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Dietmar Fuchs

Publications and source records attributed to Dietmar Fuchs.

At least 55 records · Page 3Linked to original sources
PubMed2005

Measurement of tryptophan, kynurenine and neopterin in women with and without postpartum blues.

BACKGROUND: Activation of the tryptophan-degrading enzyme indoleamine (2,3)-dioxygenase was demonstrated to be critically involved in tolerance induction to prevent fetal rejection. Our study was designed to examine alterations of tryptophan and its catabolic product kynurenine in the postpartum period and to compare them to neopterin as an immunological marker. METHODS: 95 healthy women delivering without complications provided blood during labour, and 2 and 4 days after birth. The blood samples were analysed for concentrations of tryptophan, kynurenine and neopterin. Women were asked to perform the Edinburgh Postnatal Depression Scale (EPDS) on days 2 and 4. RESULTS: In women without blues symptoms (n=86) tryptophan concentrations increased within 2 days after birth, whereas they did not change in women with postpartum blues (n=9; 9.5%). The group difference reached statistical significance (p<0.05). The change of the kynurenine to tryptophan ratio (kyn/trp), which estimates the degree of tryptophan degradation, was also different between the two groups at days 0 and 2 (p<0.05). Neopterin concentrations decreased between days 2 and 4 (p<0.05), but there were no differences between the two groups. LIMITATIONS: Our study population had a low prevalence of postpartum blues symptoms. CONCLUSION: Low postpartal mood is associated with continuously low serum tryptophan after delivery due to an increased degradation to kynurenine, but is independent of the postpartal course of neopterin.

Adult↗
PubMed2005

Antioxidants may increase the probability of developing allergic diseases and asthma.

In addition to genetic predisposition, a lack of triggers for Th1 immune response like exposure to infections, endotoxins and dirt in childhood are supposed to be responsible for the higher incidence of allergic rhinitis and asthma (hygiene hypothesis). In vitro, beverages rich in antioxidants like green tea and wine were found to suppress formation of Th1-type cytokine interferon-gamma. Due to the existing cross-regulatory interplay between Th1- and Th2-type immune response, these beverages may thus slow-down Th1-type immune response and thereby favour an over-production of Th2-type cytokines. Also food rich in antioxidants may increase the risk of atopic disease. Thus, not only a lack of triggers for Th1 type immune response, but also a nutrition rich in antioxidants suppressing interferon-gamma would result in a persistence of Th2-type immune response and increase the susceptibility for allergic reactions and asthma. In addition to improved hygienic standards in the past decades, also social changes including the availability of functional food and food enriched in antioxidants may have increased the prevalence of atopic diseases in Western countries.

Antioxidants↗
PubMed2005

Neopterin in HIV-1 infection.

Neopterin is well established as a reliable marker in HIV-1 infection. Neopterin concentrations measured in urine or serum indicate sensitively the course and progression of the disease as well as efficacy of anti-retroviral therapy. The main trigger for neopterin production is Th1-type cytokine interferon-gamma. During acute HIV-1 infection, enhanced formation of neopterin occurs already at a very early time point, before antibody seroconversion takes place. After this stage, neopterin concentrations in serum and urine closely correlate with virus load in the circulation of HIV-1-infected patients. Data provide evidence for an important role of immune activation and Th1-type cytokine interferon-gamma in the pathogenesis of HIV-1 infection. This review subsumes the importance of neopterin as a marker in HIV-1 infection. Further evidence is increasing, that neopterin derivatives might modulate immune response by interfering with the cellular redox balance, activating redox-sensitive transcription factors, or inducing apoptosis in specific cell types. The possible impact of neopterin derivatives and of other biochemical pathways induced by interferon-gamma such as indoleamine 2,3-dioxygenase in chronic diseases like HIV-1 infection is discussed.

Apoptosis↗
PubMed2005

Temporarily controlled HIV-1 replication after intravenous immunoglobulin treatment of Guillain-Barré syndrome.

