Search

Objective: To evaluate the effectiveness of a well-controlled programme of early detection and treatment of prostate cancer in the population of Tyrol, Austria, where such a programme of early detection and treatment was initiated in 1988 and where prostate-specific antigen (PSA) testing was offered for free to all men aged 45-75 years from 1993., Subjects and Methods: Comparison of prostate cancer mortality rates in Tyrol and the rest of Austria was accomplished through a generalized additive model. A piecewise linear change-point Poisson regression model was used to compare mortality rates in Tyrol and the rest of Austria. Standardized mortality ratios were calculated with reference to the mortality rates in 1986-1990., Results: In all, 86.6% of eligible men have been tested at least once since 1993. Cancer deaths in Tyrol in 2005 were 54% (95% confidence interval [CI] 34-69%) lower than expected compared with 29% (95% CI 22-35%) in the rest of Austria. The decreasing trend in prostate cancer mortality was significantly greater in Tyrol compared with the rest of Austria (P = 0.001). A significant migration to lower stage disease occurred and radical prostatectomy was associated with low morbidity., Conclusions: In the Tyrol region where treatment is freely available to all patients, where widespread PSA testing and treatment with curative intent occurs, there was a reduction in prostate cancer mortality rates which was significantly greater than the reduction in the rest of Austria. This reduction in prostate cancer mortality is most probably due to early detection, consequent down-staging and effective treatment of prostate cancer.

Inflammation is a hallmark of various diseases like infections, autoimmune syndromes, cardiovascular and neurodegenerative disorders, and cancer. Thereby, Th1-type cytokine interferon-gamma is a central pro-inflammatory mediator. Antioxidant compounds counteract the activation of T-cells and macrophages. This anti-inflammatory activity could be important for the development of immunotolerance and for treatment of above-mentioned disorders.

Background/aims: The antioxidant properties of vitamin C and E are considered to be important for their anti-inflammatory activity. Recently, antioxidant resveratrol was found to suppress neopterin production and tryptophan degradation in mitogen-treated human peripheral blood mononuclear cells., Methods: In this study, the effects of vitamin C and E were investigated in unstimulated peripheral blood mononuclear cells and in cells stimulated with the mitogens phytohaemagglutinin and concanavalin A in vitro., Results: The mitogens induced a significant production of neopterin and a degradation of tryptophan. Vitamin C (0.1-10 microM) and E (5-100 microM) suppressed these immunobiological pathways in a dose-dependent way (p < 0.01)., Conclusion: Neopterin production and tryptophan degradation in monocyte-derived macrophages are both triggered by the pro-inflammatory cytokine interferon-gamma. Thus, their concurrent suppression by vitamin C and E suggests an effect on the formation and release of this cytokine by stimulated T cells. These findings may be related to the general health benefits which are associated with the antioxidant nature of these vitamins., (Copyright 2007 S. Karger AG, Basel.)

Antioxidant preservatives prolong the quality of food and ensure the nutritional adequacy, palatability and safety of many processed foods and beverages. Effects of sodium sulfite (E221) and sorbic acid (E200) were investigated in human peripheral blood mononuclear cells (PBMC) which were purified from blood of healthy donors. Cells were stimulated with the mitogen phytohaemagglutinin in vitro, which induces proliferation of T-cells and the production of Th1-type cytokines like interferon-gamma. The latter triggers enzyme indoleamine (2,3)-dioxygenase, which degrades tryptophan, and GTP cyclohydrolase I, which leads to increased neopterin production, in monocyte-derived macrophages. Sodium sulfite and sorbic acid suppressed both these biochemical changes in a dose-dependent way (P<0.01 at 1 mM sodium sulfite and 50 mM sorbic acid). Data demonstrate a suppressive influence of sodium sulfite and sorbic acid on the activated Th1-type immune response.

