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PubMed2000

Simple dipstick assay for semi-quantitative detection of neopterin in sera.

Neopterin, a low-molecular-mass pteridine produced by macrophages, is closely associated with activation of the cellular immune system. Neopterin biosynthesis during inflammatory disease is primarily derived from interferon-activated monocytes/macrophages and neopterin concentrations may be significantly increased in a particular disease state compared to controls. A follow-up of serum neopterin concentrations during the course of an infectious disease could be useful for measuring the activity of the disease and the influence of treatment. We have developed a simple dipstick assay for the semi-quantitative detection of the neopterin concentration in the serum of patients during the course of an infectious disease. Assay performance was comparable to an ELISA, but there is no requirement for specialised equipment.

Biological Assay↗
PubMed1997

Interleukin-6 and neopterin levels in serum of patients with preterm labour with and without infection.

We estimated the levels of interleukin 6 (IL-6) and neopterin, in serum of twelve nonpregnant (group A) and 28 pregnant women between 28-36 weeks of pregnancy. Group B consisted of eight patients with uncomplicated pregnancy, group C consisted of thirteen pregnant women with clinical signs of preterm labour and without laboratory markers of infection and group D consisted of seven pregnant women with signs of preterm labour and with laboratory markers of infection. The levels of IL-6 and neopterin were significantly higher in group D compared to groups A, B and C (p < 0.05). Similarly, the level of C-reactive protein (CRP) and total white blood cell count (the laboratory markers of infection) were significantly higher in group D than in groups A, B and C. Total white blood cell count was significantly lower in group A than in group B and D (p < 0.05). There were no significant differences in values of IL-6, neopterin and CRP between groups A, B and C (p > 0.05). In all groups, significant correlations were found between IL-6 and neopterin as well as total white blood cell count and CRP. Our results suggest that IL-6 and neopterin may be the markers of preterm labour caused by infection. On the other hand, cell-mediated immune response may be involved in the mechanisms of preterm labour.

Adult↗
PubMed2003

Association of increased neopterin production with decreased humoral immunity in the elderly.

Tetanus toxoid (TT) antibodies of 447 adult persons aged 27-69 years were investigated and analyzed in relationship with the time span since the last vaccination against tetanus as well as the serum concentration of neopterin. Neopterin is a pteridine, which is produced by monocytes/macrophages upon stimulation with the type 1 T cell-derived cytokine interferon-gamma. There was an inverse correlation between serum neopterin and TT antibody concentrations (Spearman's rank correlation coefficient: r(s)=-0.259; p<0.0001) which was even stronger when persons with neopterin concentrations and TT antibodies below the third quartile of the study population were excluded (residual group: n=210; r(s)=-0.718; p<0.0001). The study demonstrates that an immunoregulatory shift towards type 1 immunity as indicated by higher neopterin concentrations coincides with lower TT antibody concentrations in the elderly.

Adult↗
PubMed1998

Increased serum neopterin levels in acutely ill and recovered schizophrenic patients.

Twenty-nine in-patients with acute schizophrenia were examined to assess serum neopterin levels by ELISA at two points of time: during the state of acute symptoms and after clinical recovery at the point of discharge (at an interval of 30.84 +/- 15.22 days). Patients showed significantly higher levels of neopterin than controls. Moreover, the neopterin levels were significantly higher in patients after clinical improvement than in acutely ill patients. Neopterin levels in patients after clinical recovery were negatively correlated to scores of psychopathological symptoms, and positively to neuroleptic medication at the acute stage of the disease. The increase of serum neopterin during treatment of schizophrenia may reflect an up-regulation of dopamine turnover, rather than immunological activity.

Acute Disease↗
PubMed1998

Vitamin A status does not influence neopterin production during illness or health in South African children.

Excessive interferon-gamma (IFN-gamma) production appears to be a primary immunological lesion in vitamin A-deficient experimental animals but comparable data from humans is lacking. We investigated IFN-gamma production in South African children by measurement of urinary excretion of neopterin, a product of IFN-gamma-activated monocytes or macrophages. Preschool children were examined during an acute inflammatory illness resulting from accidental ingestion of kerosene and they and a neighbourhood control child were examined 3 months later when well. Vitamin A status was assessed by the modified relative dose response (MRDR) test at 3 months and serum retinol and acute phase proteins were measured at both time points. Urinary neopterin was measured for forty cases in hospital, forty-six cases after recovery, and forty-one controls. Significantly increased neopterin excretion was seen following kerosene ingestion and in association with raised serum acute phase protein concentrations. There was no relationship between neopterin excretion at either time point and vitamin A status as assessed by MRDR test. Urinary neopterin was negatively correlated with serum retinol but no significant relationship was observed when acute phase protein concentrations were included in a multiple regression, suggesting the correlation was secondary to illness-induced changes in serum retinol. The results indicate that, contrary to what is observed in rodents under experimental conditions, poor vitamin A status is not associated with altered regulation of IFN-gamma production in children.

Acute Disease↗
PubMed1997

Early levels of CD4, neopterin, and beta 2-microglobulin indicate future disease progression.

Reduced CD4 T cell level and increased serum neopterin and beta 2-microglobulin levels, which reflect immunological activation and dysregulation, are three important markers of HIV disease. The aim in this study is to delineate more clearly the relation of activation to future CD4 values and disease progression. By analyzing a cohort of 198 seroconverters from the Multicenter AIDS Cohort Study with 9 years' follow-up, the dynamic changes and levels of these three markers and their interrelationships are explored. We observed that the levels of markers in the first year after seroconversion have a much stronger impact on the progression of the disease than the preseroconversion marker levels. The actual change during the year after seroconversion is not as important as the final level reached during that year. The early levels of markers after seroconversion appear to be good indicators of the subsequent course of disease as defined by CD4 level and slightly better than the quantitative changes following seroconversion or the changes in the period 1 to 2.5 years after seroconversion. To investigate the variation between subjects, the 198 seroconverters were stratified into three approximately equal-sized groups in 12 ways based on their pre- and postseroconversion levels and changes in the three markers. The group with the highest CD4 level within a year after seroconversion maintains the highest CD4 level 8 years after seroconversion. The group with the lowest level of neopterin or beta 2-microglobulin in this period has much higher future CD4 counts than the other two groups. The level of markers during the first year after seroconversion has a high predictive power for AIDS onset. Substantial differences in the hazards of AIDS are found between the groups with the highest and lowest CD4 count, neopterin, and beta 2-microglobulin following seroconversion. The three markers are generally correlated throughout the postseroconversion period but can provide distinct information. High current levels of neopterin or beta 2-microglobulin tend to be associated with low future CD4 count, while current levels of CD4 count have less association with future neopterin and beta 2-microglobulin levels.

Acquired Immunodeficiency Syndrome↗
PubMed1999

Modulation of neopterin formation and tryptophan degradation by Th1- and Th2-derived cytokines in human monocytic cells.

In order to examine the regulatory effects of major Th1-derived cytokines, such as IL-12, and Th2 cytokines, IL-4 and IL-10, on the formation of neopterin and degradation of tryptophan, two metabolic pathways induced by interferon-gamma (IFN-gamma) in human monocytes/macrophages, we investigated the human monocytic cell line THP-1, primary human macrophages, and peripheral blood mononuclear cells (PBMC). Neopterin formation and tryptophan degradation were induced similarly by IFN-gamma in all three cell types investigated, but the effects of interleukins were different between THP-1, primary macrophages and PBMC. In PBMC, but not in THP-1 cells and primary macrophages, IL-12 was found to be additive to the effects of IFN-gamma to superinduce neopterin formation and tryptophan degradation. IL-4 and IL-10 reduced the effects of IFN-gamma on monocytic cells, and both cytokines were additively antagonistic to IFN-gamma in PBMC and THP-1 cells. Finally, on preincubation, but not on addition of IL-12, the effects of IL-4 and IL-10 on PBMC could be abrogated, whereas no such effect was seen in THP-1 cells. The results show that IL-12 up-regulates neopterin formation and tryptophan degradation by inducing additional IFN-gamma production by Th1 cells, while a direct effect of IL-12 on monocytes/macrophages appears to be absent. Similarly, IL-4 and IL-10 inhibit neopterin production and tryptophan degradation in PBMC by down-regulating Th1-type cytokine production and possibly also via direct deactivation of IFN-gamma effects towards monocytes/macrophages. The results clearly show how Th1 cell-mediated immunity may be up- or down-regulated by endogenous cytokine production.

Cell Line↗
PubMedDate not supplied

[Neopterin determination in the screening for spongiosa donors].

HIV-1 and HIV-2 antibodies, erythrocyte sedimentation rate, leucocytes and additionally serum neopterin levels were measured in 100 potential spongiosa donors. HIV antibodies were negative in all patients, whereas in 24% neopterin levels were elevated (greater than 10 nmol/l). Enhanced neopterin production is related to activity in cell-mediated immune response. In further investigations of these patients we found in 29% infections, 38% tumor diseases and 13% autoimmune diseases, all being exclusion criteria for spongiosa transplantation. In 3 patients increased neopterin values were the only pathological screening parameters. The measurement of serum neopterin levels showed to be a helpful parameter for the selection of spongiosa donors.

