Showing papers on "Neopterin published in 2001"

Neopterin measurement in clinical diagnosis

Abstract: Neopterin is a marker associated with cell-mediated immunity. It is produced in monocytes/macrophages primarily upon stimulation with interferon-gamma. Due to its chemical structure, neopterin belongs to the class of pteridines. It is excreted in an unchanged form via the kidneys. Serum levels above 10 nmol/L are regarded as elevated. The levels of neopterin in body fluids are elevated in infections, autoimmune diseases, malignancies, allograft rejection, cardiac and renal failure, coronary artery disease and myocardial infarction. Neopterin measurements not only provide an insight into the present state of cell-mediated immune response but also allow monitoring and prognosis of disease progression.

Chemokines CXCL10 and CCL2: differential involvement in intrathecal inflammation in multiple sclerosis

Abstract: Studies of chemokines in cerebrospinal fluid (CSF) of patients with active multiple sclerosis (MS) have indicated that specific chemokines may have important roles in disease pathogenesis. We previously reported that CSF concentrations of CXCL10 (previously known as IP-10) were elevated in MS patients in relapse, whilst levels of CCL2 (MCP-1) were reduced. Here, we report a serial analysis of CSF CXCL10 and CCL2 concentrations in 22 patients with attacks of MS or acute optic neuritis (ON) treated with methylprednisolone, and 26 patients treated with placebo in two randomized controlled trials. Chemokine concentrations were measured by enzyme linked immunosorbent assay (ELISA) in CSF obtained at baseline and after 3 weeks, and were compared with other measures of intrathecal inflammation. At baseline CSF concentrations of CCL2 were significantly lower in the patient group than in controls. The levels of CXCL10 were higher in the patient group than in controls but two outliers in the control group also had high CSF concentrations of CXCL10. The CSF concentrations of CXCL10 did not change over time or after treatment. The CSF concentration of CXCL10 was positively correlated with the CSF leukocyte count, the CSF concentration of neopterin, matrix metalloproteinase (MMP)-9, and intrathecal IgG and IgM synthesis. The concentration of CCL2 increased between baseline for 3 weeks in both groups, more distinctly so in patients treated with methylprednisolone. CCL2 correlated negatively with MMP-9 and IgG synthesis levels. CXCL10 may be involved in the maintenance of intrathecal inflammation whereas CCL2 correlates negatively with measures of inflammation, suggesting differential involvement of CXCL10 and CCL2 in CNS inflammation.

Is hyperhomocysteinemia due to the oxidative depletion of folate rather than to insufficient dietary intake

Abstract: Hyperhomocysteinemia is considered as a risk factor for cardiovascular diseases. Usually, an inverse relationship exists between homocysteine and folate levels, and supplementation with folate lowers homocysteine concentrations in patients. Therefore, hyperhomocysteinemia is mainly ascribed to the insufficient dietary intake of folate. Hyperhomocysteinemia has also been observed in infections and inflammatory diseases. Oxidative stress appears to be involved in the pathogenesis of these disorders, and associations have been found between homocysteine and e.g., neopterin concentration. Increased neopterin concentration indicates immune system activation and also allows an estimate of thus elicited oxidative stress. It may be relevant that the active cofactor, tetrahydrofolate, is very susceptible to oxidation. Immunologically induced oxidative stress could lead to folate depletion resulting in hyperhomocysteinemia. Thus, hyperhomocysteinemia in patients can be considered as an indirect consequence of hyperconsumption of antioxidant vitamins during prolonged states of immune activation.

Blunted erythropoietic response to anemia in multiply traumatized patients.

Abstract: Objectives To assess the relations between anemia, serum erythropoietin (EPO), iron status, and inflammatory mediators in multiply traumatized patients. Design Prospective observational study. Setting Intensive care unit. Patients Twenty-three patients suffering from severe trauma (injury severity score > or =30). Interventions None. Measurements and main results Blood samples were collected within 12 hrs after the accident (day 1) and in the morning on days 2, 4, 6, and 9 to determine blood cell status, serum EPO, tumor necrosis factor-alpha (TNF-alpha), soluble tumor necrosis factor-receptor I (sTNF-rI), interleukin-1 receptor antagonist (IL1-ra), interleukin-6 (IL-6), neopterin, and iron status, respectively. Hemoglobin concentration was low at admission (mean, 10.0 g/dL; range, 6.8-12.9 g/dL) and did not increase during the observation time. Serum EPO concentration was 49.8 U/L (mean value) on day 1 and did not show significant increases thereafter. No correlation was found between EPO and hemoglobin concentrations. TNF-alpha remained within the normal range. sTNF-rI was high at admission and increased further. IL1-ra was above the normal range. IL-6 was very high at admission and did not decrease thereafter. The initial neopterin concentration was normal, but increased until day 9. Serum iron was significantly decreased on day 2 posttrauma and remained low during the study. Serum ferritin increased steadily from day 2, reaching its maximum on day 9. In contrast, concentrations of transferrin were low from admission onward. Conclusions Multiply traumatized patients exhibit an inadequate EPO response to low hemoglobin concentrations. Thus, anemia in severe trauma is the result of a complex network of bleeding, blunted EPO response to low hemoglobin concentrations, inflammatory mediators, and a hypoferremic state.

Diagnosis of Dopa-responsive Dystonia and Other Tetrahydrobiopterin Disorders by the Study of Biopterin Metabolism in Fibroblasts

Abstract: Background: Dopa-responsive dystonia (DRD) and tetrahydrobiopterin (BH4) defects are inherited disorders characterized by monoamine neurotransmitter deficiency with decreased activity of one of the BH4-metabolizing enzymes. The aim of the study was to determine the utility of cultured skin fibroblasts for the diagnosis of these diseases. Methods: Neopterin and biopterin production and GTP cyclohydrolase I (GTPCH) activity were measured in cytokine-stimulated fibroblasts; 6-pyruvoyltetrahydropterin synthase (PTPS), sepiapterin reductase (SR), and dihydropteridine reductase (DHPR) activities were measured in unstimulated fibroblasts. We examined 8 patients with DRD, 3 with autosomal recessive GTPCH deficiency, 7 with PTPS deficiency, 3 with DHPR deficiency, and 49 controls (35 fibroblast and 14 amniocyte samples). Results: Fibroblasts from patients with DRD and autosomal recessive GTPCH deficiency showed reduced GTPCH activity (15.4% and 30.7% of normal activity, respectively) compared with controls ( P <0.001). Neopterin production was very low and biopterin production was reduced in both disorders. PTPS- and DHPR-deficient cells showed no enzyme activities; in PTPS deficiency the pattern of pterin production was typical (neopterin, 334–734 pmol/mg; controls, 18–98 pmol/mg; biopterin, 0 pmol/mg; controls, 154–303 pmol/mg). Reference values of all enzyme activities and pterin production were measured in fibroblasts and also in amniocytes for prenatal diagnosis. Conclusions: Cultured skin fibroblasts are a useful tool in the diagnosis of BH4 deficiencies. Intracellular neopterin and biopterin concentrations and GTPCH activity in cytokine-stimulated fibroblasts are particularly helpful in diagnosing patients with DRD.

Serum inflammatory markers and clinical/MRI markers of disease progression in multiple sclerosis.