HIV establishes a latent infection in resting CD4(+) T-lymphocytes. A possible strategy to eliminate cellular reservoirs in long-lived, HIV-1-infected quiescent CD4(+) T-lymphocytes might be to add T-cell-activating agents to potent antiretroviral therapy. In this report we describe a patient with Guillain-Barré syndrome treated with high dose intravenous immunoglobulin (IVIG) in addition to antiretroviral therapy. A transiently increased viral load and immunoactivation during the IVIG treatment suggest activation of latently infected cells and increased turnover rate of the latent viral reservoir. HIV replication was controlled with plasma viral load <20 copies/ml, for at least 3 months after antiretroviral treatment interruption. CSF neural markers reflecting degenerative processes in the brain during the symptomatic period and follow-up were also analysed. Very high CSF sulfatide concentrations were found indicating that the pathology involves severe demyelination.We hypothesize that IVIG in this case contributed to an activation of latently infected cells, which led to a transient increase in plasma HIV-1 RNA during the IVIG treatment and a long period of undetectable viral load after antiretroviral treatment interruption. Further, this is the first time, to our knowledge, that detailed CSF findings are described in HIV-1 associated GBS.

Adult↗
PubMed2005

Anti-inflammatory compound resveratrol suppresses homocysteine formation in stimulated human peripheral blood mononuclear cells in vitro.

Inflammation, immune activation and oxidative stress play a major role in the pathogenesis of cardiovascular disorders. In addition to markers of inflammation, moderate hyperhomocysteinemia is an independent risk factor for cardiovascular disease, and there is a link between the activation of immunocompetent cells and the enhanced formation of homocysteine in vitro. Likewise, anti-inflammatory drugs and nutrients rich in antioxidant vitamins are able to reduce cardiovascular risk and to slow down the atherogenic process. Resveratrol, a phenolic antioxidant synthesized in grapes and vegetables and present in wine, has also been supposed to be beneficial for the prevention of cardiovascular events. Apart from its strong antioxidant properties, resveratrol has also been demonstrated to act as an anti-inflammatory agent. In this study the influence of resveratrol on the production of homocysteine by stimulated human peripheral blood mononuclear cells (PBMCs) was investigated. Results were compared to earlier described effects of the anti-inflammatory compounds aspirin and salicylic acid and of the lipid-lowering drug atorvastatin. Stimulation of PBMCs with the mitogens concanavalin A and phytohemagglutinin induced significantly higher homocysteine accumulation in supernatants compared with unstimulated cells. Treatment with 10-100 muM resveratrol suppressed homocysteine formation in a dose-dependent manner. Resveratrol did not influence the release of homocysteine from resting PBMCs. The data suggest that resveratrol may prevent homocysteine accumulation in the blood by suppressing immune activation cascades and the proliferation of mitogen-driven T-cells. The effect of resveratrol to down-regulate the release of homo-cysteine was comparable to the decline of neopterin concentrations in the same experiments. The suppressive effect of resveratrol was very similar to results obtained earlier with aspirin, salicylic acid and atorvastatin; however, it appeared that doses of compounds needed to reduce homocysteine levels to 50% of stimulated cells were always slightly lower than those necessary to achieve the same effect on neopterin concentrations. The influence of resveratrol and of all the other compounds on homocysteine production appears to be independent of any direct effect on homocysteine biochemistry.

Anti-Inflammatory Agents↗
PubMed2005

Atorvastatin suppresses homocysteine formation in stimulated human peripheral blood mononuclear cells.

Hyperhomocysteinemia is regarded as an independent risk factor for vascular diseases, and homocysteine is supposed to contribute to oxidative stress and endothelial damage. Statin therapy is an established intervention to reduce the risk of acute events in patients suffering from cardiovascular diseases. Apart from their lipid-lowering capacity, statins also exert anti-inflammatory and antioxidant effects. As cellular immune activation and oxidative stress play a major role in the pathogenesis of cardiovascular diseases, the anti-inflammatory capacity of statins could partly be responsible for the beneficial effects observed in patients. Earlier we reported that stimulated peripheral blood mononuclear cells (PBMCs) release homocysteine. Here we studied the influence of atorvastatin on homocysteine production in stimulated PBMCs and compared changes in cysteine concentrations and in neopterin production, which is a sensitive indicator of cellular immune activation. Stimulation of human PBMCs with the mitogens concanavalin A and phytohemagglutinin induced significant homocysteine and neopterin production compared to unstimulated cells, whereas cysteine concentrations remained unchanged. Treatment of PBMCs with increasing doses of atorvastatin (10-100 microM) suppressed both biochemical pathways in a dose-dependent manner, and cell proliferation was inhibited in parallel. Again, cysteine levels were not influenced by any treatment. The down-regulating effect of atorvastatin on homocysteine formation in vitro indicates that statins may prevent homocysteine accumulation in the blood via immunosuppression.

Anti-Inflammatory Agents↗
PubMed2005

Enhanced enzymatic degradation of tryptophan by indoleamine 2,3-dioxygenase contributes to the tryptophan-deficient state seen after major trauma.

Decreased lymphocyte proliferation, lymphopenia, immunodepression, and opportunistic infections are common after major trauma. Early alimentation in these patients corrects lymphopenia, enhances immunity, and reduces the incidence of infections, but the underlying mechanisms are poorly understood. Tryptophan is essential for the production and function of rapidly proliferating cells such as lymphocytes. Tryptophan is enzymatically degraded by indoleamine 2,3-dioxygenase (IDO), whose activity is solely dependent on expression of interferon-gamma (IFN-gamma). Because increased expression of IFN-gamma has been reported in trauma patients, we investigated whether enhanced IDO-mediated tryptophan degradation is associated with lymphopenia and poor outcomes after major trauma. The incidence of bacteremic sepsis (BS), adult respiratory distress syndrome (ARDS), multiple organ dysfunction/failure syndromes (MODS/MOF), and death was prospectively documented in 22 trauma patients with a mean ISS of 24.9 +/- 2.2. Sequential blood samples were obtained from admission through postinjury day 10. Five patients developed BS, three of whom developed ARDS; two of the three ARDS patients developed MOF and died on day 10. Trauma patients had significantly lower tryptophan levels (days 1-10), higher kynurenine:tryptophan ratios (days 1-2), and fewer lymphocytes (days 1-4) than healthy volunteers (P < 0.05). Although patients with poor outcomes (i.e., BS, ARDS, MOF, and death) had significantly lower tryptophan levels and greater lymphopenia on several days after injury, the sample size was too small to draw any definitive conclusions. These data indicate that decreased plasma tryptophan levels and lymphopenia typically occur after major trauma. A concomitant increase in kynurenine suggests that the observed tryptophan deficiency is caused, in part, by IDO-mediated tryptophan degradation.

Adolescent↗
PubMed2004

Tryptophan degradation in patients with gynecological cancer correlates with immune activation.

Tryptophan degradation by the enzyme indoleamine-(2,3)-dioxy genase (IDO) and neopterin production are induced within cellular immune activation by stimulation of monocyte-derived macrophages and dendritic cells with cytokine interferon-gamma. Deprivation of tryptophan represents an important antimicrobial and antitumoral immune defence mechanism but it also suppresses T-cell proliferation. Recently tryptophan degradation by tumor cells was proposed as strategy to escape immune response. In this study the relationship between tryptophan degradation and immune activation was examined in 20 patients with gynecological cancer. Concentrations of tryptophan and kynurenine were measured by HPLC in sera of patients, and to estimate IDO activity, the kynurenine to tryptophan ratio was calculated. In parallel, neopterin concentrations were measured by ELISA. Tryptophan concentrations (median, interquartile range: 43.5, 31.2-56.3 microM) were lower in patients with gynecological cancer compared to healthy individuals of similar age (53.5, 47.0-64.2 microM; P<0.05). Kynurenine concentrations (median: 1.91 vs. 1.73 microM in controls) and kyn/trp (median: 41 vs. 35 micromol/mmol in controls) were slightly higher in patients, but not significantly different. Neopterin concentrations were significantly higher in patients (median: 10.8 vs. 7.0 nM in controls; P<0.05) and correlated with the kynurenine per tryptophan ratio (r(s)=0.555; P<0.02). In conclusion, tryptophan degradation is detectable in patients with gynecological cancer. The relationship between kyn/trp and neopterin concentrations indicates that cellular immune activation rather than tumor-mediated IDO-activity is responsible (228 words).

