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

Yin Guo1, Liming Luan2, Whitney Rabacal3

  • 1Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232; and Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232.

Journal of Immunology (Baltimore, Md. : 1950)
|July 29, 2015
PubMed

Insights

Interleukin-15 superagonist (IL-15 SA) causes severe toxicity in mice, primarily mediated by natural killer (NK) cell hyperproliferation and IFN-γ production. These findings offer mechanistic insights into IL-15 SA immunotoxicity.

Area of Science:

  • Immunology
  • Oncology
  • Pharmacology

Background:

  • Interleukin-15 (IL-15) is under investigation for advanced cancer treatment.
  • IL-15 superagonist (IL-15 SA) demonstrates enhanced biological activity over IL-15.
  • IL-15 SA selectively expands NK and memory CD8(+) T lymphocytes, showing potential as an antitumor agent.

Purpose of the Study:

  • To define the adverse consequences of IL-15 SA treatment.
  • To evaluate the effect of IL-15 SA on the physiologic and immunologic functions in mice.
  • To elucidate the mechanisms underlying IL-15 SA-induced immunotoxicity.

Main Methods:

  • Dose- and time-dependent evaluation of IL-15 SA effects on mouse physiology and immunology.
  • Analysis of immune cell populations (NK, NKT, mCD8(+) T) in spleen and liver.
  • Assessment of NK cell activation markers (CD69, IFN-γ, perforin, granzyme B).
  • Cell depletion and adoptive transfer studies.
  • Investigation of cytokine involvement (IFN-γ, TNF-α).

Main Results:

  • IL-15 SA induced dose- and time-dependent hypothermia, weight loss, liver injury, and mortality.
  • Preferential expansion of NK, NKT, and mCD8(+) T cells was observed in spleen and liver.
  • NK cells showed activation, while NKT and mCD8(+) T cells exhibited minimal activation.
  • Systemic toxicity was mediated by hyperproliferation of activated NK cells.
  • IFN-γ production, not TNF-α or perforin, was essential for IL-15 SA-induced immunotoxicity.

Conclusions:

  • IL-15 SA causes significant systemic toxicity in mice.
  • The toxicity is primarily mediated by hyperactivated NK cells and IFN-γ production.
  • Findings provide mechanistic insights into IL-15 SA immunotoxicity, relevant to ongoing clinical trials.

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