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The Journal of Immunology, 1998, 160: 1742-1749.
Copyright © 1998 by The American Association of Immunologists

IFN-{gamma}-Inducing Factor/IL-18 Administration Mediates IFN-{gamma}- and IL-12-Independent Antitumor Effects1

Tadashi Osaki*, Jean-Marie Péron*, Quan Cai*, Haruki Okamura{ddagger}, Paul D. Robbins{dagger}, Masashi Kurimoto§, Michael T. Lotze*,{dagger} and Hideaki Tahara2,*,{dagger}

Departments of * Surgery and {dagger} Molecular Genetics and Biochemistry, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213; {ddagger} Division of Host Defenses, Institute for Advanced Medical Sciences, Hyogo College of Medicine, Nishinomiya, Hyogo; and § Fujisaki Institute, Hayashibara Biochemical Laboratories, Okayama, Japan

We evaluated the mechanism of the antitumor effects of mouse rIFN-{gamma}-inducing factor/IL-18 protein on the growth of mouse tumor cell lines in vivo. Mice received IL-18 before or after challenge with CL8-1, a mouse melanoma cell line. Both regimens significantly suppressed tumor growth and reduced the number of mice with growth of tumor from 60% (3/5) to 20% (1/5). Furthermore, IL-18 administered before and after tumor inoculation completely abrogated the establishment of CL8-1 in all animals. IL-18 administration also significantly suppressed the growth of MCA205, a sarcoma cell line, even when treatment was delayed to 7 days following tumor inoculation. Although IL-18/IL-12 combination therapy had the most significant and immediate antitumor effects, many mice so treated succumbed with markedly elevated serum IFN-{gamma} levels. The antitumor effects of IL-18 were abrogated almost completely when NK cells were eliminated using anti-asialo GM1 Ab administration, but only marginally impaired in IFN-{gamma} or IL-12 gene-disrupted mice. Immunohistochemical staining revealed that the number of the CD8+ T cells, but not CD4+ T cells, found at the tumor site was reduced in animals treated with IL-18. These results indicate that IL-18 has potent antitumor effects mediated by CD4+ T cells and NK cells, but in IFN-{gamma}- and IL-12-independent pathways.




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