It is generally accepted that the increased prevalence of atopic disease is due to a disturbed balance of T-helper (Th)1/Th2-type immunity. Upon stimulation by the Th1-type cytokine interferon (IFN)-gamma, human monocytes/macrophages release large amounts of neopterin. Thus, the determination of neopterin concentrations is an indirect measure of the levels of IFN-gamma and allows us to monitor Th1-type immune response. We evaluated whether neopterin concentrations in the neonatal cord blood could be a valuable marker predicting atopic disease in early childhood and whether there is a difference in actually determined urinary neopterin concentrations in children with and without atopic disease. Five hundred and five children born during 1997-1999 were enrolled, with cord blood neopterin data available at birth. The International study of asthma and allergies in childhood (ISAAC) questionnaire was used to assess the prevalence of wheezy bronchitis (asthma), atopic dermatitis and allergic rhinitis. Morning urinary samples were collected and urinary neopterin concentration was measured by high-pressure liquid chromatography. By the average age of 6 yr, the prevalence of atopic disease in the last 12 months was 31%. There was no significant correlation between cord blood and urinary neopterin concentrations at age 6 yr, and between cord blood neopterin and later atopic disease. Urinary neopterin concentrations were significant lower in children with a family history of atopic disease (p = 0.02). In this study, cord blood neopterin concentration was not a predictor for atopic disease in early childhood. Family history of atopic disease was associated with lower urinary neopterin levels at age 6 yr, which might mirror a Th1/Th2 imbalance.

Antitumor activity of a calcium-pterin suspension has been described in vitro and in animal model systems. Recent studies provide some evidence that this effect involves immune-mediated mechanisms. We investigated the influence of calcium-pterin on freshly isolated human peripheral blood mononuclear cells (PBMC) stimulated with the mitogens phytohaemagglutinin and concanavalin A in vitro. Influence of calcium-pterin on tryptophan-degrading enzyme indoleamine (2,3)-dioxygenase (IDO) and on neopterin production was monitored in supernatants of cells. Increased neopterin concentrations as well as accelerated tryptophan degradation have been found to predict poor prognosis in patients with cancer, and both these immunobiochemical pathways are induced by the pro-inflammatory cytokine interferon-gamma. Compared to unstimulated cells, mitogens induced degradation of tryptophan and formation of neopterin in PBMC, and upon addition of calcium-pterin, both biochemical results were suppressed in a dose-dependent way. Thus, calcium-pterin suppresses immunological pathways in vitro that in patients with malignant diseases characterize an unfavorable prognosis. The effect of the compound to suppress IDO activity could be of considerable relevance for the antitumoral effect of the compound because activation of the enzyme is considered as an immune-escape mechanism of tumor cells.

Objectives: Neopterin is produced by human monocyte-derived macrophages upon stimulation with interferon-gamma and is therefore a sensitive indicator for cellular immune activation. Common factors like age, diastolic blood pressure, body mass index, or smoking habits were found to be associated with neopterin concentrations in humans., Design and Methods: In order to find possible genetic determinants which might influence neopterin production, we investigated 8288 consecutive blood donors after exclusion of samples suspicious of infections., Results: Donors with blood group phenotype 0 had moderately, but significantly (P < 0.0001) higher neopterin concentrations (mean +/- SD: 6.94 +/- 1.52 nmol/L) than those with phenotype A (6.75 +/- 1.50 nmol/L), phenotype B (6.73 +/- 1.48 nmol/L), and phenotype AB (6.68 +/- 1.57 nmol/L)., Conclusions: Neopterin levels are higher in donors with blood group phenotype 0 than in other phenotypes. Data point to a genetic background of different neopterin concentrations. However, alterations of neopterin levels were much less expressed than the changes known to occur during diseases with an activated immune response.

