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.
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.
Yamamoto
Satoshi
S
Division of Immunoregulation, Institute for Genetic Medicine, School of Medicine, Hokkaido University, Sapporo, Japan.
Tsuji
Takemasa
T
Matsuzaki
Junko
J
Zhange
Yue
Y
Chamoto
Kenji
K
Kosaka
Akemi
A
Togashi
Yuji
Y
Sekikawa
Kenji
K
Sawada
Ken-Ichi
K
Takeshima
Tsuguhide
T
Koike
Takao
T
Nishimura
Takashi
T
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*
D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma