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 Citations (Scopus)

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

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Immunity
Transplants
Graft vs Host Disease
Spleen
T-Lymphocytes
Hematopoietic Stem Cell Transplantation
Inbred C57BL Mouse
Transplantation
Macrophages
Morbidity
Mortality
Serum

Keywords

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

ASJC Scopus subject areas

  • Immunology

Cite this

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

In: International Immunology, Vol. 16, No. 6, 06.2004, p. 811-817.

Research output: Contribution to journalArticle

Yamamoto, S, Tsuji, T, Matsuzaki, J, Zhange, Y, Chamoto, K, Kosaka, A, Togashi, Y, Sekikawa, K, Sawada, KI, 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, vol. 16, no. 6, pp. 811-817. https://doi.org/10.1093/intimm/dxh082
Yamamoto, Satoshi ; Tsuji, Takemasa ; Matsuzaki, Junko ; Zhange, Yue ; Chamoto, Kenji ; Kosaka, Akemi ; Togashi, Yuji ; Sekikawa, Kenji ; Sawada, Ken Ichi ; Takeshima, Tsuguhide ; Koike, Takao ; Nishimura, Takashi. / 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. In: International Immunology. 2004 ; Vol. 16, No. 6. pp. 811-817.
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AU - Kosaka, Akemi

AU - Togashi, Yuji

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AB - 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.

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