A wide range of biological activities of resveratrol (3,5,4'-trihydroxystilbene) in vitro and in vivo has been proved, including antioxidant, antitumor, and also anti-inflammatory effects. Resveratrol found in, e.g., grapes and red wine has been suggested to counteract the progression of coronary heart disease by lowering serum lipid concentrations and inhibiting platelet aggregation. Cellular immune activation is known to be involved crucially in the pathogenesis of coronary heart diseases. In this in vitro study, the modulatory effect of resveratrol on two interferon-gamma-mediated pathways, the degradation of tryptophan by the enzyme indoleamine 2,3-dioxygenase, and the production of neopterin by activation of the GTP-cyclohydrolase I, was tested. Cultures of human peripheral blood mononuclear cells were exposed to resveratrol, in combination with mitogenic stimulation. A significant down-regulatory effect of resveratrol on both biochemical pathways was found, and also the production of Th1-type cytokine interferon-gamma was significantly suppressed. If these results can be verified in vivo, an explanation is provided how resveratrol may interfere with immune activation and cytokine cascades, which are important in the development and progression of cardiovascular disorders and also other diseases.

Dendritic cells (DC) have been recently used as vaccines for stimulation of tumour-specific immunity in various types of cancer. Since data about interactions of DC with tumour cells derived from head and neck cancer are not available, in our study we investigated the effects of head and neck squamous cell carcinoma (HNSCC) cell lines on the maturation of DC. We found that immature DC efficiently internalise necrotic cells, but not living and apoptotic tumour cells. Although apoptotic cells induced a partial maturation of DC, they were not able to stimulate the secretion of IL-12. In contrast, necrotic tumour cell preparations from all three HNSCC cell lines induced the mature phenotype and IL-12 production by DC. Moreover, necrotic cells synergistically augmented stimulatory effects of monocyte-conditioned medium on the maturation of DC. Thus, DC-based vaccination utilizing necrotic tumour cells as a source of tumour antigens, even in combination with inflammatory stimulus, seems to be a suitable strategy for adjuvant immunotherapy in HNSCC.

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.

St. John's wort (Hypericum perforatum) is an ancient folk remedy that has antiviral and antibacterial properties. Anti-inflammatory effects of the plant have been described and the application of H. perforatum extract as an effective antidepressant is well established. In this study we assayed the effect of H. perforatum extract on cytokine-induced tryptophan degradation in human peripheral blood mononuclear cells. Simultaneously, changes in the production of the immune activation marker neopterin were monitored. Both these biochemical pathways are triggered by interferon-gamma. Our results show that extracts of H. perforatum strongly down-regulate mitogen-mediated tryptophan degradation in a dose-dependent manner. This effect seems to be based on a suppressive activity of H. perforatum on activated immunocompetent cells, resulting in a diminished production of interferon-gamma. In line with this finding, neopterin synthesis was strongly down-regulated by the plant extract. Our results suggest that the reduction of tryptophan degradation by H. perforatum might be important in the action of the plant as an antidepressant.

Recent observations suggest that the inability of the immune system to mount an effective immune response against head and neck squamous cell carcinoma (HNSCC) could be a result of the immunosuppression mediated through soluble factors that are secreted by tumour cells. Therefore, we investigated the effects of conditioned medium obtained from cultures of HNSCC cell lines (HNSCC-CM) on the function of dendritic cells (DC) and T cell immune response. In our study, we could not observe any inhibitory effect of HNSCC-CM on the maturation and the cytokine secretion pattern of DC. On the contrary, HNSCC-CM from two of three cell lines consistently decreased the quantity of IFN-gamma- and IL-4-secreting T cells upon restimulation in vitro. In conclusion, our data suggest that soluble factors secreted by HNSCC cells directly inhibit the function of effector T cells, rather than impeding the process of antigen presentation.

Neopterin (Neo) and 7,8-dihydroneopterin (H(2)Neo) are produced by human monocyte-derived macrophages upon stimulation with IFN-gamma. Increased amounts of Neo and H(2)Neo in human body fluids are found in many disorders, including viral infections and autoimmune diseases. Recent data suggest that neopterin derivatives may exhibit distinct biochemical functions activating redox-sensitive transcription factors and inducing apoptosis in various cell lines. In this study we investigated the effect of H(2)Neo on human peripheral blood T cells (PBT) from healthy blood donors in comparison with PBT isolated from patients with systemic lupus erythematosus (SLE). H(2)Neo induced apoptosis in healthy PBT in a concentration-dependent manner. In short time culture, a significantly lower ability of PBT isolated from patients with SLE to undergo apoptosis in response to H(2)Neo compared to healthy controls was detected. Our results suggest a possible role of the neopterin derivative H(2)Neo in T cell apoptosis mediated by stimulated monocytes/macrophages.

