title: Rapid generation of potent and tumor-specific cytotoxic T lymphocytes by interleukin 18 using dendritic cells and natural killer cells.
abstract: We hypothesized that antitumor-specific immunity, which is induced by interleukin (IL) 18 treatment in murine tumor models, is promoted by enhancing natural killer (NK)-mediated destruction of tumor and delivery to dendritic cells (DCs). These activated and antigen-pulsed DCs then critically and optimally induce an adoptive immune response, positioning IL-18 as an important bridge between the innate and adoptive immune response. The effect of IL-18 added to cultures of live tumor cells (MCA205, a mouse sarcoma cell line), NK cells, DCs, and T cells was assessed. When recombinant (r) mIL-18 protein was added to this culture, potent NK cytolytic activity with subsequent generation of CTLs was observed in a dose-dependent manner. Without introduction of either rmIL-18 or NK cells into this culture, systemic cytolytic activity was significantly decreased. Following the absence of direct contact of either NK cells or DCs with other cells in this cooperative coculture system using transwell, the systemic cytolytic activity of both NK cells and CTLs was greatly suppressed. The cytolysis mediated by effector cells harvested after completion of the culture was primarily restricted to MHC class I and highly specific for the tumor cells used in the coculture. Furthermore, we examined the efficiency in the induction of cytolytic T cells of other established IFN-gamma inducing T-cell growth factors, IL-2, and IL-12 in this culture system and compared them with that mediated by IL-18. Neither IL-2 nor IL-12 induced tumor-specific cytolytic T cells to the same degree as that mediated by IL-18. Efficacy of this system in induction of tumor-specific CTLs was also observed in the system using MC38 adenocarcinoma cells. These results are consistent with the notion that IL-18 induces tumor-specific immunity through enhancing NK activity, which in turn mediates tumor cell death and activates and primes DCs.
authors.affiliation: Department of Surgery, University of Pittsburgh School of Medicine, Pennsylvania 15213, USA.
authors.forename: F
authors.initials: F
authors.lastname: Tanaka
authors.forename: W
authors.initials: W
authors.lastname: Hashimoto
authors.forename: H
authors.initials: H
authors.lastname: Okamura
authors.forename: P D
authors.initials: PD
authors.lastname: Robbins
authors.forename: M T
authors.initials: MT
authors.lastname: Lotze
authors.forename: H
authors.initials: H
authors.lastname: Tahara
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology; D018920:Coculture Techniques; D003110:Colonic Neoplasms / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D005354:Fibrosarcoma / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000276:immunology / Q000494:pharmacology; D020382:Interleukin-18 / Q000276:immunology / Q000494:pharmacology*; D007376:Interleukin-2 / Q000276:immunology / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D014407:Tumor Cells, Cultured
chemical_list: D000276:Adjuvants, Immunologic; D018984:Epitopes, T-Lymphocyte; D015395:Histocompatibility Antigens Class I; D020382:Interleukin-18; D007376:Interleukin-2; D011994:Recombinant Proteins; D018664:Interleukin-12; D007371:Interferon-gamma