Adult↗
PubMed2004

Down-regulatory effect of N-chlorotaurine on tryptophan degradation and neopterin production in human PBMC.

N-Chlorotaurine (NCT) plays an important role in the human defense system as a main component of long-lived oxidants, and shows bactericidal, fungicidal, and virucidal activity. Besides this role, NCT seems to act regulatory on immunocompetent cells by altering cytokine production. NCT inhibited nitric oxide, TNF-alpha, and prostaglandin E(2) (PGE(2)) production in activated rodent macrophages, and suppressed superoxide anion, IL-6, and IL-8 formation in human polymorphonuclear leukocytes. In this study, the influence of NCT on the production of neopterin and the activation of the enzyme indoleamine-2,3 dioxygenase (IDO) was investigated in human peripheral blood mononuclear cells (PBMC). Both events are well established to be triggered by IFN-gamma and therefore related to Th1-type immune activation. Mitogen-induced neopterin production as well as tryptophan degradation were drastically reduced upon addition of NCT. Results fit in the concept of a reduction of pro-inflammatory cytokines by this compound. In contrast to earlier results, where NCT was suggested to act primarily down-regulatory on Th2 cells, we propose also a strong suppressive effect of NCT on Th1-type immunity.

Cell Survival↗
PubMed2004

Influence of neopterin on generation of reactive species by myeloperoxidase in human neutrophils.

Increased neopterin concentrations in human serum indicate activation of cell-mediated immune response. Earlier we have shown that neopterin enhanced generation of singlet oxygen, hydroxyl radical and nitric oxide in human peripheral blood neutrophils by NADPH-independent pathways. To further investigate a participation of neopterin in reactive species production by neutrophils, we studied its influence on myeloperoxidase (MPO) activity. MPO was isolated from human peripheral blood neutrophils from healthy donors. Generation of reactive species by MPO/H(2)O(2) in Earl's solution (pH=7.2) at 37 degrees C was investigated by monitoring of chemiluminescence using luminol as light emitter. In the MPO/H(2)O(2) system, neopterin increased singlet oxygen in a concentration-dependent manner, but it decreased formation of other oxidizing species. Comparing several oxygen scavengers, formation of reactive species was totally blocked by sodium azide (NaN(3)), both in the presence and in the absence of neopterin. Superoxide dismutase (SOD) and d-mannitol insignificantly decreased chemiluminescence of this reaction, but diazabicyclo[2.2.2]octane (DABCO) strongly inhibited it. We conclude that the effects of neopterin on neutrophils' MPO are directed to increase singlet oxygen and to decrease other reactive species via inhibition of MPO and/or scavenging of reactive species.

Humans↗
PubMed2004

[Soluble interleukin-2 and tumor necrosis factor receptor in liver cirrhosis. Relationship with clinical severity and prognosis].