Abstract: The aim of this study was to assess whether mean serum levels of inflammatory markers when measured serially correlate with disease progression or putative MRI markers of axonal loss in a cohort of well-characterised multiple sclerosis (MS) patients. Serial serum levels of soluble vascular cell adhesion molecule-1 (sVCAM-1), soluble intercellular adhesion molecule-1 (sICAM-1), nitric oxide metabolites nitrate and nitrite (NOx), C-reactive protein (CRP), neopterin and tumour necrosis factor alpha (TNF-alpha) were measured in 29 MS patients, 13 with a relapsing remitting (RR) and 16 with a secondary progressive (SP) course, who were participating in a phase II clinical trial of anti-CD4 therapy. Short-term whole blood stimulated TNF-alpha production was also measured. Patients were studied 12 times over an 18-month period. MRI variables included the number and volume of Gd-enhancing lesions and the change in T2-hyperintense, T1-hypointense lesions and cerebral volume between the baseline and exit studies. Disease progression required a sustained change in the EDSS. There was no correlation between mean levels of inflammatory markers over the study period and disease progression or changes in any of the MRI measures. However, mean sICAM-1 levels from the first 6 months of the study were higher in patients who progressed during the study than in those that did not (443 (SD439) vs. 235 (SD162) ng/mL, p=0.05). Mean levels of NOx were significantly higher in patients with RR MS than in patients with SP disease (59.1 micromol/L (SD 12.8) vs. 48.7 micromol/L (SD 11.9), p=0.02). Patients with either a single relapse or no relapse had significantly higher NOx levels than to patients with multiple relapses during the 18 month follow-up (59.0 micromol/L (SD 12.3) vs. 47.9 micromol/L (SD 12.0), p=0.02). The mean levels of the other inflammatory markers did not correlate with disease course or relapse-rate. Serum levels of many inflammatory markers do not correlate with short-term disease progression. Some of the data suggest that the effects of inflammation on disease progression are delayed. In addition raised levels of serum nitric oxide metabolites are associated with a lower number of clinical relapses and a non-progressive disease course. These findings, although preliminary, pose interesting questions on the role of nitric oxide in the pathogenesis of MS. Inducible NO production in the early stages of the disease may be beneficial.

Fatigue is not associated with raised inflammatory markers in multiple sclerosis

Abstract: Background: The pathogenesis of fatigue in patients with MS is poorly understood. Objective: To test the hypothesis that fatigue in MS is related to inflammatory disease activity as measured by systemic markers of inflammation. Methods: Fatigue as assessed by the Fatigue Questionnaire Scale (FQS) and Krupp’s Fatigue Severity Scale (KFSS) was correlated with several inflammatory markers in 38 patients with MS (16 relapsing–remitting [RR; 7 of whom had benign MS), 9 secondary progressive [SP], 13 primary progressive [PP]). The markers included daily urinary neopterin excretion, a marker of interferon-γ-activated macrophage activity, and serum C-reactive protein (CRP) and soluble intercellular adhesion molecule-1 (sICAM-1) levels. Urinary neopterin excretion was measured daily for 2 weeks. Results: No correlation was found between urinary neopterin excretion, CRP, or sICAM-1 and the fatigue scores. However, patients with a raised serum CRP level had higher KFSS, but not FQS, scores than patients with normal CRP levels (KFSS, 50 ± 8 vs 41 ± 14, p = 0.05; FQS, 13 ± 4 vs 11 ± 5, p = NS). When assessed using the FQS, patients with RR and SP MS were more fatigued than patients with PP MS (RR = 12.5 [4 to 23] vs SP = 13 [8 to 18] vs PP = 9 [7 to 14], p = 0.02). The patients with benign MS were as fatigued as patients with nonbenign disease. Conclusion: The pathogenesis of fatigue in MS is complex and does not appear to be directly related to systemic markers of inflammatory disease activity. Interestingly, patients with PP MS were less fatigued than patients with RR disease.

Markers for Cell-Mediated Immune Response Are Elevated in Cerebrospinal Fluid and Serum After Severe Traumatic Brain Injury in Humans

Abstract: The brain is believed to be an immunologically privileged organ, sheltered from the systemic immunological defense by the blood-brain barrier (BBB). However, there is increasing evidence for a marked inflammatory response in the brain after traumatic brain injury (TBI). Markers for cellular immune activation, neopterin, β2-microglobulin (β2M), and soluble interleukin-2 receptor (sIL-2R), were measured for up to 3 weeks in cerebrospinal fluid (CSF) and serum of 41 patients with severe TBI in order to elucidate the time course and the origin of the cellular immune response following TBI. Neopterin gradually increased during the first posttraumatic week in both CSF and serum. Concentrations in CSF were generally higher than in serum, suggesting intrathecal release of this marker. β2M showed similar kinetics but with higher serum than CSF concentrations. Nonetheless, intrathecal release as assessed by the β2M index could be postulated for most of the patients. The mean levels of sIL-2R in both CSF and serum w...