Dendritic cells (DC) represent a unique set of APCs that initiate immune responses through priming of naive T cells. Maturation of DC is a crucial step during Ag presentation and can be induced by triggering a broad spectrum of DC surface receptors. Although human DC express several receptors for the Fc portion of IgG which were described to play an important role in Ag internalization, little is known about the effects of IgG or immune complexes on DC maturation. In this study, we show that cross-linking of FcgammaR-type II (CD32) with immobilized IgG (imIgG) can induce maturation of human monocyte-derived DC via the NF-kappaB signaling pathway. IgG-mediated maturation was accompanied by a moderate increase of IL-10 secretion, whereas no IL-12 production was observed. Involvement of CD32 was further supported by experiments with the anti-CD32 mAb, which blocked IgG-triggered DC maturation and cytokine secretion significantly. Furthermore, DC cultivated in the presence of imIgG induced allogeneic T cell proliferation. Because this imIgG-induced maturation was considerably impaired in monocyte-derived DC from systemic lupus erythematosus patients, we suggest that DC, which matured in the presence of immune complexes, may contribute to prevention of pathological immune responses.

Inhibitors of 3-hydroxy-3methylglutaryl-co-enzyme A (HMG-CoA) reductase, so-called statins, are used in medical practice because of their lipid-lowering effect and to reduce the risk of coronary heart disease. Recent findings indicate that statins also have anti-inflammatory properties and can modulate the immune response. In vitro, we investigated the effect of atorvastatin on the T cell/macrophage system in peripheral blood mononuclear cells (PBMC) and in the human monocytic cell lines THP-1 and MonoMac6. We monitored neopterin production and tryptophan degradation in PBMC after treatment with 10 micro m and 100 micro m atorvastatin in the presence or absence of 100 U/ml IFN-gamma, 10 micro g/ml phytohaemagglutinin (PHA) or 10 micro g/ml concanavalin A (ConA) and in monocytic cell lines THP-1 and MonoMac6 with or without stimulation with 100 U/ml IFN-gamma or 10 ng/ml to 1 micro g/ml lipopolysaccharide (LPS). In stimulated PBMC 100 micro m atorvastatin inhibited neopterin formation and tryptophan degradation completely, whereas 10 micro m atorvastatin was only partially effective. Also in monocytic cell lines THP-1 and MonoMac6, atorvastatin was able to suppress IFN-gamma- and LPS-induced formation of neopterin and degradation of tryptophan. Our data from PBMC agree well with previous investigations that statins inhibit T cell activation within the cellular immune response. In addition we demonstrate that atorvastatin directly inhibits IFN-gamma-mediated pathways in monocytic cells, suggesting that both immunoreactivity of T cells and of monocyte-derived macrophages are down-regulated by this statin.

In mice, activation of indoleamine-2,3-dioxygenase (IDO), an enzyme converting tryptophan to N-formyl-kynurenine, was found to be necessary requirement to achieve immunotolerance against the fetus and thus uncomplicated pregnancy. In plasma from 20 healthy pregnant women with singleton pregnancies we consecutively analyzed kynurenine and tryptophan concentrations during pregnancy (1 specimen at each trimester of gestation) and postpartum (week 6). None of the women had any signs of infection at the time of plasma sampling, but the study population was otherwise unselected. The kynurenine to tryptophan ratio (kyn/trp) was calculated as an estimate of IDO activity, and data were compared to concentrations of neopterin and 55kD soluble tumor necrosis factor receptor (sTNF-R55), two indicators of immune activation, and to alanineaminotransferase (ALT) levels. Increasing kynurenine and decreasing tryptophan concentrations were found during pregnancy, data suggesting significant degradation of tryptophan. In parallel, increasing concentrations of immune activation markers neopterin and sTNF-R55 were observed, correlating significantly to kyn/trp. The data point to an involvement of cytokine-induced IDO activation in the degradation of tryptophan observed during pregnancy. After pregnancy, sTNF-R55 and also neopterin concentrations declined, whereas tryptophan concentrations increased, indicating that immune activation and activation-induced tryptophan degradation returned to baseline. By contrast, still increased kynurenine concentrations and also increased kyn/trp point to continuing catabolism of tryptophan. Postpartum elevation of liver enzyme ALT may suggest that increased activity of hepatic tryptophan pyrrolase could be involved in increased conversion of tryptophan despite low degree of immune activation. We conclude that IDO is activated in pregnancy and that the decrease of tryptophan might be related to immune activation phenomena. Sustained increase of kynurenine postpartum seems independent from immune activation process.

