title: Identification of IFN-γ-producing T cells as the main mediators of the side effects associated to mouse interleukin-15 sustained exposure.
abstract: Interleukin-15 (IL-15) is a cell growth-factor that regulates lymphocyte function and homeostasis. Its strong immunostimulatory activity coupled with an apparent lack of toxicity makes IL-15 an exciting candidate for cancer therapy, somehow limited by its short half-life in circulation. To increase IL-15 bioavailability we constructed a recombinant adeno-associated vector expressing murine IL-15 (AAV-mIL15) in the liver. Mice injected with AAV-mIL15 showed sustained and vector dose-dependent levels of IL-15/IL-15Rα complexes in serum, production of IFN-γ and activation of CD8+ T-cells and macrophages. The antitumoral efficacy of AAV-mIL15 was tested in a mouse model of metastatic colorectal cancer established by injection of MC38 cells. AAV-mIL15 treatment slightly inhibits MC38 tumor-growth and significantly increases the survival of mice. However, mIL-15 sustained expression was associated with development of side effects like hepatosplenomegaly, liver damage and the development of haematological stress, which results in the expansion of hematopoietic precursors in the bone marrow. To elucidate the mechanism, we treated IFN-γ receptor-, RAG1-, CD1d- and µMT-deficient mice and performed adoptive transfer of bone marrow cells from WT mice to RAG1-defcient mice. We demonstrated that the side effects of murine IL-15 administration were mainly mediated by IFN-γ-producing T-cells.
  
  
  CONCLUSIONS
  IL-15 induces the activation and survival of effector immune cells that are necessary for its antitumoral activity; but, long-term exposure to IL-15 is associated with the development of important side effects mainly mediated by IFN-γ-producing T-cells. Strategies to modulate T-cell activation should be combined with IL-15 administration to reduce secondary adverse events while maintaining its antitumoral effect.
authors.affiliation: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain.
authors.forename: Marianna
authors.initials: M
authors.lastname: Di Scala
authors.affiliation: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain.|Department of Translational Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Irene
authors.initials: I
authors.lastname: Gil-Fariña
authors.affiliation: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Olagüe
authors.affiliation: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain.
authors.forename: Africa
authors.initials: A
authors.lastname: Vales
authors.affiliation: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain.
authors.forename: Luciano
authors.initials: L
authors.lastname: Sobrevals
authors.affiliation: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain.
authors.forename: Puri
authors.initials: P
authors.lastname: Fortes
authors.affiliation: Imaging Unit and Cancer Imaging Laboratory, Center for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Corbacho
authors.affiliation: Gene Therapy and Regulation of Gene Expression Program, Center for Applied Medical Research (CIMA), Pamplona, Spain.
authors.forename: Gloria
authors.initials: G
authors.lastname: González-Aseguinolaza
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D055610:Antigens, CD1d / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism; D015179:Colorectal Neoplasms / Q000628:therapy; D000229:Dependovirus; D018450:Disease Progression; D005260:Female; D005786:Gene Expression Regulation; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods; D005822:Genetic Vectors; D018398:Homeodomain Proteins / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism*; D019409:Interleukin-15 / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008213:Lymphocyte Activation; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000378:metabolism*
chemical_list: D055610:Antigens, CD1d; C526879:Cd1d1 protein, mouse; D018398:Homeodomain Proteins; D019409:Interleukin-15; C064658:RAG-1 protein; D007371:Interferon-gamma
keywords: Immune response; Immunity; Immunology and Microbiology Section; T cells; genetic transfer; interferon-γ; interleukin-15; side effects