Increased blood-brain barrier permeability in neuro-asymptomatic HIV-1-infected individuals--correlation with cerebrospinal fluid HIV-1 RNA and neopterin levels.

Abstract: The objective of this study was to assess the frequency of blood-brain barrier (BBB) impairment, as measured by the albumin ratio, in neuro-asymptomatic HIV-1-infected individuals without antiretroviral treatment and the correlation between BBB disruption and intrathecal immune activation and HIV-1 RNA levels. Serum and cerebrospinal fluid (CSF) albumin, neopterin, and HIV-1 RNA levels were analysed in 110 neuro-asymptomatic HIV-1-infected individuals at different stages of disease; 63 classified as CDC A, 25 as CDC B, and 22 as CDC C. Increased BBB permeability was found in 17 of 110 (15%) of HIV-1-infected individuals. This proportion was sustained throughout the CDC stages. The albumin ratio was correlated with the CSF neopterin levels (rs = 0.36, P < 0.001), the serum neopterin levels (rs = 0.37, P < 0.001), and the CSF HIV-1 RNA levels (rs = 0.26, P < 0.01), but not with the plasma HIV-1 RNA levels. The correlations between the albumin ratio and the CSF and serum neopterin concentrations and the CSF HIV-1 RNA levels indicate that immune activation and, possibly, intrathecal HIV-1 virus replication are important factors associated with increased BBB permeability in HIV-1 infection.

Serum IFN neutralizing antibodies and neopterin levels in a cross-section of MS patients.

Abstract: Objective: To determine levels of serum interferon beta (IFNβ) neutralizing antibody (NAb) and neopterin—an IFN biologic response marker—in patients with MS treated with Betaseron or Avonex. Background: Controversy exists over the relative immunogenicity of IFNβ-1a and IFNβ-1b and the reasons for any such difference. To determine the role of patient profile and test methodology in IFNβ, NAb levels need to be measured blindly and simultaneously in a predefined closely matched MS patient cohort. Methods: Serum NAb and neopterin levels were measured in closely matched patients on Avonex (n = 98) or Betaseron (n = 64). NAb were determined by Athena Diagnostics and serum neopterin levels by Covance Laboratories using a competitive binding radioimmunoassay. Results: More patients taking Betaseron (22%) than Avonex (7%) had elevated titers of NAb ( p = 0.008). Mean serum neopterin levels were lower in patients with high as compared to low NAb titers ( p = 0.0002). No difference in mean neopterin levels was found comparing the total Betaseron group to the Avonex group; however, in the subset of patients with low NAb titers, mean neopterin levels were higher in the Betaseron than in the Avonex group ( p = 0.027). A random cross-sectional sampling of patients on Avonex showed a decrease in neopterin levels over time between weekly doses. Conclusion: NAb are more commonly found with Betaseron than Avonex. More studies are needed to determine the correlation among serum neopterin levels, other biologic response markers, NAb, and disease activity in patients with MS being treated with IFNβ.

Feeding mode, intestinal permeability, and neopterin excretion: a longitudinal study in infants of HIV-infected South African women.

Abstract: Exclusive breast feeding has been associated with a lower rate of mother-to-child HIV transmission than breast feeding plus other foods. To obtain further information on biologic outcomes of different feeding modes, we examined 272 infants of HIV-infected South African women at ages 1, 6, and 14 weeks. At each visit information about infant diet and morbidity was collected and infants underwent a lactulose/mannitol dual sugar intestinal permeability test. In a subset of infants, urinary neopterin excretion was measured as an indicator of immune system activation. Infants who had themselves become HIV-infected by 14 weeks had higher ( p <.01) intestinal permeability at 6 and 14 weeks and slightly (.05 < p <.1) higher neopterin excretion at all times than uninfected infants. At 1 week infants given no breast milk had higher ( p <.05) intestinal permeability than infants given breast milk exclusively or with other foods. Intestinal permeability in infants fed breast milk plus other foods was never increased relative to that of exclusively breastfed infants. Feeding mode had no effect on neopterin excretion. Thus, infant HIV infection induces changes in gut permeability and possibly immune system activation before clinical symptoms become apparent. The effects of feeding mode on infant intestinal permeability or urinary neopterin excretion do not explain a possible protective effect of exclusive breast feeding on mother-to-child transmission of HIV.