Aged↗
PubMed2000

Serum neopterin as an objective marker of psoriatic disease activity.

Neopterin is a non-specific marker of the activation of cell-mediated immunity. Several studies have demonstrated the crucial role of CD4+ T cells in the pathogenesis of psoriasis. We have measured serum and urine neopterin levels and urine neopterin/creatinine ratios by radioimmunoassay in 24 patients with plaque-type psoriasis before and after a course of topical treatment with triamcinolone acetonide 0.1% and coal tar 4%. Results were compared with a group of 20 healthy, non-psoriatic volunteers. Serum neopterin levels were significantly elevated in the psoriatic group compared with the control group (p=0.001) and were significantly reduced after treatment (p=0.01). There was a correlation between pretreatment serum neopterin levels and psoriasis area and severity scores (PASI) (r=0.37, p=0.03) and also for pretreatment neopterin/creatinine ratios and PASI scores (r=0.45, p=0.01). These findings indicate that serum neopterin concentrations reflect disease activity in psoriasis.

Adult↗
PubMed1999

Increasing neopterin and decreasing endothelin-1 in plasma during insulin infusion in women.

Leukocyte-derived inflammatory mediators and endothelial production of vasoconstrictive factors, such as endothelin-1, and vasodilatory and platelet anti-aggregatory factors, such as nitric oxide (NO) and prostacyclin (PGI2), may have a role in the pathogenesis of atherosclerosis. In this study we evaluated whether insulin affects the monocyte-derived inflammatory mediator neopterin and endothelin- in plasma (p), and NO and PGI2 mediators cyclic 3'-5' guanosine monophosphate (cGMP) and cyclic 3'-5' adenosine monophosphate (cAMP) in platelets. P-neopterin was measured by enzyme linked immunosorbent assay (ELISA), and p-endothelin-1, intraplatelet cAMP and cGMP were measured by radioimmunoassay (RIA) before and after euglycaemic hyperinsulinaemic clamping in 51 healthy postmenopausal women aged 53-54 years. "Placebo clamping" with NaCl infusion was performed in a subgroup of 5/51 women. During euglycaemic hyperinsulinaemic clamping, p-endothelin-1 decreased (from 3.3+/-0.2 pg/ml to 2.4+/-0.2 pg/ml; p<0.01), whereas p-neopterin (from 5.0+/-1.1 nmol/l to 6.2+/-1.4 nmol/l; p<0.001) and both intraplatelet cGMP (from 0.61+/-0.03 to 0.68+/-0.03 pmol/10(9) platelets; p<0.05) and cAMP (from 4.00+/-0.14 to 4.76+/-0.20 pmol/10(9) platelets; p<0.001) increased. Increases in cGMP (from 0.79+/-0.05 to 1.07+/-0.15 pmol/10(9) platelets; p = 0.14) and cAMP (from 4.76+/-0.15 to 5.52+/-0.36 pmol/10(9) platelets; p = 0.08) also occurred during NaCl infusion, whereas neopterin and endothelin-1 values were unchanged. In conclusion, insulin administration was associated with decreasing p-endothelin-1 levels and increasing levels of p-neopterin and intraplatelet cyclic nucleotides in accordance with vasodilatation and monocyte activation.

Blood Platelets↗
PubMed1984

Immune response-associated production of neopterin. Release from macrophages primarily under control of interferon-gamma.

Neopterin, a compound derived from GTP, represents a precursor molecule of biopterin that is an essential cofactor in neurotransmitter synthesis. We have recently reported that in vivo as well as in vitro immune responses are accompanied by an increased release of neopterin and that this phenomenon can be used for the biochemical monitoring of diseases accompanied by hyperimmune stimulation. This article deals with the cellular origin and the control of this immune response-associated neopterin release in vitro. Using highly purified or monoclonal cellular reagents we demonstrate that macrophages (M phi) stimulated with supernatants from activated T cells release large amounts of neopterin into culture supernatants. Further experiments involving induction of neopterin release from M phi with various human recombinant interferons (IFNs) or neutralization of the effect of T cell supernatants with various monoclonal anti-IFN antibodies revealed immune IFN as the active principle. It thus appears that a metabolic pathway so far exclusively known in context with the generation of an essential cofactor of neurotransmitter-synthesis during immune responses is also activated in M phi under stringent control by immune IFN-like lymphokines.

Biopterins↗
PubMed1988

Enhanced serum levels of beta-2-microglobulin, neopterin, and interferon-gamma in patients treated with recombinant tumor necrosis factor-alpha.

