Editorial [Hot Topic: Clinical Relevance of Indoleamine 2,3-Dioxygenase (Guest Editor: Dietmar Fuchs) ]

Almost 30 years ago, indoleamine 2,3-dioxygenase (IDO) was discovered as a tryptophan-degrading enzyme, which is inducible by interferons. IDO converts tryptophan to N-formyl-kynurenine, and this catabolism of the essential amino acid turned out as an important antiproliferative activity, which is directed to halt reproduction of pathogens in infected cells and to stop malignant growth. Consequently, induction of IDO was considered as one out of several anti-proliferative pathways which are induced by the Th1-type cytokine interferon-γ and which are established during immune response. For clinical studies, it was introduced to estimate the rate of tryptophan degradation by calculating the quotient of kynurenine to tryptophan concentrations (kyn/trp), although being aware that kynurenine is further converted to several down-stream products, the most important ones being quinolinic acid and nicotinamide/adenine dinucleotides. In the later eighties, the in vitro induction of tryptophan degradation by cytokines was demonstrated in various cells and cell lines of human and non-human origin. In patients enhanced tryptophan degradation has been described in cytokine-treated patients and in a variety of disorders such as infections including HIV infection, in autoimmune syndromes, in malignant diseases, in cardiovascular disorders and in neurodegeneration. These disorders often go along with inflammation and immune activation, and significant associations were observed between kyn/trp and markers of Th1-type immune activation such as neopterin or soluble cytokine receptors. Thus, accelerated tryptophan degradation was referred to enhanced IDO activity which is due to endogenous formation of its primary inducer, namely interferon-γ . In the above-mentioned clinical conditions, striking associations exist between accelerated tryptophan degradation and the extent, the activity and the course of the disease. Moreover, in case of malignancy and HIV infection accelerated catabolism of tryptophan and immune activation predicted shorter survival and it concurred with the loss of immunocompetence, the development of cachexia and anemia, and predicted shorter survival. Data suggest a pathogenetic role of tryptophan deprivation also in these symptoms typical of chronic inflammatory conditions. Because tryptophan is also required for the biosynthesis of neurotransmitter 5-hydroxytryptamine (5-HT, serotonin), accelerated catabolism of tryptophan is likely to disturb also the serotonergic system. Thus, reduced availability of tryptophan would affect serotonin biosynthesis and thus could represent an important aspect in the pathogenesis of cognitive impairment and depression. Accordingly, the immune systeminduced deprivation of tryptophan seems to provide a direct link between the higher risk for the development of depression in patients who suffer from chronic inflammatory conditions such as autoimmune syndromes, infections and myocardial infarction but also cancer. Indeed, in patients under treatment with forward-regulatory cytokines like interferon-γ a significant relationship is found between the decline of tryptophan levels which is due to enhanced degradation and the risk of mood disturbances and depression. In a similar way, in patients with cancer enhanced degradation of tryptophan is not only found to predict shorter survival but is also associated with impaired quality of life. Thus, the enhanced activity of IDO during states of immune activation suggests an important link between the neuro-and immunoendocrine systems. Accelerated tryptophan degradation together with immune activation was demonstrated also in normal human pregnancy, and in 1998 enhanced IDO activity was demonstrated to be critical in the induction of immunotolerance during pregnancy. Until that time, only a very limited number of laboratories was interested in basic research on IDO, but from now on interest in IDO was rapidly spread into several labs throughout the world. Numerous studies of basic regulation and consequences of IDO broadly extended the knowledge and understanding about the clinical relevance of IDO. In particular, studies were able to demonstrate the central place of IDO activation in the development of immunodeficiency and immunotolerance......