Clinical utility of selected disease activity markers in patients with systemic lupus erythematosus.

Abstract: The objective of this study was to assess the utility of measurement of thrombomodulin, antinucleosome antibodies, sVCAM-1, sICAM-1, neopterin, fas ligand, IL-10 and sIL-2R in patients with systemic lupus erythematosus (SLE) and to compare them with traditional markers of SLE activity (anti-dsDNA antibodies, C3, C4) and the ECLAM index of disease activity. The measurement was performed over a 6-month period at three consecutive time points after 3 months in each of the 52 patients with SLE. Anti-dsDNA antibodies, thrombomodulin, antinucleosome antibodies, sVCAM-1m sICAM-1, neopterin, fas ligand, IL-10 and sIL-2R were tested by ELISA technique, while C3, C4 components of complement were tested by nephelometry. Fas ligand and IL-10 did not correlate with the ECLAM index. The rest of the markers showed significant correlation with the disease activity index. Thrombomodulin and anti-dsDNA antibodies reflect in the best way the changing trend in disease activity. Antinucleosome antibodies seem to be a promising marker useful in early diagnosis. Soluble VCAM-1, sICAM-1, neopterin and sIL-2R are interesting molecules with a role in disease pathogenesis, but their practical utility is limited.

CD4+ T-lymphocytopenia and systemic immune activation in patients with primary and secondary liver tumours.

Abstract: Using flow cytometry, we evaluated peripheral blood leucocyte subsets in 84 patients with primary and secondary liver cancer. The patients had significantly lower absolute (659+/-386 vs. 906+/-360 cells per microl, p=0.004) numbers of CD3+ CD4+, relative (9+/-5 vs. 12+/-4%, p=0.02) and absolute (154+/-115 vs. 221+/-83 cells per microl, p=0.02) numbers of CD8+ CD28+, absolute numbers of CD3+ and relative and absolute numbers of CD19+. Relative and absolute numbers of CD3+ DR+, CD3+ CD69+ and CD14+ CD16+ cells were significantly elevated in patients compared to controls. The phenotype was similar in 54 patients exposed to chemotherapy compared to 30 untreated patients. Urinary neopterin, a marker of systemic immune activation, was significantly higher in patients with liver tumours compared to controls. A negative correlation was observed between urinary neopterin and the absolute numbers of CD3+ CD4+ (Spearman rank correlation coefficient, rs = -0.54, p<0.0025) and CD19+ (rs = -0.49, p<0.01) in untreated patients. We conclude that, independently of prior chemotherapy, patients with liver present with markedly decreased numbers of CD3+ CD4+ lymphocytes as well as with other abnormalities of peripheral blood leukocyte phenotype. Similar to patients with human immunodeficiency virus infection, the decrease in CD3+ CD4+ lymphocytes is associated with systemic immune activation.

Serum neopterin and activity of coronary artery disease.