Increased neopterin concentrations in body fluids are found in diseases associated with activated, cell-mediated immunity including infections, autoimmune diseases, and certain malignancies. Monocytes/macrophages are known to secrete large amounts of neopterin upon stimulation with interferon-gamma (IFN-gamma). Ontogenetically, the major part of dendritic cells (DC) belongs to the myeloid lineage. Therefore, we investigated whether cultured monocyte-derived DC can elaborate neopterin. Cells were treated with cytokines in the presence or absence of monocyte-conditioned medium as a maturation stimulus. DC secreted an average 3.5 nmol/l neopterin. In response to IFN-gamma, cells significantly increased their output of neopterin. In distinction to monocytes/macrophages, neopterin production in DC was highly sensitive to IFN-alpha and IFN-beta. Further, lipopolysaccharides (LPS) enhanced neopterin synthesis, whereas tumor necrosis factor alpha, interleukin (IL)-1beta, IL-2, IL-10, and IL-18 were ineffective. Simultaneously, tryptophan degradation by induction of indoleamine (2,3)-dioxygenase (IDO) was tested in stimulated cells. Our results showed that IFN-gamma as well as LPS are inducers of IDO in DC.

Serum neopterin concentrations were determined in 20,000 blood donations. For the 400 donations with neopterin concentrations above the 98 th percentile and another 1200 donations with neopterin concentrations in the lower range, results of human parvovirus (HPV) B19 tests were compared. Infectious specimens were identified by dot blot hybridization assay and polymerase chain reaction (PCR) that used the outer primers and detected 1 pg of HPV B19 DNA, corresponding to approximately 10(5) copies of the genome, in the specimens and by a nested PCR that detected 1-10 fg of DNA, corresponding to 10(2)-10(3) copies of the genome. Of 400 specimens with neopterin concentrations > or =12 nmol/L (98th percentile, current cutoff), 10 tested positive by dot blot hybridization assay (9 of these were confirmed by nested PCR). Among 1200 specimens with low neopterin concentrations (<12 nmol/L), no specimen containing HPV B19 DNA was detected. These findings suggest an association between elevated neopterin concentrations and HPV B19 infectivity.

Dendritic cells (DC) represent a class of professional antigen-presenting cells whose primary function is to alert the immune system, not to clear invading microorganisms. The objective of our study was to compare the abilities of polymorphonuclear neutrophilic leukocytes (PMN), monocytes, monocyte-derived macrophages (MDM), monocyte-derived immature DC (imDC), and mature DC (maDC) to ingest and destroy Staphylococcus aureus and Escherichia coli. Acridine orange staining and fluorescence microscopy demonstrated that MDM, followed by monocytes, imDC, and PMN, internalized bacteria well but that maDC exhibited less pronounced phagocytic activity. PMN, monocytes, and MDM exhibited a much higher capacity to kill ingested bacteria than both imDC and maDC. In summary, these data are in agreement with the generally accepted idea that different types of leukocytes fulfill specialized tasks in antigen presentation and killing of pathogens.