The effect of different doses of recombinant human tumor necrosis factor-alpha (rTNF-alpha) on serum levels of neopterin, beta-2-microglobulin and interferon-gamma (IFN-gamma) was investigated in tumor patients. Twelve patients with advanced malignant disease were treated and received single doses of either 1, 10, or 100 micrograms/m2 rTNF-alpha on days 0 and 7. Neopterin, beta-2-microglobulin and IFN-gamma serum levels were measured from day -2 to day 12 of the study. Application of rTNF-alpha leads to a marked and dose-dependent increase of neopterin and beta-2-microglobulin levels; no rTNF-alpha-dependent changes were observed after 1 microgram/m2, and maximum increments were seen in patients receiving 100 micrograms/m2. Serum levels of both parameters peaked after 2 days and returned to baseline values within 1 week. IFN-gamma levels were also elevated after application of rTNF-alpha. We failed, however, to demonstrate a clear correlation between the serum levels of IFN-gamma, beta-2-microglobulin, and neopterin because of the wide range of pre- and posttreatment levels of IFN-gamma. We conclude that neopterin and beta-2-microglobulin represent useful markers for monitoring biological response to treatment with rTNF-alpha.

Adult↗
PubMed1997

Daily urinary neopterin excretion as an immunological marker of disease activity in multiple sclerosis.

The aim of this study was to assess neopterin, a marker of interferon gamma (IFN-gamma) induced macrophage activity, as a possible surrogate marker of inflammation in patients with multiple sclerosis. Urinary neopterin to creatinine ratios (UNCRs) were measured daily in 10 primary progressive (PP). 10 relapsing remitting (RR) and 11 secondary progressive (SP) patients with multiple sclerosis, and 14 normal control (NC) subjects, for periods of up to 12 weeks. After excluding measurements related to infection, the median of the individuals' average UNCRs was significantly higher in patients than in controls (P < 0.001 for all patients and P < 0.01 for each of the three groups of patients); the median UNCRs (and interquartile ranges) were 187 (135-231), 187 (165-277), 218 (164-517) and 134 (97-152) mumol/mol for PP, RR, SP patients and controls, respectively. Similarly, patients had a greater median proportion of days with a UNCR above normal (P < 0.001 for all patients and P < 0.01 for each group); the median percentage (and interquartile ranges) were 16 (6-62), 28 (21-36), 49 (14-86) and 0 (0-6)% for PP, RR, SP patients and controls, respectively. They also had a greater number of peaks in their serial UNCR measurements than controls (P < 0.001 for all patients and P < 0.01 for each group); the means +/- SD peaks/subject/month were: 2.1 +/- 1.8; 3.0 +/- 1.7; 3.3 +/- 2.3 and 0.2 +/- 0.6 for PP, RR, SP patients and controls, respectively. Nine relapses occurred in nine patients during the study, and all were associated with increased neopterin excretion, which tended to be greater than that on days not associated with a relapse. Three of the nine relapses were preceded by an upper respiratory tract infection. In eight out of 13 patients who had infections during the study, increased neopterin excretion was noted for periods of up to 6 weeks post-infection, significantly longer than that which occurred after infections in controls. This confirms infection as a potent inducer of symptomatic and asymptomatic disease activity in mutiple sclerosis, and provides further support of a pivotal role for IFN-gamma in te pathogenesis of mutiple sclerosis. Urinary neopterin excretion is increased in patients with both progressive and relapsing mutiple sclerosis, and therefore has potential as a surrogate marker of the inflammatory component of mutiple sclerosis disease activity.

Adult↗
PubMed1993

Cerebrospinal fluid neopterin concentrations in central nervous system infection.

Cerebrospinal fluid (CSF) neopterin levels were determined by RIA in individuals with central nervous system (CNS) or human immunodeficiency virus (HIV) infections and in healthy controls. The mean CSF neopterin concentrations were 63.0 nmol/L in 15 patients with acute bacterial meningitis, 54.9 nmol/L in 15 patients with Lyme neuroborreliosis, 32.5 nmol/L in 10 patients with viral meningitis, 130.9 nmol/L in 8 patients with viral encephalitis, 13.9 nmol/L in 15 patients with asymptomatic HIV infection, 26.0 nmol/L in 11 patients with AIDS without dementia, 65.4 nmol/L in 4 patients with AIDS dementia, and 4.2 nmol/L in 24 healthy controls. Although patients with viral encephalitis had higher mean neopterin levels than any other patient category studied, the CSF neopterin concentrations cannot be used to discriminate between viral and bacterial infections. Analysis of CSF levels of neopterin may be useful as guidance in following clinical course and effect of treatment and can provide information of value in addition to CSF cell count as a measurement of CNS immune stimulation.

