This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Tanaka, F. Articles by Tahara, H. Search for Related Content PubMed PubMed Citation Articles by Tanaka, F. Articles by Tahara, H.

Rapid Generation of Potent and Tumor-specific Cytotoxic T Lymphocytes by Interleukin 18 Using Dendritic Cells and Natural Killer Cells¹

Departments of Surgery [F. T., W. H., M. T. L., H. T.] and Molecular Genetics and Biochemistry [F. T., W. H., P. D. R., M. T. L., H. T.], University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania 15213, and Division of Host Defenses, Institution for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo 663-8501, Japan [H. O.]

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- 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.

This article has been cited by other articles:

				A. Iannello, O. Debbeche, S. Samarani, and A. Ahmad Antiviral NK cell responses in HIV infection: I. NK cell receptor genes as determinants of HIV resistance and progression to AIDS J. Leukoc. Biol., July 1, 2008; 84(1): 1 - 26. [Abstract] [Full Text] [PDF]

				A. Iannello, O. Debbeche, S. Samarani, and A. Ahmad Antiviral NK cell responses in HIV infection: II. viral strategies for evasion and lessons for immunotherapy and vaccination J. Leukoc. Biol., July 1, 2008; 84(1): 27 - 49. [Abstract] [Full Text] [PDF]

				M. J. Robertson, J. W. Mier, T. Logan, M. Atkins, H. Koon, K. M. Koch, S. Kathman, L. N. Pandite, C. Oei, L. C. Kirby, et al. Clinical and biological effects of recombinant human interleukin-18 administered by intravenous infusion to patients with advanced cancer. Clin. Cancer Res., July 15, 2006; 12(14): 4265 - 4273. [Abstract] [Full Text] [PDF]

				J. N. MacGregor, Q. Li, A. E. Chang, T. M. Braun, D. P.M. Hughes, and K. T. McDonagh Ex vivo Culture with Interleukin (IL)-12 Improves CD8+ T-Cell Adoptive Immunotherapy for Murine Leukemia Independent of IL-18 or IFN-{gamma} but Requires Perforin. Cancer Res., May 1, 2006; 66(9): 4913 - 4921. [Abstract] [Full Text] [PDF]

				A. Ahmad and F. Alvarez Role of NK and NKT cells in the immunopathogenesis of HCV-induced hepatitis J. Leukoc. Biol., October 1, 2004; 76(4): 743 - 759. [Abstract] [Full Text] [PDF]

				A. Ribas, J. A. Wargo, B. Comin-Anduix, S. Sanetti, L. Y. Schumacher, C. McLean, V. B. Dissette, J. A. Glaspy, W. H. McBride, L. H. Butterfield, et al. Enhanced Tumor Responses to Dendritic Cells in the Absence of CD8-Positive Cells J. Immunol., April 15, 2004; 172(8): 4762 - 4769. [Abstract] [Full Text] [PDF]

				C. Massa, C. Guiducci, I. Arioli, M. Parenza, M. P. Colombo, and C. Melani Enhanced Efficacy of Tumor Cell Vaccines Transfected with Secretable hsp70 Cancer Res., February 15, 2004; 64(4): 1502 - 1508. [Abstract] [Full Text] [PDF]

				K. Mashino, N. Sadanaga, F. Tanaka, M. Ohta, H. Yamaguchi, and M. Mori Effective Strategy of Dendritic Cell-based Immunotherapy for Advanced Tumor-bearing Hosts: the Critical Role of Th1-dominant Immunity Mol. Cancer Ther., August 1, 2002; 1(10): 785 - 794. [Abstract] [Full Text] [PDF]

				K. G. Veenstra, Z. L. Jonak, S. Trulli, and J. A. Gollob IL-12 Induces Monocyte IL-18 Binding Protein Expression Via IFN-{gamma} J. Immunol., March 1, 2002; 168(5): 2282 - 2287. [Abstract] [Full Text] [PDF]