title: Intramuscular delivery of heterodimeric IL-15 DNA in macaques produces systemic levels of bioactive cytokine inducing proliferation of NK and T cells.
abstract: Interleukin-15 (IL-15) is a common γ-chain cytokine that has a significant role in the activation and proliferation of T and NK cells and holds great potential in fighting infection and cancer. We have previously shown that bioactive IL-15 in vivo comprises a complex of the IL-15 chain with the soluble or cell-associated IL-15 receptor alpha (IL-15Rα) chain, which together form the IL-15 heterodimer. We have generated DNA vectors expressing the heterodimeric IL-15 by optimizing mRNA expression and protein trafficking. Repeated administration of these DNA plasmids by intramuscular injection followed by in vivo electroporation in rhesus macaques resulted in sustained high levels of IL-15 in plasma, with no significant toxicity. Administration of DNAs expressing heterodimeric IL-15 also resulted in an increased frequency of NK and T cells undergoing proliferation in peripheral blood. Heterodimeric IL-15 led to preferential expansion of CD8(+)NK cells, all memory CD8(+) T-cell subsets and effector memory CD4(+) T cells. Expression of heterodimeric IL-15 by DNA delivery to the muscle is an efficient procedure to obtain high systemic levels of bioactive cytokine, without the toxicity linked to the high transient cytokine peak associated with protein injection.
authors.affiliation: Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Bergamaschi
authors.affiliation: Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA.
authors.forename: V
authors.initials: V
authors.lastname: Kulkarni
authors.affiliation: Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA.
authors.forename: M
authors.initials: M
authors.lastname: Rosati
authors.affiliation: Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA.
authors.forename: C
authors.initials: C
authors.lastname: Alicea
authors.affiliation: Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA.
authors.forename: R
authors.initials: R
authors.lastname: Jalah
authors.affiliation: Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA.
authors.forename: S
authors.initials: S
authors.lastname: Chen
authors.affiliation: Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Bear
authors.affiliation: Inovio Pharmaceuticals, Plymouth Meeting, PA, USA.
authors.forename: N Y
authors.initials: NY
authors.lastname: Sardesai
authors.affiliation: Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA.
authors.forename: A
authors.initials: A
authors.lastname: Valentin
authors.affiliation: Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA.
authors.forename: B K
authors.initials: BK
authors.lastname: Felber
authors.affiliation: Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, USA.
authors.forename: G N
authors.initials: GN
authors.lastname: Pavlakis
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D018274:Electroporation; D015870:Gene Expression; D015316:Genetic Therapy; D007273:Injections, Intramuscular; D019409:Interleukin-15 / Q000096:biosynthesis* / Q000235:genetics; D007694:Killer Cells, Natural / Q000502:physiology*; D008253:Macaca mulatta; D013601:T-Lymphocytes / Q000502:physiology*; D014162:Transfection
chemical_list: C569274:IL15 protein, human; D019409:Interleukin-15