IFN-γ receptor-deficient donor T cells mediate protection from graft-versus-host disease and preserve graft-versus-tumor responses after allogeneic bone marrow transplantation

Kai Sun, Hui Hua Hsiao, Minghui Li, Erik Ames, Myriam Bouchlaka, Lisbeth A. Welniak, Takeshi Hagino, Jared Jagdeo, Chien Chun Pai, Mingyi Chen, Bruce R. Blazar, Mehrdad Abedi, William J Murphy

Research output: Contribution to journalArticle

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Abstract

Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation. It has been previously reported that lung GVHD severity directly correlates with the expansion of donor Th17 cells in the absence of IFN-γ. However, the consequence of Th17-associated lung GVHD in the presence of IFN-γ has not been well characterized. In the current study, T cells from IFN-γ receptor knockout (IFN-γR -/-) mice, capable of producing IFN-γ but unable to signal in response to IFN-γ, have been used to elucidate further the role of IFN-γ in GVHD. We found the transfer of donor T cells from either IFN-γR -/- or IFN-γ knockout (IFN-γ -/-) mice resulted in significant increases in donor Th17 cells in the lung. Marked increases in IL-4-producing Th2 cells infiltrating the lungs were also observed in the mice of donor IFN-γR -/- T cells. Notably, despite the presence of these cells, these mice did not show the severe immune-mediated histopathological lung injury observed in mice receiving donor IFNγ -/- T cells. Increases in lung GVHD did occur in mice with donor IFN-γR -/- T cells when treated in vivo with anti-IFN-γ demonstrating that the cytokine has a protective role on host tissues in GVHD. A survival benefit from acute GVHD was also observed using donor cells from IFN-γR -/- T cells compared with control donors. Importantly, tumor-bearing mice receiving IFN-γR -/- T cells versus wild-type donor T cells displayed similar graft-versus-tumor (GVT) effects. These results demonstrate the critical role of IFN-γ on host tissues and cell effector functions in GVHD/GVT.

Original languageEnglish (US)
Pages (from-to)2033-2042
Number of pages10
JournalJournal of Immunology
Volume189
Issue number4
DOIs
StatePublished - Aug 15 2012

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Cytoprotection
Homologous Transplantation
Graft vs Host Disease
Bone Marrow Transplantation
T-Lymphocytes
Transplants
Neoplasms
Lung
Th17 Cells
Th2 Cells
Lung Injury
T-Cell Antigen Receptor
Knockout Mice
Interleukin-4
Cytokines

ASJC Scopus subject areas

  • Immunology

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IFN-γ receptor-deficient donor T cells mediate protection from graft-versus-host disease and preserve graft-versus-tumor responses after allogeneic bone marrow transplantation. / Sun, Kai; Hsiao, Hui Hua; Li, Minghui; Ames, Erik; Bouchlaka, Myriam; Welniak, Lisbeth A.; Hagino, Takeshi; Jagdeo, Jared; Pai, Chien Chun; Chen, Mingyi; Blazar, Bruce R.; Abedi, Mehrdad; Murphy, William J.

In: Journal of Immunology, Vol. 189, No. 4, 15.08.2012, p. 2033-2042.

Research output: Contribution to journalArticle

Sun, Kai ; Hsiao, Hui Hua ; Li, Minghui ; Ames, Erik ; Bouchlaka, Myriam ; Welniak, Lisbeth A. ; Hagino, Takeshi ; Jagdeo, Jared ; Pai, Chien Chun ; Chen, Mingyi ; Blazar, Bruce R. ; Abedi, Mehrdad ; Murphy, William J. / IFN-γ receptor-deficient donor T cells mediate protection from graft-versus-host disease and preserve graft-versus-tumor responses after allogeneic bone marrow transplantation. In: Journal of Immunology. 2012 ; Vol. 189, No. 4. pp. 2033-2042.
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abstract = "Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation. It has been previously reported that lung GVHD severity directly correlates with the expansion of donor Th17 cells in the absence of IFN-γ. However, the consequence of Th17-associated lung GVHD in the presence of IFN-γ has not been well characterized. In the current study, T cells from IFN-γ receptor knockout (IFN-γR -/-) mice, capable of producing IFN-γ but unable to signal in response to IFN-γ, have been used to elucidate further the role of IFN-γ in GVHD. We found the transfer of donor T cells from either IFN-γR -/- or IFN-γ knockout (IFN-γ -/-) mice resulted in significant increases in donor Th17 cells in the lung. Marked increases in IL-4-producing Th2 cells infiltrating the lungs were also observed in the mice of donor IFN-γR -/- T cells. Notably, despite the presence of these cells, these mice did not show the severe immune-mediated histopathological lung injury observed in mice receiving donor IFNγ -/- T cells. Increases in lung GVHD did occur in mice with donor IFN-γR -/- T cells when treated in vivo with anti-IFN-γ demonstrating that the cytokine has a protective role on host tissues in GVHD. A survival benefit from acute GVHD was also observed using donor cells from IFN-γR -/- T cells compared with control donors. Importantly, tumor-bearing mice receiving IFN-γR -/- T cells versus wild-type donor T cells displayed similar graft-versus-tumor (GVT) effects. These results demonstrate the critical role of IFN-γ on host tissues and cell effector functions in GVHD/GVT.",
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AU - Sun, Kai

