Indoleamine-2,3-dioxygenase (IDO) is an immunosuppressive enzyme capable of inhibiting a destructive maternal T cell response against allogeneic fetuses. Expression of IDO is evident in tumours and is thought to enable escape from immunologically mediated rejection. Consequently, clinical trials using an inhibitor of IDO, 1-methyltryptophan (1MT), have been initiated. However, a review of the current literature indicates that we are far from understanding the biological relevance of IDO expression during tumorigenesis. A better understanding of IDO biology is needed to comprehend the effect of IDO inhibitors and to provide a rationale for their therapeutic application in cancer.

Although IDO2 is expressed in human tumors, tryptophan degradation is entirely provided by IDO1. Importantly, D-1MT does not inhibit the IDO activity of malignant cells. If ongoing clinical studies show a therapeutic effect of D-1MT, this cannot be attributed to inhibition of IDO in tumor cells.

IntroductionIDO is an enzyme that catabolizes tryptophan and was shown to protect the fetus from rejection mediated by maternal T cells. 1 Such a basic mechanism that evolved for the perpetuation of species might be expected to be used for the regulation of other biologic processes. Researchers were therefore motivated to look for a role of IDO in the regulation of immune responses in health and disease. An objective that has challenged the scientific community for decades is the unraveling of immunologic conditions that enable the development of tumors and, based on this, the design of novel therapeutic strategies for tumor prevention or treatment.Tumors are the consequence of genetic mutations leading to the expression of modified proteins. 2 Despite their potential to activate the immune response, these proteins are not capable of inducing tumor-protective immunity. Many mechanisms have been made responsible for the lack of an effective immune defense against tumors. 3 If IDO has the potential to prevent rejection of the fetus during pregnancy-so went the reasoning-it might also be implicated in induction of fatal tolerance to tumors. Tolerogenic mechanisms can operate in the tumor itself or in key sites where the immune system encounters tumor antigens, such as tumor-draining lymph nodes. 4 Emerging evidence suggests that in lymph nodes, IDO-expressing dendritic cells (DCs) directly suppress and anergize tumor-reactive effector T cells responding to antigens presented by these DCs. 5,6 In addition, through bystander suppression, IDO can inhibit T-cell responses to antigens presented by neighboring DCs. 5 It was therefore appealing to trigger antitumor immunity by inhibiting the activity of IDO. Pioneering work in this field was performed by van den Eynde and colleagues. In a series of elegant experiments, they showed that the IDO-blocking agent 1-methyltryptophan (1MT) significantly reduces the volume of tumors in preimmunized mice (Uyttenhove et al 7 ). But 1MT exists in 2 forms, the levo and the dextro isomer. In the study of van den Eynde's group the levo isoform (L-1MT) was used. Other authors found that, in animal models, the dextro stereoisomer (D-1MT) has superior antitumor activity 8 and therefore chose it for phase 1 clinical trials in humans. This was a surprising choice since, on a biochemical level, in contrast to the L isomer the D form did not properly inhibit IDO. 8 In recent studies, the contradiction was apparently resolved by describing, in addition to the classic IDO (dubbed IDO1), a closely related variant called IDO2, 9 which is strongly inhibited by D-1MT but unaffected by L-1MT. 10 Natural IDO2 was found in several tissues, including a predendritic mouse cell line. 10 Taking into consideration the potential of D-1MT for cancer therapy and the already running clinical trials, it is important to know whether in humans the effect of D-1MT can be mediated by blocking the IDO activity of DCs. We tried to find an answer to this question by studying a subset of human DCs that were claimed to ...

Non-healing diabetic foot ulcers are characterized by high wound fluid lactate levels. Assessment of wound fluid lactate concentration might be helpful for confirming the suspicion of soft tissue infection, particularly when clinical signs are atypical.