Abstract: Inflammation plays a key role in the pathogenesis of atherosclerosis. In coronary artery disease (CAD), the release of different cytokines activates cellular defense. Infiltration of neutrophils and monocytes/macrophages is detected in the vessel wall in patients with CAD. Macrophages activated by interferon gamma synthesize metalloproteinases and neopterin, a pteridin derivative that has been used as an immune marker. To determine neopterin levels in patients with chronic CAD and acute coronary syndromes, the authors studied 116 subjects: 1) 25 consecutive patients (18 men, 7 women; mean age 68.5 +/- 14.3, range 40 to 86 years) with unstable angina or acute myocardial infarction (AMI); 2) 31 consecutive patients (25 men, 6 women; mean age 64 +/- 12.7, range 47 to 83 years) with signs and symptoms of clinically stable CAD; and 3) 60 consecutive healthy blood donors (38 men, 22 women; mean age 54.4 +/- 6.23, range 44 to 66 years). Neopterin levels were determined with a commercially available enzyme-linked immunosorbent assay method. In patients with unstable angina and AMI before thrombolytic therapy, neopterin levels were not significantly different from levels in patients with stable CAD (5.97 +/- 1.4 versus 7.84 +/- 3.56 nmol/L; P = 0.15). Neopterin levels in both patient groups did not significantly differ from levels in control subjects (P > 0.1). Neopterin levels in patients with unstable angina and AMI were measured four times during a 72-hour period. The lowest value was observed at baseline and differed significantly from values after 72 hours (P < 0.001; 5.97 +/- 1.4 versus 9.25 +/- 2.36). Neopterin levels after 72 hours were also significantly different from initial values in patients with stable CAD (P < 0.001). There was no correlation between neopterin and creatine kinase (CK) levels, CK-MB isoenzyme, or troponin I as markers for the extent of the myocardial injury during the observation period. These data do not support previous reports of higher baseline levels of serum neopterin in patients with unstable angina or AMI compared with patients with chronic, stable CAD and healthy controls. Neopterin as a marker of macrophage activation is significantly increased in patients with AMI and unstable angina shortly after the onset of symptoms (after a period of 72 hours), supporting the hypothesis of monocyte and macrophage activation in patients with an acute coronary syndrome or AMI.

Neopterin production and tryptophan degradation in humans infected by Streptococcus pyogenes.

Abstract: Streptococcus pyogenes may cause tonsillitis, scarlet fever and so-called “streptococcal toxic shock-like syndrome” (STSS). These streptococci produce exotoxins which are implicated as superantigens in the pathogenesis of STSS and scarlet fever. Using human peripheral blood-derived mononuclear cells in vitro, such toxins were shown to induce neopterin production and degradation of the amino acid tryptophan to metabolites such as kynurenine by activating indoleamine (2,3)-dioxygenase via interferon-γ. We investigated the sera of seven patients with streptococcal tonsillitis and of four patients with STSS. Those with STSS showed higher serum neopterin concentrations (median: 152 nmol/l; 95th percentile in healthy controls: 8.7 nmol/l) than those with tonsillitis (median: 12 nmol/l). Similarly, kynurenine to tryptophan ratios were increased in tonsillitis and extremely high in patients with STSS. Highly increased neopterin production and tryptophan degradation in patients with STSS suggest an association between a high degree of T cell activation and the severity of the disease manifestation.

Elevated serum levels of soluble interleukin‐2 receptor, neopterin and β‐2‐microglobulin in idiopathic dilated cardiomyopathy: relation to disease severity and autoimmune pathogenesis

Abstract: Background: It has not been assessed whether high levels of soluble interleukin 2 receptor (sIL-2R), neopterin and β-2 microglobulin in idiopathic dilated cardiomyopathy reflect heart failure severity and/or an active autoimmune process. The aim of this study was to relate serum levels of these markers to clinical and autoimmune features. Methods: We studied 60 patients with idiopathic dilated cardiomyopathy, 67 controls with ischemic heart failure and 34 normals. Results: Abnormal levels of sIL-2R, but not of neopterin and β-2 microglobulin, were more frequent in idiopathic dilated cardiomyopathy than in ischemic patients (35% vs. 16%; P - 0.02) or in normals (35% vs. 12%, P - 0.01); mean sIL-2R levels were, however, similar in idiopathic dilated cardiomyopathy and ischemic heart failure (842 ± 75 vs. 762 ± 93 U/ml, P - NS). In idiopathic dilated cardiomyopathy abnormal levels of sIL-2R were associated with lower peak oxygen consumption (P - 0.008), higher neopterin and HLA class II expression in the myocardium (P - 0.02), but were unrelated to cardiac autoantibody status or titer. In addition, abnormal levels of neopterin were associated with adverse prognosis and higher β-2 microglobulin; abnormal levels of β-2 microglobulin with lower echocardiographic percent fractional shortening, higher sIL-2R and higher neopterin. Conclusions: There is no convincing evidence that abnormal sIL-2R, neopterin and/or β-2 microglobulin are disease-specific markers of idiopathic dilated cardiomyopathy. The lack of association with cardiac autoantibodies suggests that these abnormalities are mainly related to heart failure severity rather than autoimmune pathogenesis. In keeping with this view, high levels of sIL-2R, neopterin and/or β-2 microglobulin identified a subset of idiopathic dilated cardiomyopathy patients with advanced disease and poor prognosis.