Adolescent↗
PubMed1994

Differential effect on serum neopterin and serum beta 2-microglobulin is induced by treatment in Pneumocystis carinii pneumonia.

Forty-three human immunodeficiency virus-infected patients with Pneumocystis carinii pneumonia (PCP) were enrolled in a study of adjunctive corticosteroid treatment for 10 days versus placebo, in addition to antimicrobial treatment. Levels of neopterin and beta 2-microglobulin (beta 2M) were determined in consecutive serum samples. Initiation of antimicrobial treatment resulted in significantly increased neopterin levels, whereas beta 2M levels slightly decreased from pretreatment levels. In patients treated with corticosteroid, both neopterin and beta 2M decreased, by approximately 50% and approximately 30%, respectively, and returned to baseline after discontinuation of corticosteroid treatment. Antimicrobial treatment alone did not affect either neopterin or beta 2M in healthy controls. Results indicate that treatment has a differential effect on the immune response: increased macrophage activation leading to neopterin production and decreased production of beta 2M by lymphocytes. Further, addition of corticosteroids modified and decreased this immune activation and may explain the earlier demonstrated beneficial effect of corticosteroids in PCP treatment.

AIDS-Related Opportunistic Infections↗
PubMed1991

2',5'-oligoadenylate synthetase, neopterin and beta 2-microglobulin in asymptomatic HIV-infected individuals.

This study examined 2',5'-oligoadenylate (2,5A) synthetase activity in 26 individuals during the asymptomatic phase of HIV infection and its correlation with neopterin or beta 2-microglobulin. In HIV-antibody-positive (HIV-Ab+) asymptomatic people, both neopterin and beta 2-microglobulin levels in sera were significantly elevated; in contrast, 2,5A-synthetase activity in peripheral blood mononuclear cells was not significantly higher than in HIV-antibody-negative controls. The 2,5A-synthetase levels in symptomatic people (AIDS-related complex and AIDS) were significantly higher than in either asymptomatic or control individuals. However, within the group of HIV-infected asymptomatic individuals, all three markers were positively correlated. In this group, neopterin values were negatively correlated with the number of CD4+ lymphocytes while a positive correlation was found between 2,5A-synthetase and the number of CD8+ lymphocytes. Asymptomatic people with detectable serum HIV p24 antigen had significantly higher 2,5A-synthetase, neopterin, beta 2-microglobulin and number of CD8+ lymphocytes. This study suggests that elevated 2,5A-synthetase activity may reflect a different aspect of host response to HIV infection than do elevated neopterin or beta 2-microglobulin.

2',5'-Oligoadenylate Synthetase↗
PubMedDate not supplied

Elevated plasma neopterin levels in Alzheimer disease.

We assessed plasma neopterin level as a marker of inflammation in Alzheimer disease (AD). Plasma neopterin levels were higher in 51 patients with AD (9.3 +/- 5.9 ng/mL) than in 38 age-matched control subjects (6.3 +/- 2.6 ng/ml, p = 0.002). There was no correlation between neopterin levels and Mini-Mental State Examination score or duration of disease; there was a weak association between neopterin level and age (r = 0.26, p = 0.02). Although measurement of plasma neopterin levels is not useful for diagnosis, this assay may provide guidance for the development of anti-inflammatory treatment strategies for AD.

Aged↗
PubMed2000

Adenosine deaminase isoenzymes and neopterin in liver cirrhosis.

The aim of this study was to define the pattern of neopterin and ADA isoenzymes in liver cirrhosis. A total of 117 patients with liver cirrhosis were included. Serum levels of ADA were assayed in the presence and absence of a specific inhibitor for ADA1. Serum neopterin was measured using a competitive enzyme-linked immunosorbent assay. The grade of liver insufficiency was assessed according to the Child-Pugh classification and the monoethylglycinexylidide test. Serum ADA, ADA1, ADA2 and neopterin were higher in cirrhotic patients than in control subjects. A stepwise increase in serum ADA level was observed with increasing severity of liver cirrhosis. The probability of ADA2 being greater than the mean was approximately 2.5 times higher (2.48, CI 95%: 1.36-4.52) in patients with liver cirrhosis due to hepatitis C virus (HCV) infection than in those patients with cirrhosis of a different etiology. No correlation was found between ADA2 and neopterin. Our data show that liver insufficiency and HCV infection increase the serum levels of ADA and its major isoenzyme ADA2. Furthermore, ADA isoenzyme determination adds no value to total ADA value. The absence of a correlation between ADA2 and neopterin suggests that different physiologic processes are involved in their increase.

Adenosine Deaminase↗