Unexpected role of TNF-α in graft versus host reaction (GVHR): Donor-derived TNF-α suppresses GVHR via inhibition of IFN-γ -dependent donor type-1 immunity

Satoshi Yamamoto, Takemasa Tsuji, Junko Matsuzaki, Yue Zhange, Kenji Chamoto, Akemi Kosaka, Yuji Togashi, Kenji Sekikawa, Ken Ichi Sawada, Tsuguhide Takeshima, Takao Koike, Takashi Nishimura

Research output: Contribution to journalArticle

9 Scopus citations

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-α 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-α in GVHD remains unclear. To elucidate this issue, we designed an acute GVHD model using (B6×D2) F1 recipient mice transferred with spleen cells derived from either wild-type or TNF-α-/- C57BL/6 mice. Surprisingly, we found that spleen cells from TNF-α-/- mice induce more severe graft versus host reaction (GVHR) than wild-type spleen cells upon transfer into B6D2F1 mice. Transplantation of TNF-α-/- mouse spleen cells was associated with enhanced anti-host CTL generation and augmented deletion of host cells. Moreover, mice receiving TNF-α-/- cells showed significantly higher levels of serum IFN-γ, which was mainly produced by donor CD8+ T cells. We also demonstrated that TNF-α deficiency in donor spleen cells caused a marked elevation of TNF-α producing capacity by LPS-stimulated host macrophages. Such enhanced GVHR was completely prevented by using TNF-α-/-TNF-γ-/- splenic cells. Our findings demonstrate, for the first time, that donor-derived TNF-α suppress GVHR by inhibiting IFN-γ -dependent donor type-1 immunity which is essential for host TNF-α elevation.

Original languageEnglish (US)
Pages (from-to)811-817
Number of pages7
JournalInternational Immunology
Volume16
Issue number6
DOIs
StatePublished - Jun 2004

Keywords

  • CTL
  • Cytokines
  • Graft vs host disease
  • Th1/Th2 cells
  • Transplantation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Yamamoto, S., Tsuji, T., Matsuzaki, J., Zhange, Y., Chamoto, K., Kosaka, A., Togashi, Y., Sekikawa, K., Sawada, K. I., Takeshima, T., Koike, T., & Nishimura, T. (2004). Unexpected role of TNF-α in graft versus host reaction (GVHR): Donor-derived TNF-α suppresses GVHR via inhibition of IFN-γ -dependent donor type-1 immunity. International Immunology, 16(6), 811-817. https://doi.org/10.1093/intimm/dxh082