Human immunodeficiency virus type 1 (HIV) infection is characterized by progressive immunodeficiency despite of an overwhelming cellular immune activation. Patients show highly elevated serum/plasma concentrations of the proinflammatory cytokine interferon-(IFN-), which induces human monocytes to form neopterin, to produce reactive oxygen species (ROS) and in parallel, to degrade tryptophan. Enhanced tryptophan degradation by the enzyme indoleamine-2, 3-dioxygenase (IDO) contributes importantly to disease progression and "complications" of HIV infection: By a subsequent impairment of protein metabolism and serotonin formation, the development of neuropsychiatric disorders and weight loss in HIV infected patients can be enforced. Furthermore, increased IDO-activation efficiently suppresses the growth and proliferation of pathogens as well as host T-cells. IDO and other IFN--mediated pathways are strongly induced in patients with HIV infection and are also linked with disease progression: Neopterin formation by GTPcyclohydrolase I sensitively reflects the stage of the disease, and determination of the pteridine in body fluids is useful to monitor the efficacy of antiretroviral therapy. Neopterin is an independent prognostic factor for the outcome of disease, and well suited to estimate the degree of immune activation in vivo and the responsiveness of immunocompetent cells to stimulation in vitro. ROS formation may contribute to the development of oxidative stress in HIV infection, resulting in depletion of antioxidants. The cause-effective role of an overwhelming Th1-type immune response together with the activation of IDO and other IFN--mediated biochemical pathways for the course of HIV infection, the development of immunodeficiency, anemia and weight loss in HIV patients is discussed.

The Th1-type cytokine interferon-gamma (IFN-gamma) is known as one of the most versatile players of the immune system. In transplantation immunology IFN-gamma has been shown to have contradictory effects on allograft survival via effects on both, the immune system and on the graft itself. The immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO), widely distributed in mammals, is induced preferentially by IFN-gamma. IDO degrades the essential amino acid tryptophan to form N-formyl kynurenine which is subsequently converted to niacin. Recently, it has been proposed that IFN-gamma-mediated activation of IDO is critically involved in the regulation of immune responses, to establish immune-tolerance in pregnant mice upon their fetuses, or to induce T-cell unresponsiveness. Proliferation of alloreactive T-cells is thereby arrested via local tryptophan deprivation and the accumulation of toxic tryptophan catabolites. Despite growing recognition of the molecular T-cell regulatory mechanisms, the physiologic role of IDO in solid organ transplantation, however, remains unclear. Available experimental data indicate that IDO is involved in the mechanism of spontaneous donor-specific tolerance of liver grafts, and that genetic manipulation by introduction of the IDO gene into allografts is associated with prolonged survival. Furthermore, antigen-presenting cells, such as dendritic cells, can increase their expression of IDO, thus regulating immune responses. Based on these findings, the concept that cells expressing IDO can inhibit T-cell responses and hence induce tolerance has emerged as a new paradigm in immunology. Here we review the current literature on IDO in the context of transplantation and outline its potential implication as a target for tolerance induction.

Background Juvenile idiopathic arthritis (JIA) is a relevant autoimmune disease in children. T cells, B cells, and damage-associated molecular patterns (DAMPS) are involved in the pathogenesis of the disease. Biomarkers for JIA and its subtypes are not established. Pro-inflammatory pathways activate enzyme indoleamine 2,3-dioxygenase (IDO) which enhances tryptophan (Trp) conversion to kynurenine (Kyn). Thus, in conditions of chronic immune activation reduced Trp availability and production of Kyn and its down-stream metabolites may inhibit cell proliferation. In rheumatoid arthritis (RA) Trp concentrations are lower in patients than in controls and the Kyn/Trp ratios are higher and correlate with neopterin concentrations [1-3]. Objectives In this study, Trp and Kyn metabolism was investigated in children with JIA and compared to serum neopterin concentrations. Fifty-four sera of 25 JIA patients and 10 samples of synovial fluid were examined with HPLC (Trp and Kyn) and Elisa (Neopterin, BRAHMS, Hennigsdorf, Germany). Eighteen sera from 18 children with non-inflammatory diseases were used as controls. Methods Fifty-four sera of 25 JIA patients and 10 samples of synovial fluid were examined with HPLC (Trp and Kyn) and Elisa (Neopterin, BRAHMS, Hennigsdorf, Germany). Eighteen sera from 18 children with non-inflammatory diseases were used as controls. Results: Results Trp in the sera of patients was mean 57.2 + SD 19.0 µmol/L and Kyn was mean 2.40 + SD 0.81 µmol/L). Serum neopterin was 5.69 + SD 1.72 nmol/L. In the synovial fluid, neopterin was mean 10.5 + SD 7.41 nmol/L), Trp was 36.7 + SD 17.4 µmol/L and Kyn was 2.13 + SD 0.75 µmol/L). In control patients, neopterin was 6.93 + SD 3.10), Trp was 57.6 + SD 14.8) and Kyn was 2.60 + SD 1.60 µmol/L. Conclusions Serum Trp concentrations showed no relevant difference in JIA patients vs. controls. IDO activity reduces Trp primarily in the synovial fluid in JIA patients. References Schroecksnadel K, et al. Increased degradation of tryptophan in blood of patients with rheumatoid arthritis. J Rheumatol 2003;30:1935-9. Fagerer N. et al. Expression of neopterin and chemokines in rheumatoid arthritis and cardiovascular disease. Pteridines 2011;22:7-12. Kurz K, et al. Effects of adalimumab therapy on disease activity and interferon-γ-mediated biochemical pathways in patients with rheumatoid arthritis. Autoimmunity 2011;44:235-42. Disclosure of Interest None Declared

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