BACKGROUND AND OBJECTIVE: The mechanism responsible for the beginning and progression of hepatic injury in liver cirrhosis of viral and alcoholic etiology are unknown currently. However, there are abnormalities in the immune system which may be implied in the pathogenesis. PATIENTS AND METHOD: The concentrations of the soluble receptor of tumor necrosis factor (sTNF-R55) and the soluble receptor of interleukin-2 (sIL-2R) in 49 cirrhotic patients were determined by enzyme-linked inmunoassay. Patients were grouped according to the etiology (33 alcoholic and 16 viral) and prognosis (Child-Pugh classification) and they were compared with the values obtained in 26 healthy non-drinkers who made up the control group. RESULTS: The concentrations of sTNF-R55 and sIL-2R were significantly higher in both groups of patients when compared with controls. We found significant differences in sTNF-R55 concentrations in viral and alcoholic but not in sIL-2R concentrations. There was a positive correlation between the concentrations of both receptors and the degrees of Child-Pugh classification, as well as with albumin, total bilirubin and alkaline phosphatase (all of them parameters related to the severity and prognosis of liver cirrhosis). CONCLUSIONS: The serum concentrations of soluble receptors of tumor necrosis factor and interleukin-2 correlate with the prognosis of liver cirrhosis independently of its etiology. This fact may reflect the stimulation of T lymphocytes, monocytes and macrophages, in liver cirrhosis.

Adult↗
PubMed2004

Overexpression of indoleamine 2,3-dioxygenase in human inflammatory bowel disease.

T-cells are causally involved in the pathogenesis of inflammatory bowel disease (IBD). The tryptophan-metabolizing enzyme indoleamine 2,3-dioxygenase (IDO) regulates T-cell proliferation and survival. We show in this report that IDO mRNA is markedly induced in lesional colonic biopsies of IBD patients. IDO is primarily expressed in CD123(+) mononuclear cells infiltrating the submucosal areas of the inflamed lesions. In Crohn's disease (CD), IDO is also strongly expressed in perifollicular regions of lymphoid follicles. Upregulation of IDO is of functional significance, as we detected an increase of kynurenine and of the kynurenine/tryptophan ratio in supernatants from colonic explant cultures (CECs) of CD patients. Immunohistochemistry of colonic biopsies taken from CD patients prior and after treatment with the TNF-blocking antibody Infliximab revealed reduced IDO expression in patients with good clinical response to Infliximab. In summary, high local expression of IDO may represent an anti-inflammatory mechanism tempting to counterbalance the tissue-damaging effects of activated T-cells infiltrating the colonic mucosa in IBD.

Adult↗
PubMed2004

Increasing production of homocysteine and neopterin and degradation of tryptophan with older age.

OBJECTIVES: Aging is associated with an increased frequency of abnormal immune system function, which may cause infections, autoimmune diseases, and cardiovascular or neurodegenerative disorders. Th1-type cytokine interferon-gamma (IFN-gamma) induces neopterin production as well as tryptophan degradation via indoleamine (2,3)-dioxygenase (IDO), and quantification of these biochemical alterations allows one to monitor immune system activation. Homocysteine is known to be elevated in the elderly, which is possibly due to an insufficient availability of folate, B6, and/or B12. DESIGN AND METHODS: Serum concentrations of neopterin, homocysteine, tryptophan and kynurenine, and of vitamins folate and B12 were measured in 43 healthy individuals (21 females, 22 males) aged 34-93 years. The ratio of the concentration of the product of IDO, kynurenine, versus the substrate tryptophan (kyn/trp) was calculated to estimate IDO activity. RESULTS: Comparing three age groups of similar size (34-60, 61-71, and 72-93 years), neopterin and homocysteine concentrations as well as the kyn/trp ratio were found to increase with older age (all P < 0.01). Folate concentrations were lower in the middle-aged group as compared with the other two subgroups of individuals. Vitamin B12 concentrations did not differ between groups. Positive correlations were found between kyn/trp and neopterin and homocysteine concentrations (all P < 0.01). CONCLUSIONS: Increasing neopterin concentrations and kyn/trp with older age are in line with the view that aging in healthy people is associated with immune activation especially of the T-cell/macrophage system.

Adult↗