The role of immune activation in endotoxin-induced atherogenesis.

Abstract: Some infectious agents may contribute to atherosclerosis by maintaining a heightened state of inflammatory response. Although the risk for atherosclerosis was associated with elevated plasma levels of endotoxin, it is difficult to firmly establish what place endotoxin assumes in the etiology of this disease. As the ability for endotoxin to promote disease may depend on its ability to initiate an inflammatory response, it may be controlled by additional regulatory factors. We measured plasma levels of endotoxin and serum levels of neopterin and soluble interleukin-2 receptor in a random population of 402 men and women, 50-79 years old at the 1990 baseline evaluation (Bruneck Study). End point of the prospective survey was incident (early) atherosclerosis in the carotid arteries as assessed with duplex ultrasound. Subjects with high endotoxin levels (90th percentile) in combination with low neopterin or soluble interleukin-2 receptor levels (below median) did not differ from those with low endotoxin in their risk of incident atherosclerosis. The risk associated with high endotoxin, however, was markedly elevated in subjects with high (above median) neopterin or soluble interleukin-2 receptor levels. The study provides epidemiological evidence that the atherogenic potential of endotoxemia is affected by concomitant immune activation.

Distributional and functional alterations of immunocompetent peripheral blood lymphocytes in patients with chronic pancreatitis.

Abstract: Chronic pancreatitis is characterized by a painful, progressive destruction of the pancreatic gland, with increasing loss of exocrine and endocrine function. Approximately 30% of patients with chronic pancreatitis develop pancreatic head enlargement; this can lead to complications such as obstruction of the bile duct, pancreatic duct, and duodenum or compression of the portal vein or mesenteric artery. These complications represent an indication for surgical treatment. 1–3 Besides removal of the local complication, the resection of the enlarged pancreatic head offers several other advantages, because the inflamed pancreatic head is suspected to be the element that supports chronic pancreatitis. 4 However, recent studies have provided evidence that patients with chronic pancreatitis have up to a 10-fold increased risk for pancreatic carcinoma. 5 In recent studies, several groups have investigated the infiltrating lymphocytes in tissue specimens from patients with chronic pancreatitis. 6–9 All investigators found an increased number of infiltrating lymphocytes, and most groups support the hypothesis of involvement of cell-mediated cytotoxicity in the pathogenesis of chronic pancreatitis, as shown by increased frequencies of perforin-expressing cells 10 or CD8+CD103+ T cells 6 in chronic pancreatitis. In contrast to this hypothesis of cell-mediated toxicity, Emmrich et al 8 found a more common inflammatory type of infiltrating lymphocytes in chronic pancreatitis tissue specimens. With regard to alterations of the systemic immune function, few data are available. In previous studies we have investigated serum levels of immunologic parameters such as neopterin, sIL-2Rα, sCD44s, and sCD44v6 in chronic pancreatitis. Interestingly, we found reduced serum levels of sCD44v6, whereas serum levels of sIL-2Rα and neopterin were not altered in patients with chronic pancreatitis. 11 The aim of our study was to investigate the distribution and proliferative capacity of phytohemagglutinin (PHA), concavalin A (ConA), pokeweed mitogen (PWM), and anti-CD3 antibodies of peripheral blood lymphocytes in patients with chronic pancreatitis compared with a gender- and age-matched group of healthy volunteers. We also compared these data in 16 patients with chronic pancreatitis before and 1 year after resection of the pancreatic head to evaluate whether resection of the inflamed pancreatic head leads to a return to normal of the distribution and function of peripheral blood lymphocytes.

