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Title page for ETD etd-09302016-120529

Type of Document Dissertation
Author Guo, Yin
Author's Email Address yin.guo@vanderbit.edu
URN etd-09302016-120529
Title Interleukin-15-mediated immunotoxicity and exacerbation of sepsis: role of natural killer cells and interferon γ
Degree PhD
Department Microbiology and Immunology
Advisory Committee
Advisor Name Title
Luc Van Kaer Committee Chair
Daniel Moore Committee Member
Edward Sherwood Committee Member
Lorraine Ware Committee Member
Stokes Peebles Committee Member
  • IFNγ
  • NK cells
  • sepsis
  • immunotoxicity
  • IL-15
  • inflammation
Date of Defense 2016-09-26
Availability unrestricted
Immunotherapy has been a rapidly evolving field of basic and clinical research over the past decades. Interleukin (IL)-15 and its analog IL-15 superagonist (IL-15 SA, or IL-15/IL-15 receptor α) have shown promise in cancer and viral immunotherapy as they play an essential role in development, proliferation and activation of cytotoxic lymphocytes including natural killer (NK) and memory phenotype (m) CD8+ T lymphocytes. My dissertation study showed that IL-15 SA caused dose- and time-dependent immunotoxicity in mice by expansion and activation of NK cells as well as induction of interferon γ (IFNγ) production. Additionally, although IL-15 SA is considered a candidate immunotherapeutic for reversing lymphocyte dysfunction in the late phase of sepsis, my results showed that IL-15 SA exacerbated physiological dysfunction and systemic inflammation during acute sepsis by activation of NK cells and induction of IFNγ production. Endogenous IL-15 also contributes to the pathogenesis of acute sepsis by maintenance of NK cell number and effector function. Taken together, findings from my dissertation provide mechanistic insights into IL-15 SA-mediated immunotoxicity that will be useful as IL-15 SA advances through clinical drug development in the field of cancer and sepsis. My studies further illuminate the essential role of endogenous IL-15 in the pathogenesis of sepsis and its regulatory effect on maintaining lymphocyte number and function during sepsis.
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