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IL-15 Superagonist-Mediated Immunotoxicity: Role of NK Cells and IFN-γ.
J Immunol. 2015 Sep 01; 195(5):2353-64.JI

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+Show Affiliations

Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; and Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232.Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232.Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; and.Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232.Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; and.Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232.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.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

26216888

Citation

Guo, Yin, et al. "IL-15 Superagonist-Mediated Immunotoxicity: Role of NK Cells and IFN-γ." Journal of Immunology (Baltimore, Md. : 1950), vol. 195, no. 5, 2015, pp. 2353-64.
Guo Y, Luan L, Rabacal W, et al. IL-15 Superagonist-Mediated Immunotoxicity: Role of NK Cells and IFN-γ. J Immunol. 2015;195(5):2353-64.
Guo, Y., Luan, L., Rabacal, W., Bohannon, J. K., Fensterheim, B. A., Hernandez, A., & Sherwood, E. R. (2015). IL-15 Superagonist-Mediated Immunotoxicity: Role of NK Cells and IFN-γ. Journal of Immunology (Baltimore, Md. : 1950), 195(5), 2353-64. https://doi.org/10.4049/jimmunol.1500300
Guo Y, et al. IL-15 Superagonist-Mediated Immunotoxicity: Role of NK Cells and IFN-γ. J Immunol. 2015 Sep 1;195(5):2353-64. PubMed PMID: 26216888.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - IL-15 Superagonist-Mediated Immunotoxicity: Role of NK Cells and IFN-γ. AU - Guo,Yin, AU - Luan,Liming, AU - Rabacal,Whitney, AU - Bohannon,Julia K, AU - Fensterheim,Benjamin A, AU - Hernandez,Antonio, AU - Sherwood,Edward R, Y1 - 2015/07/27/ PY - 2015/02/10/received PY - 2015/07/01/accepted PY - 2015/7/29/entrez PY - 2015/7/29/pubmed PY - 2015/12/17/medline SP - 2353 EP - 64 JF - Journal of immunology (Baltimore, Md. : 1950) JO - J. Immunol. VL - 195 IS - 5 N2 - 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. SN - 1550-6606 UR - https://www.unboundmedicine.com/medline/citation/26216888/IL_15_Superagonist_Mediated_Immunotoxicity:_Role_of_NK_Cells_and_IFN_γ_ L2 - http://www.jimmunol.org/cgi/pmidlookup?view=long&pmid=26216888 DB - PRIME DP - Unbound Medicine ER -