Tryptophan catabolism through IDO activity can cause nonresponsiveness and tolerance acting on T cells. Given the crucial importance of dendritic cells (DCs) in the initiation of a T cell response, surprisingly little is known about the impact of IDO activity and tryptophan deprivation on DCs themselves. In the present study, we show that human DCs differentiated under low-tryptophan conditions acquire strong tolerogenic capacity. This effect is associated with a markedly decreased Ag uptake as well as the down-regulation of costimulatory molecules (CD40, CD80). In contrast, the inhibitory receptors ILT3 and ILT4 are significantly increased. Functionally, tryptophan-deprived DCs show a reduced capacity to stimulate T cells, which can be restored by blockade of ILT3. Moreover, ILT3highILT4high DCs lead to the induction of CD4+CD25+ Foxp3+ T regulatory cells with suppressive activity from CD4+CD25− T cells. The generation of ILT3highILT4high DCs with tolerogenic properties by tryptophan deprivation is linked to a stress response pathway mediated by the GCN2 kinase. These results demonstrate that tryptophan degradation establishes a regulatory microenvironment for DCs, enabling these cells to induce T regulatory cells. The impact of IDO thus extends beyond local immune suppression to a systemic control of the immune response.

The stage of a colorectal carcinoma represents the most important prognostic factor regarding the probability of survival. The primary objective of this study was to document the management of patients with colorectal carcinoma after onset of symptoms. Factors influencing the delay in definitive therapy should thus be determined. Anthropometric, social, and operative data were obtained by standardized questionnaires from 40 patients with colonic cancer and 30 patients with rectal cancer. The influence of delayed treatment on outcome was analyzed. A significant correlation was found for the time between onset of first symptoms and definitive surgical therapy with tumor stage (colon cancer: r = 0.52, p < 0.05; colorectal cancer: r = 0.62, p < 0.05). The time delay in rectal carcinoma patients averaged 224 days and in patients with colonic carcinoma 149 days. Social influences such as profession, type of education, marital status, and quality of health insurance had a significant influence on treatment delay, as did the clinical experience of the physician first contacted. The leading symptom in patients with rectal cancer was peranal hemorrhage, and in patients with colonic cancer it was abdominal pain. The main causes of iatrogenic delay were insufficient clinical investigation and a lack of awareness when typical first symptoms were present. Delayed treatment of colorectal cancer seems to be a multifactorial problem. Causes for such delay are found not only in the patients and their social environments but also in the type and quality of their medical care systems. Intensified education and earlier prevention are the major aims for patients and their physicians.

HSV type 1 (HSV-1) has evolved numerous strategies for modifying immune responses that protect against infection. Important targets of HSV-1 infection are the MHC-encoded peptide receptors. Previous studies have shown that a helper T cell response and Ab production play important roles in controlling HSV-1 infection. The reduced capacity of infected B cells to stimulate CD4+ T cells is beneficial for HSV-1 to evade immune defenses. We investigated the impact of HSV-1 infection on the MHCII processing pathway, which is critical to generate CD4+ T cell help. HSV-1 infection targets the molecular coplayers of MHC class II processing, HLA-DR (DR), HLA-DM (DM), and invariant chain (Ii). HSV-1 infection strongly reduces expression of Ii, which impairs formation of SDS-resistant DR-peptide complexes. Residual activity of the MHC class II processing pathway is diminished by viral envelope glycoprotein B (gB). Binding of gB to DR competes with binding to Ii. In addition, we found gB associated with DM molecules. Both, gB-associated DR and DM heterodimers are exported from the endoplasmic reticulum, as indicated by carbohydrate maturation. Evaluation of DR, DM, and gB subcellular localization revealed abundant changes in intracellular distribution. DR-gB complexes are localized in subcellular vesicles and restrained from cell surface expression.

Alterations in the epidermal growth factor receptor (EGFR) and its main ligand, transforming growth factor-alpha (TGF alpha), were investigated for a possible prognostic relevance in 125 astrocytic gliomas (44 World Health Organization (WHO) Grade II, 19 WHO Grade III, and 62 WHO Grade IV tumors). The TGF alpha and EGFR proteins were detected immunohistochemically using monoclonal antibodies. A positive immunoreaction to TGF alpha was detected in 33 (75%) of 44 WHO Grade II astrocytomas, 18 (95%) of 19 WHO Grade III astrocytoma, and 50 (81%) of 62 WHO Grade IV glioblastomas. No correlation between TGF alpha immunoreaction and duration of survival could be found. A positive EGFR immunoreaction was detected in seven (16%) of 44 WHO Grade II astrocytomas, five (26%) of 19 WHO Grade III astrocytomas, and 32 (52%) of 62 WHO Grade IV glioblastomas. Of these gliomas, 97 (26 WHO Grade II, 17 WHO Grade III, and 54 WHO Grade IV gliomas) were examined for EGFR gene amplification using a differential polymerase chain reaction assay. Amplification of the EGFR gene was detected in none of the WHO Grade II astrocytomas, one (6%) of 17 WHO Grade III astrocytomas, and 18 (33%) of 54 WHO Grade IV glioblastomas. Twenty-two of the tumors investigated showed a positive EGFR immunoreaction without detectable gene amplification (five WHO Grade II, four WHO Grade III, and 13 WHO Grade IV tumors). Gene amplification was invariably associated with a positive EGFR immunoreaction. For the entire study group, a strong correlation between EGFR alterations (gene amplification and positive immunoreaction) and survival could be found. However, this correlation only reflected the higher percentages of cases with EGFR alterations in malignant gliomas and was not an independent prognostic factor as determined by multifactorial analysis. These data demonstrate that EGFR alterations are frequent events in astrocytic gliomas and are largely restricted to glioblastomas. However, within one tumor grade they do not provide prognostic information.

Dendritic cells (DC) change their phenotype and functional properties during maturation. CD83 cell surface expression is induced on mature DC (mDC). In this study, we investigated intracellular CD83 localization and transport in human monocyte-derived DC. The enhanced level of CD83 cell surface expression in mDC resulted predominantly from increased protein synthesis, and in addition from regulated intracellular transport of CD83 protein. An internal pool of CD83 protein is present in immature DC (iDC). Although CD83 protein in iDC and in mDC was localized in the Golgi compartment and in recycling endosomes, only in mature cells did CD83 co-localize with MHC class II molecules in endocytic vesicles. CD83 cell surface expression on iDC was induced by inhibition of endocytosis. This result could be explained by CD83 cycling between endosomes and the cell surface in iDC. The mDC also rapidly internalized membrane-bound CD83 protein. Furthermore, a thiol protease inhibitor and specific cathepsin inhibitors impaired CD83 up-regulation in DC, indicating a role of endosomal proteases in the maturation-induced exposure of CD83 on the plasma membrane.