Regulation of indoleamine 2,3 dioxygenase and its role in a porcine model of acute kidney allograft rejection

Youli Wang, Todd David Merchen, Xuexiu Fang, Randi Lassiter, Chak Sum Ho, Ryan Jajosky, Daniel T Kleven, Thomas Thompson, Eslam Mohamed, Miao Yu, Jennifer L Waller, Norris Stanley Nahman

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

In kidney transplantation acute allograft rejection is the most common cause of late allograft loss. Changes in indoleamine 2,3 dioxygenase (IDO) activity, which catabolizes the degradation of tryptophan to kynurenine, may predict rejection. However, exogenous IDO is immunosuppressive in rodent kidney transplantation. Thus, the increase in IDO activity observed in acute allograft rejection is insufficient to prevent rejection. To address this question, we assessed the regulation of IDO and its role in acute rejection in a porcine model of kidney transplant. In tissue samples from rejecting kidney allografts, we showed a 13-fold increase in IDO gene transcription and 20-fold increase in IDO enzyme activity when compared with autotransplanted kidneys. Allografts also demonstrated an over fourfold increase in tissue interferon (IFN)-γ 3, with marked increases in tumor necrosis factor (TNF)-α, TNF-β and interleukin 1β. Gene transcription and protein levels of kynurenine 3-monooxygenase (KMO) were decreased. KMO generates the immunosuppressive kynurenine, 3-hydroxykynurenine. The results of these studies demonstrate a clear association between rejection and increased allograft IDO expression, likely driven in part by IFN-γ 3 and facilitated by other cytokines of the allogeneic response. Moreover, the loss of downstream enzymatic activity in the IDO metabolic pathway may suggest novel mechanisms for the perpetuation of rejection.

Original languageEnglish (US)
Pages (from-to)1109-1117
Number of pages9
JournalJournal of Investigative Medicine
Volume66
Issue number8
DOIs
StatePublished - Dec 1 2018

Fingerprint

Indoleamine-Pyrrole 2,3,-Dioxygenase
Allografts
Swine
Kidney
Kynurenine 3-Monooxygenase
Kynurenine
Transcription
Immunosuppressive Agents
Kidney Transplantation
Interferons
Tumor Necrosis Factor-alpha
Genes
Tissue
Transplants
Enzyme activity
Metabolic Networks and Pathways
Interleukin-1
Tryptophan
Rodentia
Association reactions

Keywords

  • immune tolerance
  • kidney transplantation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Regulation of indoleamine 2,3 dioxygenase and its role in a porcine model of acute kidney allograft rejection. / Wang, Youli; Merchen, Todd David; Fang, Xuexiu; Lassiter, Randi; Ho, Chak Sum; Jajosky, Ryan; Kleven, Daniel T; Thompson, Thomas; Mohamed, Eslam; Yu, Miao; Waller, Jennifer L; Nahman, Norris Stanley.

In: Journal of Investigative Medicine, Vol. 66, No. 8, 01.12.2018, p. 1109-1117.

Research output: Contribution to journalArticle

Wang, Youli ; Merchen, Todd David ; Fang, Xuexiu ; Lassiter, Randi ; Ho, Chak Sum ; Jajosky, Ryan ; Kleven, Daniel T ; Thompson, Thomas ; Mohamed, Eslam ; Yu, Miao ; Waller, Jennifer L ; Nahman, Norris Stanley. / Regulation of indoleamine 2,3 dioxygenase and its role in a porcine model of acute kidney allograft rejection. In: Journal of Investigative Medicine. 2018 ; Vol. 66, No. 8. pp. 1109-1117.
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abstract = "In kidney transplantation acute allograft rejection is the most common cause of late allograft loss. Changes in indoleamine 2,3 dioxygenase (IDO) activity, which catabolizes the degradation of tryptophan to kynurenine, may predict rejection. However, exogenous IDO is immunosuppressive in rodent kidney transplantation. Thus, the increase in IDO activity observed in acute allograft rejection is insufficient to prevent rejection. To address this question, we assessed the regulation of IDO and its role in acute rejection in a porcine model of kidney transplant. In tissue samples from rejecting kidney allografts, we showed a 13-fold increase in IDO gene transcription and 20-fold increase in IDO enzyme activity when compared with autotransplanted kidneys. Allografts also demonstrated an over fourfold increase in tissue interferon (IFN)-γ 3, with marked increases in tumor necrosis factor (TNF)-α, TNF-β and interleukin 1β. Gene transcription and protein levels of kynurenine 3-monooxygenase (KMO) were decreased. KMO generates the immunosuppressive kynurenine, 3-hydroxykynurenine. The results of these studies demonstrate a clear association between rejection and increased allograft IDO expression, likely driven in part by IFN-γ 3 and facilitated by other cytokines of the allogeneic response. Moreover, the loss of downstream enzymatic activity in the IDO metabolic pathway may suggest novel mechanisms for the perpetuation of rejection.",
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AU - Wang, Youli

AU - Merchen, Todd David

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AU - Lassiter, Randi

AU - Ho, Chak Sum

AU - Jajosky, Ryan

AU - Kleven, Daniel T

AU - Thompson, Thomas

AU - Mohamed, Eslam

AU - Yu, Miao

AU - Waller, Jennifer L

AU - Nahman, Norris Stanley

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AB - In kidney transplantation acute allograft rejection is the most common cause of late allograft loss. Changes in indoleamine 2,3 dioxygenase (IDO) activity, which catabolizes the degradation of tryptophan to kynurenine, may predict rejection. However, exogenous IDO is immunosuppressive in rodent kidney transplantation. Thus, the increase in IDO activity observed in acute allograft rejection is insufficient to prevent rejection. To address this question, we assessed the regulation of IDO and its role in acute rejection in a porcine model of kidney transplant. In tissue samples from rejecting kidney allografts, we showed a 13-fold increase in IDO gene transcription and 20-fold increase in IDO enzyme activity when compared with autotransplanted kidneys. Allografts also demonstrated an over fourfold increase in tissue interferon (IFN)-γ 3, with marked increases in tumor necrosis factor (TNF)-α, TNF-β and interleukin 1β. Gene transcription and protein levels of kynurenine 3-monooxygenase (KMO) were decreased. KMO generates the immunosuppressive kynurenine, 3-hydroxykynurenine. The results of these studies demonstrate a clear association between rejection and increased allograft IDO expression, likely driven in part by IFN-γ 3 and facilitated by other cytokines of the allogeneic response. Moreover, the loss of downstream enzymatic activity in the IDO metabolic pathway may suggest novel mechanisms for the perpetuation of rejection.

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