AU - Hsiao, Hui Hua

AU - Li, Minghui

AU - Ames, Erik

AU - Bouchlaka, Myriam

AU - Welniak, Lisbeth A.

AU - Hagino, Takeshi

AU - Jagdeo, Jared

AU - Pai, Chien Chun

AU - Chen, Mingyi

AU - Blazar, Bruce R.

AU - Abedi, Mehrdad

AU - Murphy, William J

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N2 - Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation. It has been previously reported that lung GVHD severity directly correlates with the expansion of donor Th17 cells in the absence of IFN-γ. However, the consequence of Th17-associated lung GVHD in the presence of IFN-γ has not been well characterized. In the current study, T cells from IFN-γ receptor knockout (IFN-γR -/-) mice, capable of producing IFN-γ but unable to signal in response to IFN-γ, have been used to elucidate further the role of IFN-γ in GVHD. We found the transfer of donor T cells from either IFN-γR -/- or IFN-γ knockout (IFN-γ -/-) mice resulted in significant increases in donor Th17 cells in the lung. Marked increases in IL-4-producing Th2 cells infiltrating the lungs were also observed in the mice of donor IFN-γR -/- T cells. Notably, despite the presence of these cells, these mice did not show the severe immune-mediated histopathological lung injury observed in mice receiving donor IFNγ -/- T cells. Increases in lung GVHD did occur in mice with donor IFN-γR -/- T cells when treated in vivo with anti-IFN-γ demonstrating that the cytokine has a protective role on host tissues in GVHD. A survival benefit from acute GVHD was also observed using donor cells from IFN-γR -/- T cells compared with control donors. Importantly, tumor-bearing mice receiving IFN-γR -/- T cells versus wild-type donor T cells displayed similar graft-versus-tumor (GVT) effects. These results demonstrate the critical role of IFN-γ on host tissues and cell effector functions in GVHD/GVT.

AB - Graft-versus-host disease (GVHD) is a major complication of allogeneic bone marrow transplantation. It has been previously reported that lung GVHD severity directly correlates with the expansion of donor Th17 cells in the absence of IFN-γ. However, the consequence of Th17-associated lung GVHD in the presence of IFN-γ has not been well characterized. In the current study, T cells from IFN-γ receptor knockout (IFN-γR -/-) mice, capable of producing IFN-γ but unable to signal in response to IFN-γ, have been used to elucidate further the role of IFN-γ in GVHD. We found the transfer of donor T cells from either IFN-γR -/- or IFN-γ knockout (IFN-γ -/-) mice resulted in significant increases in donor Th17 cells in the lung. Marked increases in IL-4-producing Th2 cells infiltrating the lungs were also observed in the mice of donor IFN-γR -/- T cells. Notably, despite the presence of these cells, these mice did not show the severe immune-mediated histopathological lung injury observed in mice receiving donor IFNγ -/- T cells. Increases in lung GVHD did occur in mice with donor IFN-γR -/- T cells when treated in vivo with anti-IFN-γ demonstrating that the cytokine has a protective role on host tissues in GVHD. A survival benefit from acute GVHD was also observed using donor cells from IFN-γR -/- T cells compared with control donors. Importantly, tumor-bearing mice receiving IFN-γR -/- T cells versus wild-type donor T cells displayed similar graft-versus-tumor (GVT) effects. These results demonstrate the critical role of IFN-γ on host tissues and cell effector functions in GVHD/GVT.

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