In Austria serum neopterin measurement was introduced as an additional unspecific screening marker for the detection of routinely unscreened viral infections in blood donations in 1994. This study was performed to test for associations between serum neopterin concentrations in blood donations and cytomegalovirus infections of the donors. All consecutive blood donations from volunteer blood donors collected during 1 year were incorporated into the study. Serum neopterin concentrations were measured by enzyme-linked immunosorbent assay (ELISA), and each donation of donors with CMV seronegativity or unknown CMV status was also screened for CMV antibodies by CMV IgG/IgM antibody ELISA. Data of donors who had two or more donations within this period were retrospectively analyzed for CMV seroconversions. CMV seroconversion was defined as a change in the donor's CMV status from antibody negative to positive. Frozen, stored plasma samples of the matching donors were tested for CMV IgM antibodies to confirm seroconversion. CMV seroconversions were classified by antibody patterns. In total, 56,068 consecutive blood donations were given by 44,427 volunteer donors. Among these, 9,105 had more than one donation during the observation period, and 4,329 (47.5%) out of these repeated donors were initially CMV antibody negative, of whom 36 were recruited as candidates for CMV seroconversion; 20 conversions were confirmed. All early infections ( n=8) were associated with neopterin concentrations of more than 13 nmol/l (98th percentile of all donations = 12.1 nmol/l) and all donations were excluded from transfusion solely on the basis of their elevated neopterin level. In addition, 17% of late and carrier states ( n=12) showed elevated neopterin concentrations. Acute CMV infections among blood donors presented with elevated serum neopterin concentrations even before CMV IgG/IgM antibodies were detectable.

Stem cell transplantation from unrelated donors is associated with an increased risk of graft failure and graft-versus-host disease (GVHD). Addition of pretransplant antithymocyte globulin (ATG), although reducing the risk of graft rejection and GVHD, bears the risk of overimmunosuppression, resulting in an increased relapse rate and transplant-related mortality. Therefore, we evaluated in 21 consecutive patients receiving unrelated stem cell grafts from either HLA-matched (38%) or -mismatched (62%) donors whether low-dose rabbit ATG added to cyclosporin A and methotrexate at a total dose of 3.5 mg/kg for HLA-identical and 5.0 mg/kg for HLA-mismatched transplants given in two divided doses on days -2 and -1 provides sufficient immunosuppression for prevention of GVHD and graft rejection but is associated with an acceptable risk of relapse and transplant-related mortality. Stable leukocyte engraftment was achieved in all patients (100%). Overall survival after a median follow-up of 26 (median, range 14-42) months was 56 +/- 26% (95% confidence interval, CI) and the overall relapse rate at 3 years was 24 +/- 21%. Three-year survival for standard-risk patients, i.e., chronic myeloid leukemia (CML) in first chronic phase or acute leukemia in first complete remission, was 87% +/- 13% versus 40% +/- 31% for patients with more advanced disease. The incidence of acute GVHD II-IV degrees was 55 +/- 22%; that of severe acute GVHD III-IV degrees was 21 +/- 19%. Chronic GVHD was observed in 5/17 (29%) patients surviving more than 100 days post stem cell transplantation. Transplant-related mortality was 16 +/- 15% (95% CI) at day + 100 and 25 +/- 19% (95% CI) at 1 year after the transplant. The data presented show that pretransplant in vivo T cell depletion with low-dose rabbit ATG results in a low transplant-related mortality due to a low incidence of severe acute and chronic GVHD and a low relapse rate. To find out the optimal rabbit ATG dose in the unrelated stem cell transplantation setting, further dose-finding studies comparing high- and low-dose regimens are necessary.

