| Content Provider |
World Health Organization (WHO)-Global Index Medicus |
| Author |
Hernandez, Antonio Sherwood, Edward R. Luan, Liming Bohannon, Julia K. Guo, Yin Fensterheim, Benjamin A. Rabacal, Whitney |
| Description |
Author Affiliation: Guo Y ( Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232); Luan L ( Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232.); Rabacal W ( Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232); Bohannon JK ( Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232.); Fensterheim BA ( Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232); Hernandez A ( Department of Anesthesiology, Vanderbilt University Medical Center, Nashville, TN 37232.); Sherwood ER ( Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232) |
| 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-15R 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- 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. |
| ISSN |
00221767 |
| e-ISSN |
15506606 |
| DOI |
10.4049/jimmunol.1500300 |
| Journal |
The Journal of Immunology |
| Issue Number |
5 |
| Volume Number |
195 |
| Language |
English |
| Publisher |
The American Association of Immunologists |
| Publisher Date |
2015-09-01 |
| Publisher Place |
United States |
| Access Restriction |
Open |
| Subject Keyword |
Cytotoxicity, Immunologic Immunology Interferon-gamma Interleukin-15 Receptor Alpha Subunit Interleukin-15 Killer Cells, Natural Animals Antigens, Cd Metabolism Antigens, Differentiation, T-lymphocyte Body Temperature Drug Effects Cd8-positive T-lymphocytes Cell Proliferation Dose-response Relationship, Drug Flow Cytometry Granzymes Genetics Lectins, C-type Lymphocyte Activation Mice, Inbred C57bl Mice, Knockout Multiprotein Complexes Pharmacology Perforin Research Support, N.i.h., Extramural Discipline Immunology |
| Content Type |
Text |
| Resource Type |
Article |
| Subject |
Immunology and Allergy Immunology |
