Premium
Improved expression and delivery of IL‐15 DNA vectors in combination with IL‐15 receptor alpha in mice and macaques provide a potent growth signal for NK and T cells
Author(s) -
Bergamaschi Cristina,
Valentin Antonio,
Jalah Rashmi,
Rosati Margherita,
Kulkarni Viraj,
Alicea Candido,
Patel Vainav,
Zhang GenMu,
Kjeken Rune,
Felber Barbara K,
Pavlakis George N
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.2_supplement.429
Subject(s) - electroporation , receptor , spleen , in vivo , cytokine , biology , dna vaccination , effector , microbiology and biotechnology , interleukin 12 , transfection , immunology , in vitro , immune system , cytotoxic t cell , gene , biochemistry , immunization
Optimized DNA vectors expressing IL‐15 and IL‐15 Receptor alpha (IL‐15Ra) were generated by optimizing mRNA expression and protein trafficking. Co‐expression of IL‐15 with IL‐15Ra allowed for the intracellular interaction of the two proteins, resulting in increased stability and secretion of both molecules (Bergamaschi et al, JBC, 2007). Mutual stabilization of IL‐15 and IL‐15Ra leads to remarkable increase in production of bioactive IL‐15 in vivo. Co‐injection of IL‐15 and IL‐15Ra DNAs into mice resulted in about 1000‐fold increase of IL‐15 serum levels, compared to the wild type IL‐15 alone. This high concentration of systemic IL‐15 in mice was biologically active, as demonstrated by the increased frequency of NK and effector memory T cells in lung, liver and spleen. Rhesus macaques receiving these vectors by intramuscular in vivo electroporation also express high levels of plasma IL‐15, which peaks at day 4. As a result of DNA injection, the frequency of NK and T cells in blood decreased between day 0 and day 5 after injection (p=0.002), suggesting their mobilization to the periphery, where they mediate surveillance and effectors functions. These results indicate that the most potent form of IL‐15 is as part of a complex with IL‐15Ra. The high level of expression of bioactive cytokine, achieved by the optimized vectors in primates, suggest that they will be useful in DNA‐based vaccines or immunotherapy protocols.