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International Immunology Advance Access published online on May 4, 2004
International Immunology, doi:10.1093/intimm/dxh082
© 2004 by The Japanese Society for Immunology
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Received January 9, 2004
Accepted March 4, 2004

Article

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

Satoshi Yamamoto 1, Takemasa Tsuji 2, Junko Matsuzaki 2, Yue Zhange 2, Kenji Chamoto 2, Akemi Kosaka 2, Yuji Togashi 2, Kenji Sekikawa 3, Ken-ichi Sawada 4, Tsuguhide Takeshima 2, Takao Koike 4, Takashi Nishimura 2*

1 Division of Immunoregulation, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan; Department of Internal Medicine II, School of Medicine, Hokkaido University, Sapporo, Japan
2 Division of Immunoregulation, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan
3 National Institute of Animal Health, Tsukuba, Japan
4 Department of Internal Medicine II, School of Medicine, Hokkaido University, Sapporo, Japan

* To whom correspondence should be addressed. E-mail: tak24{at}igm.hokudai.ac.jp.


  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 (B6xD2) 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.

Keywords: CTL, cytokines, graft vs host disease, Th1/Th2 cells, transplantation


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