In Vietnamese and Chinese traditional medicine, hot aqueous extract of Crinum latifolium is used because of its antitumor activity. The genus Crinum is thought to possess antiviral and immunostimulative properties. Green and black tea derived from Camellia sinensis have similar qualities. A growing body of evidence suggests that moderate consumption of green and black tea may protect, e.g., against several forms of cancer, cardiovascular diseases, and bacterial infections. In this study, the immunomodulatory property of C. latifolium (L.) extracts should further be investigated and compared to those of black and green tea. Human peripheral mononuclear cells were cultured in the presence of tea extracts with or without mitogens or interferon-gamma. The effect of plant extracts on cultured cells was assayed by neopterin production, a sensitive marker reflecting the activation of cell-mediated immunity. Our experiments showed that extracts of C. latifolium (L.) slightly enhance neopterin production in unstimulated peripheral mononuclear cells, whereas an effective reduction of neopterin formation in cells stimulated with concanavalin A (Con A), phytohemagglutinin (PHA), or interferon-gamma (IFN-gamma) was observed. Green and black tea extracts displayed similar immunomodulatory properties in our in vitro system, whereas C. latifolium (L.) extracts seemed to be more effective in reducing neopterin formation in stimulated cells.

Iron chelation therapy of Plasmodium falciparum infection alleviates the clinical course of cerebral malaria in children. This study assessed the underlying mechanisms of this therapy. Cytokine stimulation of human (intestinal cell line DLD-1) or murine cells (murine macrophage cell line RAW 264.7) resulted in increased nitric oxide (NO) formation and decreased survival of plasmodia within cocultured human erythrocytes. The addition of desferrioxamine (DFO) before cytokine treatment increased both NO formation and parasite killing but had no effect in the presence of the inhibitor of NO formation, L-N6-(1-iminoethyl)-lysine. Moreover, peroxynitrite, which is formed after chemical reaction of NO with superoxide, appears to be the principal effector molecule for macrophage-mediated cytotoxicity toward P. falciparum, and interferon-gamma is a major regulatory cytokine for this process. The effect of DFO on the clearance of plasmodia appears to be due to enhanced generation of NO, rather than to limitation of iron availability to the parasite.

Mononuclear phagocytes, which include circulating blood monocytes and differentiated tissue macrophages, are believed to play a central role in the sexual transmission of HIV infection. The ability of HIV to productively infect these cells may be influenced by action of exogenous or host-derived substances at the site of viral entry. Given the potent capacities of inflammatory mediators to stimulate anaphylatoxic and immunomodulatory functions in mucosa, the effects of complement-derived anaphylatoxins on the susceptibility of monocytes and monocyte-derived macrophages (MDM) to HIV-1 infection were examined. In our in vitro system, the susceptibility to infection was up to 40 times increased in MDM that had been exposed to C5a or C5a(desArg), but not to C3a or C3a(desArg), for 2 days before adding of virus. By contrast, the treatment with complement anaphylatoxins did not affect HIV replication in fresh monocytes. Stimulatory effect of C5a and its desArg derivative on HIV infection correlated with the increase of TNF-alpha and IL-6 secretion from MDM. All these functional effects of C5a and C5a(desArg) were reversible by treatment of cells with the mAb that functionally blocks C5aR. Taken together, these results indicate that C5a and C5a(desArg) may increase the susceptibility of MDM to HIV infection through stimulation of TNF-alpha and IL-6 secretion from these cells.

A method was established to measure tryptophan and kynurenine in serum simultaneously. Tryptophan is converted to kynurenine by the action of the enzyme indoleamine 2,3-dioxygenase induced by interferon-gamma (IFN-gamma). Since IFN-gamma is a Th1-cell derived cytokine, an increased tryptophan degradation rate via the kynurenine pathway can be found when the cellular immune system is activated as it is, e.g., in viral infections or in autoimmune diseases. Thus, the ratio kynurenine per tryptophan provides a possibility to estimate IFN-gamma activity in vivo and furthermore reflects the degree of immune activation. The HPLC method requires 100 microL serum. Protein is removed by trichloroacetic acid. An external albumin-based calibrator is applied, and analysis is referred to an internal standard, 3-nitro-L-tyrosine. Kynurenine and nitrotyrosine are detected via UV absorbance at 360 nm wavelength, and tryptophan is detected via its natural fluorescence at 285 nm extinction and 365 nm emission. Representative normal values of kynurenine and tryptophan were measured in the sera of 49 healthy blood donors.