PT  - JOURNAL ARTICLE
AU  - Youli Wang
AU  - Todd D Merchen
AU  - Xuexiu Fang
AU  - Randi Lassiter
AU  - Chak-Sum Ho
AU  - Ryan Jajosky
AU  - Daniel Kleven
AU  - Thomas Thompson
AU  - Eslam Mohamed
AU  - Miao Yu
AU  - Jennifer L Waller
AU  - N Stanley Nahman Jr
TI  - Regulation of indoleamine 2,3 dioxygenase and its role in a porcine model of acute kidney allograft rejection
AID  - 10.1136/jim-2018-000742
DP  - 2018 Dec 01
TA  - Journal of Investigative Medicine
PG  - 1109--1117
VI  - 66
IP  - 8
4099  - http://hw-f5-jim.highwire.org/content/66/8/1109.short
4100  - http://hw-f5-jim.highwire.org/content/66/8/1109.full
SO  - J Investig Med2018 Dec 01; 66
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, 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 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.