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

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, 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.

Tryptophan Metabolism via Kynurenine Pathway: Role in Solid Organ Transplantation

“…In a recent porcine kidney allo-Tx study, the allogenic immune response significantly promoted the IDO gene and proinflammatory cytokines expression and, additionally, suppressed another tryptophan kynurenine pathway enzyme KMO [ 131 ]. As 3-HK, a KMO-catalyzed reaction product, is known to be a more potent immunosuppressive catabolite than L-kynurenine [ 83 ], its loss due to KMO suppression may explain the inability of elevated allograft IDO activity to fully inhibit rejection [ 131 ] and give some implications about KMO or KAT as another potential therapeutic target of immune modulation.…”

Protective Role of Kynurenine 3-Monooxygenase in Allograft Rejection and Tubular Injury in Kidney Transplantation

“…Protein concentrations were determined using a bicinchoninic acid protein assay reagent kit (Pierce). Proteins were separated by SDS-PAGE, and Western blotting was carried out as previously described (40). The following antibodies were used as probes for Western blotting: b-actin (Sigma, A5316); KMO (NBP1-86335), kynureninase (AF4887-SP), alpha-smooth muscle actin (NB300-978SS), snail (NBP2-27184SS), E-cadherin…”

“…Five of the twenty pigs (two of which were twins) experienced allograft rejection rated IIA on the Banff scale, while six pigs experienced allograft rejection below IIA on the Banff scale. Pigs with allograft rejection rated IIA and lower had normal physiological parameters (40,50). Nine of the twenty pigs had allograft rejection rated above Banff scale IIA and abnormal physiological function (Figure 1A).…”

“…IDO downstream enzymes, kynurenine 3-monooxygenase (KMO) and kynureninase produce kynurenine derivatives 3HK (hydroxyl-3 kynurenine) and 3HAA (hydroxyl-3 anthranilic acid), which have been shown to effectively inhibit T cell proliferation (21), thus improving tolerance (22)(23)(24)(25)(26). Although induced IDO can increase tolerance in some rodent transplantation models (18,(26)(27)(28)(29)(30)(31)(32)(33)(34)(35), our recent study and other scientists' observations have indicated that IDO, itself, only predicts allograft rejection (36)(37)(38)(39)(40). Using our own porcine kidney transplant model, we showed that rejection allografts was associated with down-regulation of KMO and kynureninase and up-regulation of IDO (40).…”

Recombinant Lactaptin Induces Immunogenic Cell Death and Creates an Antitumor Vaccination Effect in Vivo with Enhancement by an IDO Inhibitor

“…Kaplan-Myer survival curves and Log-Rank statistics were calculated using GraphPad Prizm Software (San-Diego, CA, USA). IDO is activated under various stress conditions including allograft rejection and tumor growth [32,33]. IDO catalyzes non-dietary tryptophan catabolism, and the breakdown of tryptophan in the tumor microenvironment and tumor-draining lymph nodes leads to DCs-and T-cell dependent immunosuppression [21].…”