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Published online before print August 4, 2005

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(Journal of Leukocyte Biology. 2005;78:1001-1007.)
© 2005 by Society for Leukocyte Biology

The role of TNF in hepatic histopathological manifestations and hepatic CD8+ T cell alloresponses in murine MHC class I disparate GVHD

Jihad M. El-Hayek^*, Thomas E. Rogers and Geri R. Brown^*,,1

^* Department of Internal Medicine, The University of Texas Southwestern Medical School at Dallas; and
Dallas VA Medical Center, Texas

¹Correspondence: Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Blvd., Dallas, TX 75235-9151. E-mail: geri.brown{at}utsouthwestern.edu

Transfer of B6 T cells to major histocompatibility complex (MHC) class I disparate bm1 x B6 F1 mice leads to the development of hepatic graft-versus-host disease (GVHD) characterized by an active hepatitis with portal and lobular inflammation as well as bile duct inflammation and venulitis. The present studies determined the role of tumor necrosis factor (TNF) in hepatic GVHD. B6 responder cells were cultured with irradiated MHC class I disparate bm1 or syngeneic spleen cells (SpC) in the presence or absence of TNF receptor inhibitor [TNFR-immunoglobulin (Ig)]. Recipient bm1 x B6 F1 mice were irradiated (600 cGy) and reconstituted with 5 x 10⁶ T cell-depleted B6 bone marrow cells and 1 x 10⁷ B6 SpC. Mice were injected with an adenovirus encoding TNFR-Ig [TNF inhibitor-encoding adenovirus (Adv-TNFi)] or ß-galactosidase (Adv-ßgal). Severity of liver GVHD was assessed by a composite histopathological score consisting of the sum of scores for venulitis, lobular hepatitis, and bile duct inflammation. Addition of TNFR-Ig reduced cell proliferation in mixed lymphocyte cultures using B6 responder SpC by 71% ± 12.8% and interferon- responses by 78% ± 18%. GVHD-induced "wasting disease" was reduced in Adv-TNFi recipients [4.4%±5.2% weight loss (n=11)] compared with Adv-ßgal recipients [16.1%±7.6% weight loss (n=11; P=0.0004)] 9 days post-transplant. Composite histopathological scores and individual venulitis scores were reduced with the addition of Adv-TNFi. Hepatic CD8+ T cells in the recipients of Adv-TNFi were reduced as compared with recipients of Adv-ßgal. In conclusion, Adv-TNFi reduces MHC class I disparate alloproliferative responses and hepatic GVHD.

Key Words: cytokines • bone marrow transplantation • cytotoxic T cells • interferon- • therapy

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