Safety and immunologic effects of IL-15 administration in nonhuman primates
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Safety and immunologic effects of IL-15 administration in nonhuman primates. / Berger, Carolina; Berger, Michael; Hackman, Robert C; Gough, Michael; Elliott, Carole; Jensen, Michael C; Riddell, Stanley R.
in: BLOOD, Jahrgang 114, Nr. 12, 17.09.2009, S. 2417-26.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Safety and immunologic effects of IL-15 administration in nonhuman primates
AU - Berger, Carolina
AU - Berger, Michael
AU - Hackman, Robert C
AU - Gough, Michael
AU - Elliott, Carole
AU - Jensen, Michael C
AU - Riddell, Stanley R
PY - 2009/9/17
Y1 - 2009/9/17
N2 - The administration of cytokines that modulate endogenous or transferred T-cell immunity could improve current approaches to clinical immunotherapy. Interleukin-2 (IL-2) is used most commonly for this purpose, but causes systemic toxicity and preferentially drives the expansion of CD4(+)CD25(+)Foxp3(+) regulatory T cells, which can inhibit antitumor immunity. IL-15 belongs to the gamma(c) cytokine family and possesses similar properties to IL-2, including the ability to induce T-cell proliferation. Whereas IL-2 promotes apoptosis and limits the survival of CD8(+) memory T cells, IL-15 is required for the establishment and maintenance of CD8(+) T-cell memory. However, limited data are available to guide the clinical use of IL-15. Here, we demonstrate in nonhuman primates that IL-15 administration expands memory CD8(+) and CD4(+) T cells, and natural killer (NK) cells in the peripheral blood, with minimal increases in CD4(+)CD25(+)Foxp3(+) regulatory T cells. Daily administration of IL-15 resulted in persistently elevated plasma IL-15 levels and transient toxicity. Intermittent administration of IL-15 allowed clearance of IL-15 between doses and was safe for more than 3 weeks. These findings demonstrate that IL-15 has profound immunomodulatory properties distinct from those described for IL-2, and suggest that intermittent administration of IL-15 should be considered in clinical studies.
AB - The administration of cytokines that modulate endogenous or transferred T-cell immunity could improve current approaches to clinical immunotherapy. Interleukin-2 (IL-2) is used most commonly for this purpose, but causes systemic toxicity and preferentially drives the expansion of CD4(+)CD25(+)Foxp3(+) regulatory T cells, which can inhibit antitumor immunity. IL-15 belongs to the gamma(c) cytokine family and possesses similar properties to IL-2, including the ability to induce T-cell proliferation. Whereas IL-2 promotes apoptosis and limits the survival of CD8(+) memory T cells, IL-15 is required for the establishment and maintenance of CD8(+) T-cell memory. However, limited data are available to guide the clinical use of IL-15. Here, we demonstrate in nonhuman primates that IL-15 administration expands memory CD8(+) and CD4(+) T cells, and natural killer (NK) cells in the peripheral blood, with minimal increases in CD4(+)CD25(+)Foxp3(+) regulatory T cells. Daily administration of IL-15 resulted in persistently elevated plasma IL-15 levels and transient toxicity. Intermittent administration of IL-15 allowed clearance of IL-15 between doses and was safe for more than 3 weeks. These findings demonstrate that IL-15 has profound immunomodulatory properties distinct from those described for IL-2, and suggest that intermittent administration of IL-15 should be considered in clinical studies.
KW - Animals
KW - Apoptosis
KW - CD8-Positive T-Lymphocytes/immunology
KW - Enzyme-Linked Immunosorbent Assay
KW - Flow Cytometry
KW - Genes, T-Cell Receptor
KW - Glycosylation
KW - Immunologic Memory/immunology
KW - Interleukin-15/administration & dosage
KW - Interleukin-2/metabolism
KW - Killer Cells, Natural/immunology
KW - Macaca nemestrina
KW - T-Lymphocyte Subsets/immunology
KW - T-Lymphocytes, Regulatory/immunology
U2 - 10.1182/blood-2008-12-189266
DO - 10.1182/blood-2008-12-189266
M3 - SCORING: Journal article
C2 - 19605850
VL - 114
SP - 2417
EP - 2426
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 12
ER -