Inflammatory BAL-fluid and serum parameters in HLA DR17 positive vs. DR17 negative patients with pulmonary sarcoidosis.

Abstract: BACKGROUND AND AIM OF THE WORK We have previously shown that HLA DR17 is associated with a favourable prognosis in Scandinavian sarcoidosis patients. By studying inflammatory parameters in these patients we wished to increase the knowledge of the involved mechanisms that may underlie good prognosis. METHODS BAL was performed in 118 sarcoidosis patients, 67 HLA DR17 positive and 51 DR17 negative. BAL cell profile was analysed. The CD4 and CD8 lymphocyte phenotype was determined by flow cytometry. BALF-albumin, BALF-fibronectin (FN) and BALF-procollagen III aminoterminal peptide (PIIINP) were analysed by nephelometric, ELISA and RIA methods respectively. Neopterin and soluble interleukin-2 receptor (sIL2R) in serum were also determined by ELISA. Angiotensin-converting enzyme (ACE) in serum was analysed by spectrophotometry. RESULTS In DR17+ patients, BAL lymphocytes and eosinophils were significantly decreased (median 30.2 and 0.19 x10(6)/L) compared to DR17- (median 50.2 and 0.64 x 10(6)/L respectively). However the BAL CD4/CD8 ratio was increased in the DR17+ group compared to DR17- (6.2 vs. 4.3). BALF-albumin, FN and PIIINP did not differ between the groups. Serum parameters were decreased in DR17+ patients compared to DR17- (ACE median 28.7 vs. 35.1 U/L, neopterin 9.1 vs. 12.7 nmol/L and sIL2R 296 vs. 605 U/L). CONCLUSIONS The study revealed that an increased BAL CD4/CD8 ratio, in contrast to BAL lymphocytosis, was seen in a subgroup of sarcoidosis patients earlier associated with a favourable prognosis. Our results support that an increased BAL CD4/CD8 ratio is a favourable parameter in sarcoidosis. The lower ACE activity in the DR 17+ group indicates a reduced granuloma burden in this patient subgroup.

Immunological response to interferon-gamma priming prior to interferon-alpha treatment in refractory chronic hepatitis C in relation to viral clearance.

Abstract: The aim of this study was to clarify the immunological and virological responses to pre-administration of interferon-gamma prior to initiation of interferon-alpha treatment in patients with refractory chronic hepatitis C. Twenty-two nonresponders to 6-months of IFN-alpha treatment were enrolled. The hepatitis C virus (HCV) genotype was Ib in all. Natural IFN-gamma (1 MIU/day) was administered daily for 14 days followed by natural IFN-alpha (5 MIU/day) daily for 14 days and then three times weekly for 22 weeks. Serum immunological parameters (IL-10, neopterin, BMG, sCD8, sCD4, IL-6, IL-12) were measured as were the levels of several cytokines (IFN-gamma, TNF-alpha, IL-2, IL-4, IL-5, IL-6, IL-10). Three patients dropped out; two because of the occurrence of other diseases and one because of an adverse effect. At the end of the period of IFN-alpha treatment, HCV-RNA had become negative in six of 19 patients (end-of treatment response; ETR). Six months after the completion of IFN administration, a virological sustained response (SR) was seen in two of 19 patients. The mean serum levels of IL-10 were significantly decreased 6 weeks after the start of treatment. Other immunological parameter levels increased significantly during the period of IFN-gamma administration, and tended to return to the pretreatment level after the start of IFN-alpha administration. Univariate logistic regression analysis showed that the initial change in the levels of these parameters or the change in the ratios of Th1/Th2 parameter levels are useful factors indicative of the end of the treatment response. These findings suggest that priming with IFN-gamma prior to the initiation of IFN-alpha treatment in patients with refractory chronic hepatitis C can modulate the host immune response and this might contribute to viral clearance.