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Role of TNF- Produced by Nonantigen-Specific Cells in a Fulminant Hepatitis Mouse Model

Hiroyasu Ito^1,*, Kazuki Ando^*,, Tetsuya Ishikawa, Kuniaki Saito^*,¶, Masao Takemura^*, Michio Imawari^||, Hisataka Moriwaki and Mitsuru Seishima^*

^* Department of Informative Clinical Medicine and First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu City, Japan; Goto Clinic, Ohgaki City, Gifu Prefecture, Japan; Cancer Immunotherapy Center, Nagoya Kyoritsu Hospital, Nakagawa, Nagoya, Japan; ^¶ Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Shogoin, Sakyo, Kyoto, Japan; and ^|| Second Department of Internal Medicine, Showa University School of Medicine, Shinagawa-ku, Tokyo, Japan

In previous studies, the mechanisms of acute liver injury and virus exclusion have been examined using a model wherein HBsAg-specific CTL are injected into HBsAg transgenic (Tg) mice. The importance of the role of TNF- in virus exclusion was shown, but its role in liver injury was unclear. We crossed the TNF- knockout mouse and HBsAg-Tg mouse to establish the HBsAg-Tg/TNF- KO mouse, and examined the influence of TNF- on liver injury. The severity of liver damage, as determined by serum alanine aminotransferase activity, was 100 times greater in HBsAg-Tg/TNF-^+/+ than in HBsAg-Tg/TNF-^–/– mice after i.v. administration of 5 x 10⁶ CTLs. This liver damage reached the peak of its severity within 24–48 h, and was restored 7 days later. Histopathological examination showed hepatocellular necrosis and inflammatory cell infiltrate 24 h after the CTL injection in HBsAg-Tg/TNF-^+/+ mice but not in HBsAg-Tg/TNF-^–/– mice. The liver damage was fatal for all HBsAg-Tg/TNF-^+/+ mice that received 1.5 x 10⁷ CTLs. In contrast, 1.5 x 10⁷ CTLs could not kill the HBsAg-Tg/TNF-^–/– mice. The TNF- production level was enhanced after the CTL injection in not only intrahepatic macrophages but also other types of mononuclear cells from non-HBsAg-Tg/TNF-^+/+ mice. An adoptive transfer examination revealed that severe liver damage occurred in HBsAg-Tg/TNF-^–/– mice that had received mononuclear cells from TNF-^+/+ mice. In conclusion, the present study provides evidence that TNF- produced by intrahepatic non-Ag-specific inflammatory cells is critical in the development of lethal necroinflammatory liver disease.

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¹ Address correspondence and reprint requests to Dr. Hiroyasu Ito, Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, 1-1 Yanagido, Gifu, Japan. E-mail address: hito{at}gifu-u.ac.jp

² Abbreviations used in this paper: HBV, hepatitis B virus; Tg, transgenic; sALT, serum alanine aminotransferase; MNC, mononuclear cell.