim
authors.affiliation: Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232.
authors.forename: Antonio
authors.initials: A
authors.lastname: Hernandez
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; and Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232 edward.r.sherwood@vanderbilt.edu.
authors.forename: Edward R
authors.initials: ER
authors.lastname: Sherwood
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology / Q000378:metabolism; D001831:Body Temperature / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005434:Flow Cytometry; D053804:Granzymes / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D019409:Interleukin-15 / Q000276:immunology* / Q000378:metabolism; D053720:Interleukin-15 Receptor alpha Subunit / Q000276:immunology* / Q000378:metabolism; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D037181:Lectins, C-Type / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000276:immunology / Q000378:metabolism / Q000494:pharmacology; D054353:Perforin / Q000276:immunology / Q000378:metabolism; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D053804:Granzymes; D007371:Interferon-gamma; D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D037181:Lectins, C-Type; D046912:Multiprotein Complexes; D054353:Perforin; D000099192:CD69 Antigens