Tryptophan Metabolism via Kynurenine Pathway: Role in Solid Organ Transplantation

Abstract

Solid organ transplantation is a gold standard treatment for patients suffering from an end-stage organ disease. Patient and graft survival have vastly improved during the last couple of decades; however, the field of transplantation still encounters several unique challenges, such as a shortage of transplantable organs and increasing pool of extended criteria donor (ECD) organs, which are extremely prone to ischemia-reperfusion injury (IRI), risk of graft rejection and challenges in immune regulation. Moreover, accurate and specific biomarkers, which can timely predict allograft dysfunction and/or rejection, are lacking. The essential amino acid tryptophan and, especially, its metabolites via the kynurenine pathway has been widely studied as a contributor and a therapeutic target in various diseases, such as neuropsychiatric, autoimmune disorders, allergies, infections and malignancies. The tryptophan-kynurenine pathway has also gained interest in solid organ transplantation and a variety of experimental studies investigating its role both in IRI and immune regulation after allograft implantation was first published. In this review, the current evidence regarding the role of tryptophan and its metabolites in solid organ transplantation is presented, giving insights into molecular mechanisms and into therapeutic and diagnostic/prognostic possibilities.

Keywords: indoleamine-2,3-dioxygenase; ischemia-reperfusion; kynurenine; rejection; tolerance; transplantation; tryptophan.

Figure 1

Tryptophan metabolism via the kynurenine pathway. Abbreviations: Trp: tryptophan, N-formyl-Kyn: N-formyl-kynurenine, Kyn: kynurenine, 3-HK: 3-hydroxykynurenine, 3-HAA: 3-hydroxyanthranilic acid, ACMS: 2-amino-3-carboxymuconate-semialdehyde, PIC: picolinic acid, KYNA: kynurenic acid, AA: anthranilic acid, XA: xanturenic acid, QUIN: quinolinic acid, NAD+: nicotinamide adenine dinucleotide, TDO: tryptophan-2,3-dioxygenase, IDO: indoleamine-2,3-dioxygenase, KMO: kynurenine-3-monooxygenase, KYNU: kynureninase, 3-HAO: 3-hydroxyanthranilate-3,4-dioxygenase, ACMSD: amino-carboxy-muconate-semialdehyde-decarboxylase and KAT: kynurenine aminotransferase.

Figure 2

Simplified scheme of IDO activity in immune regulation. IDO is expressed in various cells, such as APCs, fibroblasts, endothelial, epithelial, smooth muscle cells, etc., in response to proinflammatory mediators. Due to IDO activity, decreased levels of tryptophan activate the GCN2 kinase, which leads to T-cell anergy, T-cell cycle arrest and apoptosis. The deactivated mTOR pathway results in suppressed T-cell proliferation and differentiation. Increased levels of toxic tryptophan-kynurenine pathway metabolites induce effector T-cell apoptosis and promote Treg formation and activation. Abbreviations: Trp: tryptophan, IDO: indoleamine-2,3-dioxygenase, APCs: antigen-presenting cells, GCN2: general control nonderepressible 2, mTOR: mammalian target of rapamycin and Tregs–regulatory T cells.