title: Unexpected role of TNF-alpha in graft versus host reaction (GVHR): donor-derived TNF-alpha suppresses GVHR via inhibition of IFN-gamma-dependent donor type-1 immunity.
abstract: Graft versus host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation, leading to significant morbidity and mortality. Host-derived TNF-alpha play a role in the induction of allo-reactive donor T cell activation and the pathogenesis of GVHD. On the other hand, the precise role of donor-derived TNF-alpha in GVHD remains unclear. To elucidate this issue, we designed an acute GVHD model using (B6 x D2) F1 recipient mice transferred with spleen cells derived from either wild-type or TNF-alpha(-/-) C57BL/6 mice. Surprisingly, we found that spleen cells from TNF-alpha(-/-) mice induce more severe graft versus host reaction (GVHR) than wild-type spleen cells upon transfer into B6D2F1 mice. Transplantation of TNF-alpha(-/-) mouse spleen cells was associated with enhanced anti-host CTL generation and augmented deletion of host cells. Moreover, mice receiving TNF-alpha(-/-) cells showed significantly higher levels of serum IFN-gamma, which was mainly produced by donor CD8+ T cells. We also demonstrated that TNF-alpha deficiency in donor spleen cells caused a marked elevation of TNF-alpha producing capacity by LPS-stimulated host macrophages. Such enhanced GVHR was completely prevented by using TNF-alpha(-/-)IFN-gamma(-/-) splenic cells. Our findings demonstrate, for the first time, that donor-derived TNF-alpha suppress GVHR by inhibiting IFN-gamma-dependent donor type-1 immunity which is essential for host TNF-alpha elevation.
authors.affiliation: Division of Immunoregulation, Institute for Genetic Medicine, School of Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Takemasa
authors.initials: T
authors.lastname: Tsuji
authors.forename: Junko
authors.initials: J
authors.lastname: Matsuzaki
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhange
authors.forename: Kenji
authors.initials: K
authors.lastname: Chamoto
authors.forename: Akemi
authors.initials: A
authors.lastname: Kosaka
authors.forename: Yuji
authors.initials: Y
authors.lastname: Togashi
authors.forename: Kenji
authors.initials: K
authors.lastname: Sekikawa
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Sawada
authors.forename: Tsuguhide
authors.initials: T
authors.lastname: Takeshima
authors.forename: Takao
authors.initials: T
authors.lastname: Koike
authors.forename: Takashi
authors.initials: T
authors.lastname: Nishimura
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000276:immunology; D006087:Graft vs Host Reaction / Q000276:immunology*; D007371:Interferon-gamma / Q000037:antagonists & inhibitors*; D008212:Lymphocyte Depletion; D051379:Mice; D008815:Mice, Inbred Strains; D013154:Spleen / Q000166:cytology / Q000276:immunology; D014019:Tissue Donors; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000502:physiology*
chemical_list: D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma