Schroccksnadel Κ. et air. Neopterin to Monitor Clinical Pathologies Involving IFN-γ Production 75

Pteridines Vol. 15, 2004, pp. 75 - 90

Neopterin to Monitor Clinical Pathologies Involving Interferon-γ Production*

Katharina Schroecksnadel1, Christian Murr1, Christiana Winkler1·2, Barbara Wirleitner1--, Lothar C. Fuith', Dietmar Fuchs1·2

'Institute for Medical Chemistry and , Medical University of Innsbruck, 12Ludwig Boltzmann Institute of AIDS Research, 'Division of Gynecology and Obstetrics, Hospital Barmherzige Brüder, Eisenstadt

^Dedicated to Prof. Dr. Dr. h. c. Helmut Wächter on the occasion of his 75,h birthday

Abstract

Upon stimulation with the interferon-γ human monocytes/ produce neopterin. Accordingly, measurement of neopterin concentrations in body fluids like blood, urine or cerebrospinal fluid provides infor- mation about activation of immune response involving type 1 Τ helper cells. Increased neopterin production is found in infections by viruses including human immunodeficiency virus (HIV), infections by intracellular living and parasites, autoimmune diseases, malignant tumor diseases and in allograft rejection episodes, but also in some neurodegenerative and in cardiovascular diseases. Major diagnostic applications of neopterin measurements are monitoring of the immune status of allograft recip- ients, detection of infectious diseases in blood donations and monitoring of therapy in HIV-infected individuals. Neopterin concentrations also provide prognostic information in HIV-infected individuals and in several malig- nant tumor diseases, high neopterin production at the moment of diagnosis is associated with poorer survival expectations. As high neopterin production is associated with increased production of reactive oxygen species and with low serum concentrations of antioxidants like α-tocopherol, neopterin can be regarded as a marker of oxidative stress caused by an activated . Therefore, by neopterin measurements not only the extent of cellular immune activation, but also the extent of tissue damage caused by reactive oxygen specics may be estimated.

Key words: neopterin, laboratory diagnosis, immunobiology, cellular immune response, in vitro testing

Introduction class of which biosynthetically derives from (GTP). Unconjugated pteridi- Neopterin, 2-amino-4-hydroxy-6-(D-erythro-l 2', 3'- nes are synthesized de novo by mammals and by other trihydroxypropyl)- (Fig.l), belongs to the higher animals (1, 2). In contrast to , the bio- logical function of most unconjugated pteridines is still unknown, despite their common occurrence in various organisms. The reason for this comparatively limited research partly lies in analytical difficulties. In some cases the problems of isolation and characterization are caused by the low concentrations of pteridines in bio- logical samples; they are generally present only in trace amounts, are photolabile and hardly soluble in aqueous solution (3, 4). In 1979, neopterin determination was demonstrated to detect and further characterize rare inborn error of Figure 1: Neopterin = 2-amino-4-hydroxy-6-(D-ery- metabolism namely atypical phenylketonuria (PKU) thro- 1', 2', 3'-tryhydroxypropyl)-pteridine (5). In this subgroup of PKU, protein phenylalanine

Correspondence to: Dr. Dietmar Fuchs, Institute of Medical Chemistry and Biochemistry, Fritz Pregi Str. 3, A-6020 Innsbruck, Austria, Phone: ++43-512-507-3519, Fax: ++43-512-507-2865, e-mail: [email protected]

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hydroxylase is not affected, but the biosynthesis of the like fibroblasts or endothelial cells of several species necessary cofactor 5. 6, 7, 8-tetrahydrobiopterin (H4- produce H4-bip and only scarce amounts of neopterin bip) is disturbed. In the same year, Helmut Wächter derivatives are formed. However, due to a relative and coworkers described increased neopterin concen- deficiency of 6-pyruvoyl tetrahydropterin synthase in trations in patients suffering from malignant diseases human and primate monocytes/macrophages, activa- but also in patients with virus infections (6) and there- tion of GTP cyclohydrolase I leads to an accumulation by opened a much broader area for the application of of H2-nep-triphosphate at the expense of H4-bip. H2- neopterin measurements. While searching for a tumor Nep-triphosphate is then converted by phosphatases to marker, this first result appeared rather disappointing neopterin and H2-nep (Fig. 2) (13). The latter products at the first glancc, however, at the end this finding was are detectable in cell culture supernatants of activated a basis for a remarkable variety of applications of human monocytes/macrophages and in body fluids of neopterin determination (7-11 ). which also contributed humans and primates in a rather constant ratio of to a deeper understanding of the complex interrelation- neopterin per H2-nep of about 1:3 (14). From this ship between immune response and pathogenesis of background, human monocytes/macrophages appear diseases. to constitute the most relevant source of neopterin and H2-nep. Interferon-γ (IFN-γ) is the central stimulus for the activation of GTP cyclohydrolase I, and therefore Immunological background of neopterin biosynthe- in human monocytes/macrophages neopterin and H2- sis nep accumulate (15). Besides, also lipopolysaccharide and tumor necrosis factor-α (TNF-α) superinduce GTP-cyclohydrolase I (EC 3.5.4.16), the key IFN-y-mediated neopterin production (16). enzyme of pteridine biosynthesis, cleaves the purin to Upon stimulation with interferons also monocyte - synthesize 7, 8-dihydroneopterin-(H2-nep)-triphos- derived dendritic cells were found to produce phate (Fig.2). This intermediate is converted by neopterin in similar concentrations as macrophages (17). Other cells like human umbilical vein endothelial lnterferon-γ cells (18) or cultured kidney epithelial cells (19), may produce neopterin upon stimulation with IFN-γ, but to a smaller extent than macrophages (19). In addition, V M Guanosirtriphosphate (GTP) neopterin production by epithelial cells is accompa- GTP-Cyclohydrolase I Γ nied by production of H4-bip (20). As in human dis- ^ 7,8-Dihydroneopterintri phosphate eases like, e.g., infections by human immunodeficien- cy virus (HIV), increased neopterin but no or only slight changes of bioplerin production can be found Neopterin 5,6,7,8-Tetvahydrobiopterin 7,8-Dihydroneopterin (21), in case of immune stimulation by IFN-γ neopterin is mainly produced by human macrophages and not by (human macrophages) (other cells) epithelial cells (22). Figure 2: Biosynthesis of neopterin derivatives in In patients several such as, e.g. inter- human monocytes/macrophages and monoycte- leukin-(IL)-2, which are able to induce IFN-γ -release derived dendritic cells. Synthesis starts from GTP from Τ cells, also provoke neopterin release (23). (guanosin triphosphate) by induction of GTP cyclohy- Similarly, administration of granulocyte/monocyte d rol as e I via interferon-γ. Large amounts of neopterin stimulating factor (GM-CSF) enhances neopterin pro- derivatives are accumulating at the expense of duction in patients (24) probably by increasing the bioplerin derivatives due to a constitutive deficiency number of monocytes/macrophages. of 6-pyruvoyl tetrahydrobiopterin synthase in the As IL-2 and especially IFN-γ are cytokines typical- cells. Other cells like human fibroblasts or endothelial ly produced by Τ helper (Th) cells subtype 1 (25), cells and cells of other species do synthesize biopterin which are promoting immune response mediated by derivatives and only little neopterin becomes cytotoxic Τ cells, increased production of neopterin in detectable. body fluids can be used to monitor activation of cell- mediated immunity. Accordingly, diseases like, e.g., 6-pyruvoyl tctrahydroptenn synthase to form dihydro- virus infections are accompanied by increased biopterin in the biosynthetic pathway of H4-bip. H4- neopterin production, because cell mediated immune Qip is an essential cofactor of several mono-oxygenas- response dominates (6, 7). On the other hand, in situa- es including phenylalanine-, tyrosine- and tryptophan- tions like, e.g., acute bacterial infections, only moder- s-hydroxylase, and the nitric oxide synthases (12). ate neopterin production can be found. In this case. When GTP-cyclohydrolase I is activated, most cells Th2 cell immune response dominates, characterized by

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the formation of IL-4, -5. -6, -9, -10 and -13, which are duction by the activated human macrophages has not supporting humoral immune response (26). A cross- been demonstrated by now, but recently neopterin regulatory influence exists between Thl-type and Th2- derivatives were found to interfere with reactive oxy- type immune responses, down-regulating each other gen species in vitro (36-42). Therefore it seems possi- when activated (Fig. 3). This is evident from in vitro ble that neopterin derivatives influence the effects and cytotoxicity of reactive oxygen species like hydrogen Th1-type cell G Th2-type cell peroxide which are produced by activated macrophages within the oxidative burst reaction. Formation of nitric oxide by stimulated human macrophages seems to be of limited relevance (43), although in in vitro investigations human macrophages could be stimulated to produce nitric oxide, but only after rather complex pretreatment with cytokines such as IL-4 (44). Rather it seems that production of neopterin derivatives may compensate for the relative deficiency to produce nitric oxide in human and pri- mate macrophages (45) by modulating the toxicity ol other reactive oxygen species like hydrogen peroxide. From in vitro investigations it may further be Figure 3: During activation of Thl-type immune hypothesized that neopterin and H2-nep may act as response in humans and primates, cytokine interfe- endogenous agents influencing redox balances in bio- ron-γ (IFN-γ) stimulates macrophages to produce logical systems (34). Neopterin and H2-nep were also neopterin derivatives in parallel to reactive oxygen found to interfere with intracellular signaling pathways species such as H 0 . Thl-type cytokines down-regu- 2 2 known to be influenced by oxidative stress (46. 47; see late Th2-type cells, vice versa, Th2-type cytokines like also Hoffmann G & Schobersberger W, this issue of inlerlekin-4 (IL-4) and -10 (IL-10) suppress Thl-type Pteridines). Moreover, neopterin was found to induce response and neopterin production. Cytokines and additional production of reactive oxygen species by chemicals (e.g. antioxidants) suppressing Thl-type granulocytes recently (48). In vivo observations are cells and the production of Thl-type cytokines also able to further substantiate the relationship between affect rate of neopterin formation. increase of neopterin concentrations and production of oxidizing compounds: In older-aged people (49) and in (27) and in vivo investigations. Neopterin concentra- elderly demented patients with neurodegenerative dis- tions in human serum, which reflect Thl cell activity, eases (50) an inverse correlation between increased were compared to serum antibody concentrations, neopterin levels and decreased levels of the antioxidant which are a product of Th2 cell activation. Inverse α-tocopherol was found. In patients with diabetic correlation between neopterin concentrations and anti- nephropathy a correlation was found between body levels were found (28, 29). However, sometimes neopterin and advanced oxidation protein products an activation of both Τ helper cell-compartments alter- (33), the latter compounds represent a reliable indica- natively or a shift to the ThO phenotype seems to exist tor for the degree of oxidant-mediatcd protein damage. (30). E.g., in acute episodes of graft-versus-host dis- Therefore, the result suggests a relation between ease after human allogeneic bone marrow transplanta- oxidative stress and monocyte activation as monitored tion, a significant positive correlation between plasma by neopterin concentrations. The data agree well with neopterin levels and the Th2-derived cytokine IL-10 the conclusion that neopterin is not only a indicator for was found (31). The amount of neopterin secreted by oxidative stress resulting from immune activation, but human monocytes/macrophages upon stimulation with neopterin itself contributes to oxidative stress by mod- IFN-γ correlates with the capacity of the same cells to ulating the effects of ROS (34). produce reactive oxygen species (ROS) (32, 33), neopterin derivatives may be regarded as an indicator for oxidative stress due to immune activation as well Measurement of neopterin concentrations in bio- (34. 35). logical fluids

Neopterin and H2-nep are small molecular mass The biological impact of neopterin derivatives molecules (253 and 255 D), which are produced and released in a remarkably constant proportion with a A biological function of increased neopterin pro- ratio of aromatic neopterin to total (aromatic plus acid-

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oxidizable H2-nep) neopterin of 1:3 for urine and arte- Neopterin in infectious diseases rial blood (14) and 1:2 for serum obtained from venous blood samples. Since dihydroforms of pteridines are Upon recognition of foreign or non-self cell struc- labile, collection and storage of samples is critical and tures T-lymphocytes may produce different mediators, problematic for large scale clinical handling. In daily so-called lymphokines, such as interferon-γ. which clinical routine, advantageously only the more stable stimulates human monocytes/macrophages to the pro- neopterin is being quantified. Serum neopterin may be duction and release of neopterin (15). During acute determined by immunoassays in an easy way, viral infections strongly increased neopterin produc- neopterin concentrations averaging 5.3 ± 2.7 nM in tion can be observed, which correlates with the activi- healthy adults, 95"' percentile being 8.7 nM for adults ty of the disease. This was shown in, e.g., acute viral aged between 19 and 75 years (8, 9, 51). Cerebrospinal hepatitis, Epstein-Barr-virus and cytomegalovirus fluid concentrations of neopterin were found to be infections, measles, mumps, chickenbox, rubella and lower than serum (4.2 ± 1.0; upper limit of normal influenza (7, 9, 53 - 57). Elevated neopterin levels in 5.5 nM) (51; for more details of the application of body fluids may already be found at the end of the neopterin determinations in cerebrospinal fluid see incubation period just before onset of clinical symp- also Hagberg L, et al., this issue of Pteridines). Since toms. The highest neopterin levels occur just before neopterin is constantly distributed in body fluids, alter- specific antibodies against the virus become native or additional measurement of neopterin concen- detectable, which occurs up to about two to four weeks trations in urine specimens as compared with serum or after onset of increased neopterin production. On sero- plasma can be performed. To take variations of urine conversion, neopterin concentrations decline and nor- densities into account, urinary neopterin concentra- malize, if the immune system successfully competes tions are expressed in μηιοΐ/mol creatinine which can the infecting agent (Fig. 4). This sequence of events advantageously be done by examining samples by high-pressure liquid chromatography (52). Reference values of urinary neopterin per creatinine concentra- tions are slightly influenced by gender and age (8, 9, 11): as compared with males (average neopterin con- centrations ranging between 101 - 133 pmol/mol crea- tinine; 97.5th percentiles ranging for 176 - 229 μιτιοΐ/mol creatinine), females present with higher lev- els (average neopterin concentrations ranging between 124 - 156 pmol/mol creatinine; 97.5"1 percentiles ran- ging for 208 - 251 μηιοΐ/mol creatinine) mostly because of lower creatinine excretion, in both groups of individuals older age is associated with increasing neopterin concentrations (8, 9, 11).

Time Figure 4: Schematic course of serum or urine Neopterin determination in clinical laboratory neopterin concentrations during acute human immun- immunology odeficiency virus (HIV) infection (open circles) as compared with acute infection with other viruses such In diseases like infections, autoimmune and malig- as cytomegalovirus (CMV) or Epstein Barr virus nant tumor diseases or in cases of allograft rejection (EBV) (filled squares). In case of CMV and EBV ccllular immune activation is clearly involved in the infection, neopterin concentrations return to baseline pathogenesis or affected by the underlying disease upon recovery, in most cases of HIV infection process, but also in neurological and cardiovascular neopterin concentrations remain at a higher level also diseases immunological processes are discussed. To in the asymptomatic phase after seroconversion. clarify pathogenesis and finding appropriate therapy, early and sensitive monitoring of immunological appears to be true for every acute virus infection (58), changes in patients but also in vitro experiments with and it was also observed in, e.g., Ebola virus infections cells involved in immune reactions could be important. when high concentrations of neopterin in plasma were By measurements of neopterin in human body fluids or observed as soon as a few days after the disease onset cell culture supernatants monitoring of cellular and were indicative of a fatal outcome (59). By con- immune activation can by easily done. trast, in HIV infection, neopterin concentrations increase during acute infection and decline after sero-

Pteridines/VoL 15/No. 3 Schroecksnadel Κ. et al.: Neopterin to Monitor Clinical Pathologies Involving IFN-γ Production 79 conversion, but do not normalize (60). Thus, more than tion (70, 71). three quarters of the HIV-infected still show elevated In acute bacterial infections neopterin production is neopterin production although being without symp- usually low, as humoral immune response dominates. toms (7, 61). From these neopterin data the crucial role Therefore neopterin measurements could be an addi- of immune activation in the pathogenesis of the tional tool to support differential diagnosis between acquired immunodeficiency syndrome (AIDS) has viral and bacterial infection in special clinical situa- been deduced very early (62): Activated T-cells are tions. This was reported in patients with pneumonia, more susceptible to HIV infection and activation of where neopterin discriminated better than blood sedi- infected T-cells induces virus replication (Fig. 5). mentation rate or leukocyte counts between viral and

HIV binds to T-cell via CD4 receptor

T-helper cell

1st step: Infection nd with 2 step: Activation of

0 HIV T-helper cells as pre-requisite for progressive HIV infection e.g. co-infections

HIV budding, HIV RNA transcribed T-cell function into T-cell genome, diminished reproduction begins

Figure 5: Crucial role of immune activation in AIDS pathogenesis: Activated T-cells are more susceptible to HIV infection and activation of infected cells induces virus replication (adapted from ref. 62)

Already in the early phase of HIV infection, bacterial infection (26, 72). In protracted bacterial neopterin concentrations have prognostic impact: The infection neopterin production increases. Highest higher the neopterin concentration in serum or urine, neopterin concentrations in body fluids are found in the higher will be the risk to develop (AIDS). With dis- case of septic complications (73) due to lipopolysac- ease progression neopterin production increases again charides of Gram-negative bacteria like, e.g., with the highest values when full-blown AIDS devel- Pseudomonas pseudomallei (74) or Brucella meliten- ops, paralleled by decreasing CD4+ T-lymphocyte sis (75). On the other hand, bacteria like Streptococcus counts (62-67). In general, neopterin concentrations pyogenes produce exotoxins with superantigen charac- provide similar prognostic values for disease progres- ter (76), which are supposed to play a key role in the sion as other predictive markers like CD4 T-cell counts so called "streptococcal toxic shock like syndrome" or quantitative PCR for HIV RNA. Neopterin values which is associated with high neopterin production as also correlate with viral load (68, 69). Antiretroviral well (77). therapy is reflected in a decrease of neopterin produc- In infections by Mycobacterium tuberculosis, a fac-

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ultative intracellular bacterium, cellular immunity stages show higher neopterin values than earlier ones. plays a central role in immune defense. Indeed, in lung On the other hand, successful treatment, indicated by tuberculosis neopterin production correlates with the remission in hematological neoplasias, is associated extent and activity of the disease (78) and provides with decline or even normalization of neopterin values useful information in therapy control (79) even if there in most cases (88). Also a correlation between urinary is HIV co-infection (80). Also in leprosy, which is neopterin levels and the estimated total mass of tumor caused by Mycobacterium leprae, activated cellular cells was shown (90). immune response is indicated by increased neopterin The most striking observation from several studies on production and. 75% of patients with tuberculoid and malignant tumor diseases is that neopterin concentra- lepromatous leprosy present with elevated urinary tions proved to be a significant and independent pre- neopterin excretion (81 ). dictor of patients' survival. Higher urinary or serum In infections with parasites, like acute , high neopterin concentrations were associated with a worse neopterin formation was found (82, 83). After effective outcome. This was shown, e.g., in hematological neo- chemotherapy elevated concentrations in serum or plasias (91-92), in carcinoma of the uterine cervix (93) urine rapidly decrease to normal values within several or of the ovaries (94), in colon carcinoma (95), lung days (84). An inverse association between the duration (96, 97), prostate cancer (98), hepatocellular of parasitic load and neopterin production was found, cancer (99), squamous cell carcinoma of the oral cavi- indicating that with duration of the disease humoral ty ( 100) and female breast cancer (101). Furthermore, immunity develops while severity of the disease and neopterin monitoring in the post-thcrapeutic phase can cellular immune activation decline (85). help to detect tumor relapse earlier and may provide an In infections with Borrelia burgdorferi, a tick-born indication for adjuvant therapeutic measures (94). spirochete, which may cause so called Lyme neurobor- Nevertheless, it is important to stress that in most cases reliosis, high neopterin concentrations are found in conventional tumor markers, which are released by the cerebrospinal fluid of patients, whereas serum tumor cells themselves, correlate better with tumor neopterin levels are only slightly increased indicating growth than neopterin, whereas neopterin concentra- intrathecal neopterin production in Lyme neuroborre- tions represent a better predictor of patients' survival liosis (86. 87). (94). The worse prognosis of those with higher neopterin production might be explained by a cellular immune Neopterin in malignant tumor diseases response against the tumor which might be stronger in patients with more aggressive tumors. However, the As malignant tumor cells exhibit an altered cell-sur- immune system seems unable to eradicate the malig- face compared to non-malignant cells, they may pro- nant process, and a kind of chronic immune activation voke reactions of the specific cellular immune system has been induced. From additional investigations it and thereby also neopterin production. The frequency appears that phenomena like tumor anemia or tumor of elevated neopterin concentrations in serum or urine cachexia, which are often associated with malignant of patients with malignant diseases at the moment of disease, might be a consequence of this immune stim- diagnosis depends on the tumor type and varies from ulation. In hematological neoplasias increased about 90% in hematological neoplasias like chronic neopterin showed a significant inverse correlation with myelogenous leukemia, non-Hodgkin's disease or blood hemoglobin (102). IFN-γ and TNF-a, produced Hodgkin's disease, to about 20% in tumors like breast by activated monocytes/macrophages (103), might cancer or malignant melanoma (88). Intermediate fre- contribute to these phenomena. Thus, high levels of quencies of elevated neopterin concentrations are soluble tumor necrosis factor receptors were reported found in ovarian cancer and uterine sarcoma (about in hematological neoplasias, the concentrations of 80%), pancreatic carcinoma and multiple myeloma which correlated with weight loss as well as with (about 70%), lung cancer (about 58%), cervix carcino- increased neopterin and decreased hemoglobin levels ma (about 55%) and colon and stomach carcinoma (104). (40%). Therefore neopterin measurements are certain- The finding of increased neopterin concentrations in ly insufficient for screening or diagnostic purposes, cancer patients and their predictive value fits very well however neoptenn determination was proposed as a to the assumption that chronic inflammation and the diagnostic aid to identify individuals with increased production of reactive oxygen species may induce risk for breast cancer in menopausal women with DNA damage and mutations and, as a result, be car- genetic predisposition (89). cinogenic (105, 106). Thereby, chronic inflammation Not only tumor type, but also tumor stage influence the could be essential for the development and progression extent of neopterin elevation. In general, advanced of the neoplastic process so that therapeutic interven-

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lion aimed at inhibiting inflammation may have a tion (120, 123). An association of serum neopterin major role in future reducing the incidence of common concentrations with the presence of angiographically ( 105). demonstrated complex lesions in patients with unsta- ble angina could be shown, neopterin representing as a marker for coronary disease activity (124). Besides Neopterin in autoimmune diseases and related neopterin, other markers of inflammation like C-reac- inflammatory disorders tive protein or serum amyloid A are increased in patients with atherosclerosis indicating the inflamma- In autoimmune diseases an attack of the immune sys- tory nature of atherosclerotic disease (117, 118, 125). tem against homologous structures of the organism However, prognostic value of neopterin levels was occurs. Thus, in case of involvement of cellular immu- almost independent from these other parameters in, nity neopterin elevations should be expected. And e.g., treated patients with hypertension and chest pain indeed, in elevated neopterin con- but without obstructive coronary artery disease (126). centrations are found in blood and urine correlating A strong association was found between neopterin with the disease activity (106). Highest neopterin lev- concentrations and another cardiovascular risk factor els are seen in synovial fluids of patients during the namely hyperhomocysteinemia (127). From the data it acute exacerbation of the disease (107). Neopterin appears that development of hyperhomocysteinemia is measurement can also be applied as an additional cri- another consequence of immune activation, degrada- terion to discriminate rheumatoid arthritis from tion of B-vitamins due to oxidative stress might be osteoarthritis, because in the latter case neopterin pro- responsible for disturbed homocysteine conversion. duction is usually within the normal range (108). In patients with systcmic erythematosus neopterin production correlates with disease activity, as well. In Neopterin in neurodegenerative diseases a multivariate analysis, neopterin proved as one of the most representative immune activation markers, corre- Increased neopterin levels were described rather early lating with disease activity better than, e.g., 55kD-sol- in cerebrospinal fluid and other body fluids of patients uble tumor necrosis factor receptor, soluble inter- with multiple sclerosis. They were found to be signifi- leukin-2 receptor or beta-2-microglobulin (109). cantly higher in the acute phase of disease than in sta- Increased neopterin production in accordance with dis- ble periods (128), and even the measurement of uri- ease activity was also demonstrated in Wegener's gran- nary neopterin concentrations was found as an ulomatosis (110), dermatomyositis (111), and inflam- immunological marker of disease activity in patients matory bowel diseases, such as Crohn's disease (112, with multiple sclerosis and to monitor treatment with 1 13) and colitis ulcerosa (114). interferon-ß (129). Neopterin measurement in cere- brospinal fluid may be able to support differential diagnosis, e.g., it is important to note that patients with Neopterin in cardiovascular diseases amyotrophic lateral sclerosis have normal neopterin levels in serum and CSF (130). Increased neopterin production is also found in In neurodegenerative diseases like Alzheimer's demen- patients with dilated cardiomyopathy or chronic tia or Parkinson's disease, signs of immune activation myocarditis, correlating with the cardiac functional and increased oxidative stress are evident. However, class according to the New York Heart Association usually activation of immunocompetent cells and re- (1 15). As immune activation plays an important role lease of reactive oxygen species are considered to be in the pathogenesis of acute rheumatic fever, about confined to the brain so that oxidative stress might un- 80% of patients show increased neopterin production derlie local pathological processes in patients. In- at the onset of disease. Higher neopterin concentra- creased neopterin concentrations can be found in pa- tions are found in patients developing a combined aor- tients with various forms of dementia such as Alz- tic and mitral insufficiency. Thus, neopterin measure- heimer's disease (131) and Huntington's disease ( 1 32) ment may allow easy assessment of the severity of car- and vascular dementia (133) but also in patients suf- diac involvement in acute rheumatic fever (116). fering from Parkinson's disease (134), and interestin- Increased neopterin production was found in athero- gly neopterin concentrations are usually higher in the sclerosis of the coronary (117, 118) and carotid arteries serum/plasma than in the cerebrospinal fluid. The (119), and in acute and chronic coronary syndromes background of this chronic immune stimulation is still (120-122). Neopterin was significantly increased in unclear. Since it is observed rather in late stages of the patients with chronic coronary artery disease and more disease, it seems to represent a consequence of the pronounced m patients with acute myocardial infarc- underlying pathology rather than being initial. In

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patients with dementia, neopterin concentrations are increased neopterin concentrations and accelerated associated with the loss of cognitive function, tryptophan degradation as well as hyperhomocysteine- neopterin levels are higher in patients with lower men- mia in older aged individuals (139). Data support the tal state (131-133). Likewise, in patients with cardio- view that there is an immunologic background of these vascular diseases (127), also in patients with various neopterin elevations rather than renal dysfunction. forms of dementia a relationship between neopterin From this point of view T-cell abnormalities develop- concentrations and hyperhomocysteinemia has been ing with older age or low level chronic infections could observed (135). play an important role. It is still unclcar, if chronic immune activation, indi- cated by increased neopterin production and by oxida- tive stress (133), is important in the pathogenesis of Neopterin in organ transplantation this disease, but monitoring of immune activation markers like neopterin might lead to better understand- Monitoring of solid allograft (kidney, heart, liver, ing of disease progression and reveals prognostic pancreas) recipients by neopterin measurements in information for the future course of the disease. As in morning urine or serum/plasma has become a useful other clinical conditions characterized by , e.g., tool in surveillance after transplantation. In uncompli- increased neopterin concentrations, chronic immune cated courses neopterin production decreases to nor- activation may well contribute to the development of mal values after surgery, whereas sustaining high con- immunodeficiency and weight loss in these patients. centrations indicate an immunological complication The relationship between immune activation and loss such as organ rejection or infection. In recipients of of cognitive ability might relate to the link between renal allografts it was found that an increase of neopterin production and degradation of tryptophan by neopterin production precedes clinical rejection diag- enzyme indoleamine (2,3)-dioxygenase (136). Like nosis up to four days and that high neopterin values neopterin production also tryptophan degradation is during the initial post-transplant period are associated strongly inducible by cytokine IFN-γ. Insufficient with poorer long-term graft survival (55. 144). biosynthesis of neurotransmitter serotonin on the basis Neopterin measurements were also suggested to be as a consequence of subnormal tryptophan availability useful for differential diagnosis of rejection and infec- might link cognitive abnormalities with immune acti- tion, but only in combination with other inflammatory vation phenomena. parameters (145, 146). In liver transplantation, parallel measurement of neopterin concentrations in urine and bile allows discrimination between ongoing rejection Neopterin in aging and infection, because excessive bilary neopterin excretion is restricted to rejection episodes but is not Scrum neopterin concentrations but also urinary found in, e.g., cytomegalovirus infection or hepatitis neopterin excretion of healthy children is higher than (147). Also in pancreas transplantation, measurement that of adults and is declining from the newborn peri- of neopterin excretion in the pancreatic juice provides od up to adolescence (8, 10). Highest neopterin con- additional information about the origin of immune centrations are found in cord blood (95"1 percentile, activation (148). In bone marrow transplantation, 20.9 nM) (137). Higher neopterin production in early neopterin measurement allows to monitor the course of childhood may relate to activation of immune response immune system destruction and hemopoietic reconsti- involving adaptive and/or innate immune response tution. After hemopoietic reconstitution it enables to (138). discriminate between patients with or without In the elderly neopterin concentrations increase with increased risk of developing graft versus host disease age (139). This is evident from the age dependency of and viral infection, respectively (149). the reference values of neopterin concentrations in dif- ferent body fluids and could be confirmed by all so far known studies with healthy individuals (28, 29, MO- Neopterin in blood transfusion MS). The reason for this phenomenon is still a matter >f discussion. Possibly the higher incidence of diseases During the last years considerable progress con- associated with immune activation in the elderly such cerning safety of blood transfusion was achieved either . e.g., arteriosclerosis or dementia would contribute by serologic or molecular biology techniques like higher reference values. Thereby it is assumed that polymerase chain reaction (PCR) supporting blood some of the individuals of the reference population donor screening. Nevertheless, residual infectious risk - pathological process has already started but is clin- still remains in blood transfusion. Potential hazardous - - .lv not yet detectable. Correlations exist between pathogens may remain undetected either because they

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are known but not screened or they are unknown so immunosuppressive and anti-inflammatory capacity that usually performed screening technologies are inef- could be demonstrated for tea extracts (157) and for fective. In addition, it is possible that blood donation is extracts and alkaloids from Uncaria tomentosa (158) drawn within the diagnostic window — the period as well as for the Tibetan herbal remedy PADMA 28 between infection and antibody production — of an (159). In a similar way wine and grape juice were infectious process so that antibody production is not found to suppress neopterin formation and tryptophan yet detectable. During acute infections neopterin con- degradation in stimulated PBMC (160). All together centrations in serum generally reach rather high val- data indicate that antioxidant compounds are able to ues. This enhanced neopterin production is not specif- down-regulate Thl-type immune response as it was ic for a certain infectious disease, but indicates that an shown earlier for histamine (160). Indeed, antioxidants immunological process caused by a known or even appear to favor Th2-type immune response whereas hitherto unknown pathogen is going on. Thus, apply- pro-oxidants are part of the Thl-type machinery (Fig. ing neopterin measurements for blood donor screening 3) (161). can exclude virus infections during the acute phase Also HMG-Co A reductase inhibitor atorvastatin when virus load is highest and allows to further short- was found to interfere with Thl-type immune activa- en the diagnostic window in addition to serologic tion as it suppressed neopterin and IFN-γ production in screening methods (150, 151). In 1994 neopterin the in vitro system of mitogen-treated PBMC (161), screening of blood donations became compulsory in and most importantly a similar influence was found in Austria. Subclinical infections or silent systemic disor- individuals undergoing coronary angiography, patients ders may be detected in a higher frequency by who were treated with statins presented with signifi- increased neopterin concentrations and suspicious cantly lower neopterin concentrations than those not blood units are discarded to increase the security of being under such treatment (162). transfusion (151). It was shown that in blood donors Finally since also lipopolysaccharides may induce with neopterin concentrations above 10 nM that acute neopterin formation by macrophages, the measurement cytomegalovirus infections which have been unrecog- of neopterin production allows to sensitively detect nized during anamnesis were about 19 times more fre- bacterial pyrogens, it thus provides a simple in vitro quent than in such infected individuals with neopterin assay to detect pyrogenic contamination (163). below 10 nM (152). Similarly, the incidence of acute Epstein-Barr virus and parvovirus Β19 infections was accompanied by a about three times higher frequency References in individuals with neopterin above 10 nM (153). Also in chronic and clinically unsuspicious 1 Kraut H, Pabst W, Rembold H, Wildemann L. On infections PCR-positively tested donations were about the behavior of biopterin in the mammalian body. I. seven times more frequent when neopterin was above Balance and growth experiments on rats. Hoppe 10 nM (154). Seyler's Ζ Physiol Chem 1963;332:101-108. 2 Pabst W, Rembold H. On the behavior of biopterins in the mammalian organism. II. Effect of vitamin Neopterin measurements for "in vitro" diagnostics deficiency and of an antagonist on biopterin differ- entiation and on the growth of the rat. Hoppe In cultures of stimulated peripheral blood mononu- Seyler's Ζ Physiol Chem 1966;344:107-112. clear cells (PBMC) neopterin concentrations sensitive- 3 Rembold H. Gyure WL. Biochemistry of the ly indicate IFN-γ production by Thl-type cells. The pteridines. Angew Chem Int Ed Engl. model system of PBMC stimulated with mitogens like 1972;11:1061-1072. phytohemagglutinine or concanavalin A can be 4 Pfleiderer W. New developments in pteridine applied to detect possible influences of chemicals, chemistry. Angew Chemie 1963; 75: 993-1040. drugs or plant extracts on the activation of the cells. 5 Niederwieser A, Curtius HC, Bettoni O, Bieri J, First observations were made with colchicines which Schircks B, Viscontini M, Schaub J. Atypical significantly suppressed neopterin production (155). phenylketonuria caused by 7, 8-dihydrobiopterin Using monocytic cell line THP-1 the influence of his- synthetase deficiency. Lancet. 1979;1:131-133. tamine to suppress neopterin production was demon- 6 Wächter Η, Hausen A, Graßmayr Κ. Erhöhte strated (156). However, the application of PBMC Ausscheidung von Neopterin im Harn von turned out to be superior because it allows to monitor Patienten mit malignen Tumoren und the interplay between activation Thl-type cells and Viruserkrankungen. Biol Chem Hoppe-Seyler macrophages in one cellular system and it seems to 1979; 360: 1957-1960. mimic more closely what is going on in vivo, e.g. 7 Fuchs D, Hausen A, Reibnegger G, Werner ER,

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Dierich MP. Wächter H. Neopterin as a marker for 19 Moutabarrik A, Takahara S, Nakamshi I, Kokado activated cell-mediated immunity: application in Y, Takano Y, Kameoka H, Ishibashi M, Zaid D. HIV infection. Immunol Today 1988; 9: 150-155. Interferon-γ stimulates neopterin release from cul- 8 Wächter H, Fuchs D, Hausen A, Reibnegger G, tured kidney epithelial cells. Scand J Immunol Werner ER. Neopterin as a marker for activation of 1994; 39: 27-30. cellular immunity: Immunologic basis and clinical 20 Werner-Felmayer G, Werner ER, Fuchs D, Hausen application. Adv Clin Chem 1989; 27: 81-141. A, Reibnegger G, Schmidt Κ, Weiss G, Wächter H. 9 Wächter H, Fuchs D, Hausen A, Reibnegger G, Pteridine biosynthesis in human endothelial cells. We i ss G, Werner ER, Werner-Felmayer G. Impact on nitric oxide-mediated formation of Neopterin - Biochemistry Methods Clinical cyclic GMP. J Biol Chem 1993; 268: 1842-1846. Application. Berlin-New York: Walter de Gruyter 21 Abita JP, Cost H, Milstien S, Kaufman S, Saimot 1992. G. Urinary neopterin and biopterin levels in 10 Widner Β, Murr C, Wirleitner Β, Mayr C. Spöttl Ν, patients with AIDS and AIDS-related complex. Baier-Bitterlich G, Fuchs D. The importance of Lancet 1995; 2: 51-52. neopterin as a laboratory diagnostic marker of 22 Fuchs D, Blair JA, Wächter H. Does increased immune activation. Pteridines 1999; 10: 101-111. neopterin during cell-mediated immune response 11 Murr C, Widner Β. Wirleitner Β, Fuchs D. stem from activated macrophages? Pteridines Neopterin as a marker for immune system activa- 1996; 7: 45-46. tion. Curr Drug Metab 2002; 3:175-187. 23 Brown RR, Lee CM, Köhler PC, Hank JA, Storer 12 Werner-Felmayer G, Golderer G, Werner ER. BE, Sondel PM. Altered tryptophan and neopterin Tetrahydrobiopterin biosynthesis, utilization and metabolism in cancer patients treated with recom- pharmacological effects. Curr Drug Metab 2002; 3: binant interleukin-2. Cancer Res 1989; 49: 4941- 159-173. 4944. 13 Werner ER, Werner-Felmayer G, Fuchs D, Hausen 24 Marth C, Weiss G, Koza A, Reibnegger G, A, Reibnegger G, Yim JJ, Pfleiderer W, Wächter H. Daxenbichler G, Zeimet AG, Fuchs D, Wächter H, Tetrahydrobiopterin biosynthetic activities in Dapunt O. Increased production of immune activa- human macrophages fibroblasts THP-1 and Τ 24 tion marker neopterin by colony-stimulating fac- cells GPT-cyclohydrolase I is stimulated by inter- tors in gynecological cancer patients. Int J Cancer feron^ 6-pyruvoyl tetrahydropterin synthase and 1994; 58: 20-23. sepiapterin reductase are constitutively present. J 25 Lucey DR, Clerici M, Shearer GM. Type 1 and Biol Chem 1990; 265: 3189-3192. type 2 cytokine dysregulation in human infectious, 14 Fuchs D. Milstien S Krämer G, Reibnegger G, neoplastic, and inflammatory diseases. Clin Werner ER, Dierich MP, Wächter H. Urinary Microbiol Rev 1996; 9:532-562. neopterin concentrations versus total neopterins for 26 Denz H, Fuchs D, Hausen A, Huber H, Nachbaur clinical utility. Clin Chem 1989; 35: 2305-2307. D, Reibnegger G, Thaler J, Werner ER, Wächter H. 1 5 Huber C, Batchelor JR, Fuchs D, Hausen A, Lang Value of urinary neopterin in the differential diag- A, Niederwieser D. Reibnegger G, Swetly P, nosis of bacterial and viral infections. Klin Troppmair J, Wächter H. Immune response-associ- Wochenschr 1990; 68: 218-222. ated production of neopterin. Release from 27 Weiss G, Murr C, Zoller H, Haun M, Widner Β, macrophages primarily under control of interferon Ludescher C, Fuchs D. Modulation of neopterin gamma. J Exp Med 1984; 160: 310-316. formation and tryptophan degradation by Thl- and 16 Werner-Felmayer G, Werner ER, Fuchs D, Hausen Th2-derived cytokines in human monocytic cells. A, Reibnegger G, Wächter H. Tumor necrosis fac- Clin Exp Immunol 1999; 116: 435-440. tor-α and lipopolysaccharide enhance interferon- 28 Ledochowski M, Murr C, Widner B, Fuchs D. induced tryptophan degradation and pteridine syn- Inverse relationship between neopterin and thesis in human cells. Biol Chem Hoppe-Seyler immunoglobulin E. Clin Immunol 2001; 98: 104- 1989;370:1063-1069. 108. 17 Wirleitner B, Reider D, Ebner S, Böck G, Widner 29 Murr C, Hainz U, Asch E, Berger Ρ, Jenewein Β, Β, Jaeger M, Schennach H, Romani N, Fuchs D. Saurwein-Teissl M, Grubeck-Loebenstein B, Fuchs Monocyte-deri vcd dendritic cells release neopterin. D. Association of increased neopterin production J Leukocyte Biol 2002; 72: 1148-1153. with decreased humoral immunity in the elderly. 1 8 Ändert SE, Griesmacher A, Zuckermann A, Müller Exp Gerontol 2003; 38: 583-587. MM. Neopterin release from human endothelial 30 Romagnani S. Thl and Th2 in human disease. Clin cells triggered by interferon-gamma. Clin Exp Immunol Immunopathol 1996; 80: 225-235. Immunol 1992; 88: 555-558. 31 Weiss G, Schwaighofer H, Herold M, Nachbaur D,

π dines/Vol. 15/No. 3 Schroecksnadel Κ. et cd:. Neopterin to Monitor Clinical Pathologies Involving IFN-γ Production 85

Wächter H, Niederwieser D, Werner ER. Nitric 41 Wede I, Semenitz E, Wächter H, Fuchs D. oxide formation as predictive parameter for acute Neopterin and 7,8-dihydroneopterin modulate graft-versus-host disease after human allogeneic microbicidal effects of reactive oxygen and chlo- bone marrow transplantation. Transplantation rine species on Escherichia coli. Pteridines 1996; 7: 1995; 60: 1239-1244. 64-65. 32 Nathan CF. Peroxide and pteridine: A hypothesis 42 Otti Κ, Wirleitner Β, Baier-Bitterlich G, Grammer on the regulation of antimicrobial Τ, Fuchs D, Reibnegger G. Formation of oxygen activity by interferon-g. In: Gresser I. Vilcek J, eds. radicals in solutions of 7,8-dihydroneopterin. Interferon 7. London: Acadcmic Press 1986; 125- Biochem Biophys Res Commun 1999; 264: 262- 143. 267. 33 Witko-Sarsat V, Friedlander M, Capeillere-Blandin 43 Schneemann M, Schoedon G, Hofer S, Blau Ν, C, Nguyen-Khoa T, Nguyen AT, Zingraff J, Jüngers Guerrero L, Schaffner A. Nitric oxide synthase is Ρ, Descamps-Latscha Β. Advanced oxidation pro- not a constituent of the antimicrobial armature of tein products as a novel marker of oxidative stress human mononuclear phagocytes. J Infect Dis 1993; in uremia. Kidney Int 1996; 49:1304-1313. 167: 1358-1363. 34 Fuchs D. Baier-Bitterlich G, Wede I, Wächter Η. 44 Kolb JP, Paul-Eugene N, Damais C, Yamaoka K, Reactive oxygen and apoptosis. In: Scandalios J, Drapier JC, Dugas B. Tnterleukin-4 stimulates ed. Oxidative Stress and the Molecular Biology of cGMP production by IFN-gamma-activated human Antioxidant Defenses. Cold Spring Harbor-New monocytes. Involvement of the nitric oxide syn- York: Cold Spring Harbor Laboratory Press 1997; thase pathway. J Biol Chem 1994; 269: 9811-9816. 139-167. 45 Fuchs D, Murr C, Reibnegger G, Weiss G. Werner 35 MurrC. Fuith L-C, Widner B, Wirleitner B, Baier- ER, Werner-Felmayer G, Wächter H. Nitric oxide B itterlich G, Fuchs D. Increased neopterin con- synthase and antimicrobial armature of human centrations in patients with cancer: indicator of macrophages. J Infect Dis 1994 ; 169: 224-225. oxidative stress Anticanccr Res 1999; 19(3A): 46 Baier-Bitterlich G, Fuchs D. Zangerle R, Bacuerle 1721-1728. PA, Werner ER, Fresser F. Überall F. Baier G, 36 Weiss G, Fuchs D, Hausen A, Reibnegger G, Wächter H. Transactivation of the HIV-1 promoter Werner ER, Werner-Felmayer G, Semenitz E, by 7,8-dihydroneopterin in vitro. AIDS Res Hum Dierich MP, Wächter H. Neopterin modulates toxi- Retroviruses 1997; 13: 173-178. city mediated by reactive oxygen and chlorine 47 Hoffmann G, Schobersberger W, Erede S, Pelzer L, species. FEBS Lett 1993; 321: 89-92. Fandrey J, Wächter H, Fuchs D, Grote J. Neopterin 37 Murr C, Fuchs D, Gössler W, Hausen A, activates transcription factor nuclear factor-kB in Reibnegger G, Werner ER, Werner-Felmayer G, vascular smooth muscle cells. FEBS Lett 1996; Esterbauer H, Wächter H. Enhancement of hydro- 391: 181-184. gen peroxide-induced luminol-dependent chemilu- 48 Razumovitch JA, Semenkova GN, Fuchs D, minescence by neopterin depends on the presence Cherenkevich SN. Influence of neopterin on the of iron chelator complexes. FEBS Lett 1994; 338: generation of reactive oxygen species in human 223-226. neutrophils. FEBS Lett 2003; 549: 83-86. 38 Ideales SJR, Blair JA, Meinschad C, Ziegler I. 49 Solichová D, Melichar B, Svobodová I. Bláha V, Inhibition of monocyte luminol-dependent chemi- Zadák Ζ. Fluorescence analysis of antioxidant vita- luminescence by tetrahydrobiopterin and the free mins and neopterin in nonagenarians. Biomed radical oxidation of tetrahydrobiopterin dihydro- Chromatogr 1999; 13: 117-118. biopterin and dihydropterin. Cell Biochem Funct 50 Sattler W, Leblhuber F, Walli J, Widner B, Fuchs 1988; 6: 191-195. D. Cerebrospinal fluid levels of a-tocopherol and 39 Baier-Bitterlich G, Fuchs D, Murr C, Reibnegger neopterin in patients with dementia. Pteridines G, Werner-Felmayer G, Sgonc R, Bück G, Dierich 1999; 10: 220-224. MP, Wächter H. Effect of neopterin and 7,8-dihy- 51 Hagberg L, Dotevall L, Norkrans G, Larsson M, droneopterin on tumor necrosis factor-a induced Wächter Η, Fuchs D. Cerebrospinal fluid neopterin programmed cell death. FEBS Lett 1995; 364: 234- concentrations in central nervous system infection. 238. J Infect Dis 1993 ; 168: 1285-1288. 40 Murr C, Baier-Bitterlich G, Fuchs D, Werner ER, 52 Fuchs D, Werner ER, Wächter H. Soluble products Esterbauer H, Pfleiderer W, Wächter H. Effects of of immune activation: neopterin. In: Rose NR, neopterin-derivatives on H202-induced luminol Conway de Macario E, Fahey JL, Friedman H, chemiluminescence: mechanistic aspects. Free Penn GM, eds. Manual of clinical Laboratory Radie Biol Med 1996; 21: 449-456. Immunology. Washington DC: American Society

Pteridines/Vol. 15/No. 3 S6 Schroecksnadel Κ. et al.: Neopterin to Monitor Clinical Pathologies Involving IFN-γ Production

for Microbiology 1992; 251-255. Werner ER, Werner-Felmayer G, Wächter Η. 53 Reibnegger G, Auhuber I, Fuchs D, Hausen A, Neopterin as a predictive marker for disease pro- Judmaier G, Prior C, Werner ER, Wächter H. gression in human immunodeficiency virus type 1 Urinary neopterin levels in acute viral hepatitis. infection. Clin Chem 1989; 35: 1746-1749. Hepatology 1988; 8 771-774. 65 Fahey JL, Taylor JMG, Detels R, Hofman B, 54 Reibnegger G, Fuchs D, Grubauer G, Hausen A, Melmed R, Nishanian P, Giorgi JV. The prognostic Wächter H. Neopterin excretion during incubation value of cellular and serological markers in infec- period clinical manifestation and reconvalescence tion with human immunodeficiency virus type 1. Ν of viral infection. In: Pfleiderer W, Wächter H, Engl J Med 1990; 322: 166-172. Curtius HC, eds. Biochemical and Clinical Aspects 66 Zangcrle R, Fuchs D, Reibnegger G, Fritsch P, of Pteridines. Vol 3. Berlin-New York: Walter de Wächter Η. Markers of disease progression in intra- Gruyter 1984; 433-437. venous drug users infected with HIV-1. AIDS 55 Tilg H, Margreiter R, Scriba M, Marth C, 1991; 5: 985-991. Niederwieser D, Aulitzky W, Spielberger M, 67 Krämer A, Biggar RJ, Hampl H, Friedman RM. Wächter H, Huber C. Clinical presentation of CMV Fuchs D, Wächter H, Goedert JJ. Immunologie infection in solid organ tranplant recipients and its markers of progression to acquired immunodefi- impact on graft rejection and neopterin excretion. ciency syndrome are time-dependent and illness- Clin Transplantation 1987; 1: 37-43. specific. Am J Epidermiol 1992; 136: 71-80. 56 Griffin DE, Ward BJ, Jauregui E, Johnson RT, 68 Mellors JW, Kingsley LA, Rinaldo CR, Todd JA. Vaisberg A. Immune activation during measles: Hoo BS, Kokka RP, Gupta P. Quantitation of HIV- and neopterin in plasma and 1 RNA in plasma predicts outcome after serocon- cerebrospinal fluid in complicated and uncompli- version. Ann Intern Med 1995; 122; 573-579. cated disease. J Infect Dis 1990; 161: 449-453. 69 Zangerle R, Steinhuber S, Sarcletti M, Dierich MP, 57 Zaknun D, Weiss G, Glatzl J, Wächter H, Fuchs D. Wächter H, Fuchs D, Möst J. Serum HIV-1 RNA Neopterin levels during acute rubella in children. levels compared to soluble markers of immune Clin Infect Dis 1993; 17: 521-522. activation to predict disease progression in HIV-1 58 Schennach H, Meyersbach P, Schönitzer D, Fuchs infected individuals. Int Arch Allergy Immunol D. Additional neopterin screening to improve safe- 1998; 116: 228-239. ty of blood donations. Pteridines 2000; 11: 76-80. 70 Gisslen M, Norkrans G, Svennerholm B. Hagberg 59 Baize S, Leroy EM, Georges AJ, Georges-Courbot L. The effect on human immunodeficiency virus MC, Capron M, Bedjabaga I, Lansoud-Soukate J, type 1 RNA levels in cerebrospinal fluid after initi- Mavoungou E. Inflammatory responses in Ebola ation of zidovudine or didanosine. J Infect Dis virus-infected patients. Clin Exp Immunol 2002; 1997; 175: 434-437. 128:163-168. 71 Hutterer J, Armbruster C, Wallner G, Fuchs D, 60 Zangerle R, Schönitzer D, Fuchs D, Möst J, Vetter Ν, Wächter Η. Early changes of neopterin Dierich MP, Wächter H. Reducing HIV transmis- concentrations during treatment of human immun- sion by seronegative blood. Lancet 1992; 339; 130- odeficiency virus infection with zidovudine. J 131. Infect Dis 1992; 165: 783-784. 61 Fuchs D, Banekovich M, Hausen A, Hutterer J, 72 Niederwieser A, Joller P, Seger R, Blau Ν, Prader Reibnegger G, Werner ER, Gschnait FD, Dierich A, Bettex JD. Ltithy R, Hirschel B, Schaedelin J, MP, Wächter H. Neopterin estimation compared Vetter U. Neopterin in AIDS, other immunodefi- with the ratio of T-cell subpopulations in persons ciencies and bacterial and viral infections. Klin infected with human immunodeficiency virus-1. Wochenschr 1986; 64: 333-337. Clin Chem 1988; 34: 2415-2417. 73 Strohmaier W, Redl Η, Schlag G, Inthorn D. D- 62 Fuchs D, Wächter H. Neopterin - ein Marker für eythro-neopterin plasma levels in intensive care den zellulären Immunstàtus - Bedeutung bei AIDS, patients with and without septic complications. Crit ARC und AIDS-Risikogruppen, in: AIDS Care Med 1987; 15: 757-760. (Gschnait F, Wolff Κ, eds.), Springer-Verlag, Wien, 74 Brown AE, Dance DAB, Chaowagul W, Webster New York, 1985, pp 97-127. HK, White NJ. Activation of cellular immune 63 Melmed RN, Taylor JMG, Detels R, Bozorgmehri response in melioidosis patients assessed by uri- M, Fahey JL. Serum neopterin changes in HIV- nary neopterin. Trans Roy Soc Trop Med Hyg infected subjects: indicator of significant pathology 1990; 84: 583-584. CD4 Τ cell changes and the development of AIDS. 75 Diez-Ruiz A, Al-Amrani M, Weiss G, Gutierrez- J Aquir Immune Defic Syndr 1989; 2; 70-76. Gea F, Wächter H, Fuchs D. Increased interferon- 64 Fuchs D, Spira TJ, Hausen A, Reibnegger G, gamma and neopterin concentrations in patients

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with acute brucellosis. J Infect Dis 1993; 167: 504- tryptophan degradation in acute Lyme neuroborre- 505. liosis versus late Lyme encephalopathy. Eur J Clin 76 Murr C, Baier-Bitterlich G, Fuchs D, Gerlach D, Chem Clin Biochem 1994; 32: 685-689. Werner-Fclmayer G, Dierich MP, Wächter H. 88 Reibnegger G, Fuchs D. Fuith LC, Hausen A. Streptococcal erythrogenic toxins induce the for- Werner ER, Werner-Felmayer G, Wächter H. mation of neopterin in human peripheral blood Neopterin as a marker for activated cell-mediated mononuclear cclls but not in the human immunity: application in malignant disease. Cancer myelomonocytoma cell line THP-1. Immunobiol Detect Prev 1991; 15: 483-490. 1996; 195: 314-322. 89 Bayram M, Bayram O, Boyunaga H, Ozer G. A 77 Murr C, Gerlach D, Widner B, Dicrich MP, Fuchs research on the level of urine neopterin to see if it D. Neopterin production and tryptophan degrada- may provide a vital clue for a provisional diagnosis tion in humans infected by Streptococcus pyo- of breast cancer in menopausal women. Maturitas genes. Med Microbiol Immunol 2001; 189: 161- 2004; 48: 432-437. 163. 90 Mura Ρ, Piriou A, Tallineau C, Reiss D. La 78 Fuchs D. Hausen A, Kotier M, Kosanowski H, néopterine urinaire: Intérêt dans l'exploration de Reibnegger G, Wächter H. Neopterin as an index of certaines néoplasies. Ann Biol Clin (Paris) 1986: immune response in patients with tuberculosis. 44: 505-510. Lung 1984; 162: 337-346. 91 Denz H, Grünewald Κ, Thaler J, Huber Η, Fuchs 79 Horak E, Gassner I, Solder Β, Wächter Η. Fuchs D. D, Hausen A, Reibnegger G, Werner ER, Wächter Neopterin levels and pulmonary tuberculosis in H. Urinary neopterin as a prognostic marker in infants. Lung 1998; 176: 337-344. haematological neoplasias. Pteridines 1989; 1: KO Hosp M. Elliott AM, Raynes JG, Mwinga AG, Luo 167-170. N. Zangerle R, Pobee JOM. Wächter H, Dierich 92 Reibnegger G, Krainer M, Herold M, Ludwig H. MP, M c Ad am KPWJ, Fuchs D. Neopterin, beta 2- Wächter H. Huber H. Predictive value of inter- microglobulin and the acute phase proteins in HIV- leukin-6 and neopterin in patients with multiple 1- seropositive and -seronegative Zambian patients myeloma. Cancer Res 1991; 51: 6250-6253. with tuberculosis. Lung 1997; 175: 265-275. 93 Reibnegger G, Bichler A, Dapunt O, Fuchs D. 8 I Schmutzhard E, Fuchs D, Hausen A, Reibnegger Fuith LC, Hausen A, Hetzel H, Lutz H, Werner ER, G, Wächter H. Is neopterin—a marker of cell medi- Wächter H. Neopterin as a prognostic indicator in ated immune response — helpful in classifying lep- patients with carcinoma of the uterine cervix. rosy? East Afr Med J 1986; 63: 577-580. Cancer Res 1986; 46: 950-955. 82 Reibnegger G. Boonpucknavig V, Fuchs D, Hausen 94 Reibnegger G, Hetzel H, Fuchs D, Fuith LC. A, Schmutzhard E, Wächter H. Urinary neopterin is Hausen A, Wächter H. Clinical significance of elevated in patients with malaria. Trans Roy Soc neopterin for prognosis and follow-up in ovarian Trop Med Hyg 1984; 78: 545-546. cancer. Cancer Res 1987; 47: 4977-4981. 83 Kern P, Hemmer CJ, Van Damme J, Gruss HJ, 95 Weiss G, Kronberger P, Conrad F, Bodner E, Dietrich M. Elevated tumor necrosis factor alpha Wächter H, Reibnegger G. Neopterin and progno- and interIeukin-6 serum levels as markers for com- sis in patients with adenocarcinoma of the colon. plicated Plasmodium falciparum malaria. Am J Cancer Res 1993; 53: 260-265. Med 1989; 87: 139-143. 96 Kronberger P, Weiss G, Tschmelitsch J, Fuchs D, 84 Brown AE, Webster HK, Teja-Isavadharm P. Salzer GM, Wächter H, Reibnegger G. Predictive Keeratithakul D. Macrophage activation in falci- value of urinary neopterin in patients with lung parum malaria as measured by neopterin and inter- cancer. Eur J Clin Chem Clin Biochem 1995; 33: fe roil-γ. Clin Exp Immunol 1990; 82: 97-101. 831-837. 85 Reibnegger G, Fuchs D, Hausen A, Schmutzhard 97 Prommegger R, Widner B, Murr C, Unger A. E, Wei ner ER, Wächter Η. The dependence of cell- Fuchs D, Salzer GM. Neopterin: a prognostic vari- mediated immune activation in malaria on age and able in operations for lung cancer. Ann Thorac endemicity. Trans Roy Soc Trop Med Hyg 1987; Surg 2000; 70; 1861-1864. 81:729-733. 98 Lewenhaupt A, Ekman P, Eneroth P, Eriksson A, 86 Dotevall L. Fuchs D, Reibnegger G, Wächter H, Nilsson B, Nordstrom L. Serum levels of neopterin Hagberg L . Cerebrospinal fluid and serum as related to the prognosis of human prostatic car- neopterin levels in patients with Lyme neuroborre- cinoma. Eur Urol 1986; 12: 422-425. liosis. Infection 1990; 18:210-214. 99 Kawasaki H, Watanabe H, Yamada S, Watanabe K, 87 Gasse Τ, Murr C. Mayersbach Ρ, Schmutzhard E, Suyama A. Prognostic significance of urinary Wächter Η, Fuchs D. Neopterin production and neopterin levels in patients with hepatocellular car-

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cinoma. Tohoku J Exp Med 1988; 155: 311-318. Werner ER, Wächter H. Urinary neopterin a mark- lOOMurr C, Berchtold J, Norer B, Waldhart E, Wächter er of clinical activity in patients with Crohn's dis- H, Fuchs D. Neopterin as a prognostic parameter in ease. Clin Chim Acta 1986; 155: 11-21. patients with squamous cell carcinomas of the oral 113 Reibnegger G, Bollbach R, Fuchs D, Hausen A, cavity. Int J Cancer 1998; 79: 476-480. Judmaier G, Prior C, Rotthauwe HW, Werner ER, 101 Murr C, Bergant A, Widschwendter M, Heim Κ, Wächter H. A simple index relating clinical activi- Schröcksnadel Η. Fuchs D. Neopterin is an inde- ty in Crohn's disease with Τ cell activation: hemat- pendent prognostic variable in females with breast ocrit, frequency of liquid stools and urinary cancer. Clin Chem 1999; 45: 1998-2004. neopterin as parameters. Immunobiology 1986; 102 Den ζ Η. Fuchs D, Huber H, Nachbaur D, 173: 1-11. Reibnegger G, Thaler J, Werner ER, Wächter H. 114Niederwieser D, Fuchs D, Hausen A, Judmaier G, Correlation between neopterin interferon-gamma Reibnegger G, Wächter Η, Huber C. Neopterin as a and hemoglobin in patients with haematological new biochemical marker in the clinical assessment neoplasias. Eur J Haematol 1990; 44: 186-189. of ulcerative colitis. Immunobiology 1985; 170: 103Diez-Ruiz A. Tilz GR Zangerle R, Baier-Bitterlich 320-326. G, Wächter H, Fuchs D. Soluble tumor necrosis 115Samsonov M, Fuchs D, Reibnegger G, Belenkov factor and neopterin as parameters of cell mediated JN, Nassonov EL, Wächter H. Patterns of serologi- immune activation. Eur J Haematol 1995; 54: 1-8. cal markers for cellular immune activation in 104Denz H, Orth Β, Weiss G, Gallati H, Hermann R, patients with dilated cardiomyopathy and chronic Huber R Wächter H, Fuchs D. Serum soluble tumor myocarditis. Clin Chem 1992; 38: 678-680. necrosis factor receptor 55 is increased in patients llóSamsonov M, Tilz GP, Pisklakov VP, Reibnegger with haematological neoplasias and is associated G, Nassonov EL, Nassonova VA, Wächter H, with immune activation and weight loss. Eur J Fuchs D. Serum-soluble receptors for tumor necro- Cancer 1993; 29A: 2232-2235. sis factor-alpha and interleukin-2 and neopterin in 105 0'Byrne KJ, Dalgleish AG. Chronic immune acti- acute rheumatic fever. Clin Immunol vation and inflammation as the cause of malignan- Immunopathol 1995; 74: 31-34. cy. Br J Cancer 200! ; 85: 473-483. 117Tatzber F, Rabl H, Koriska K, Erhart U, Puhl H. l()6Coussens LM, Werb Z. Inflammation and cancer. Waeg G, Krebs A, Esterbauer H. Elevated serum Nature 2002; 420: 860-867. neopterin levels in atherosclerosis. Atherosclerosis 107 Reibnegger G, Egg D, Fuchs D, Günther R, Hausen 1991; 89: 203-208. A, Werner ER, Wächter H. Urinary neopterin 118Erren M, Reinecke H, Junker R, FobkerM, Schulte reflects clinical activity in patients with rheumatoid H, Schurek JO, Kröpf J, Kerber S, Breithardt G. arthritis. Arthritis Rheumat 1986; 29: 1063-1070. Assmann G, Cullen P. Systemic inflammatory 108Märker-A1 zer G, Diemer O, Strümper R, Rohe M. parameters in patients with atherosclerosis of the Neopterin production in inflammed knee joints: coronary and peripheral arteries. Arterioscler high levels in synovial fluids. Rheumatol Int 1986; Thromb Vase Biol 1999; 19: 2355-2363. 6: 151-154. 119 Weiss G, Willeit J, Kiechl S, Fuchs D, Jarosch E, 109Samsonov MY, Tilz GR Egorova O, Reibnegger G, Oberhollenzer F, Reibnegger G, Tilz GP. Balabanova RM, Nassonov EL, Nassonova VA, Gerstenbrand F. Wächter H. Increased concentra- Wächter H, Fuchs D. Serum soluble markers of tions of neopterin in carotid atherosclerosis. immune activation and disease activity in systemic Atherosclerosis 1994; 106: 263-271. lupus erythematosus. Lupus 1995; 4: 29-32. 120Melichar B, Gregor J, Solichova D, Lukes J, Tichy 1 lONassonov EL, Samsonov MY, Tilz GP, Beketova M, Pidrman V. Increased urinary neopterin in acute TV, Semenkova F,N, Baranov A, Wächter H, Fuchs myocardial infarction. Clin Chem 1994; 40: 338- D. Serum concentrations of neopterin soluble inter- 339. leukin 2 receptor and soluble tumor necrosis factor 121 Gupta S, Fredericks S, Schwartzman RA, Holt DW, receptor in Wegener" s granulomatosis. J Kaski JC. Serum neopterin in acute coronary syn- Rheumatol 1997; 24: 666-670. dromes. Lancet 1997; 349: 1252-1253. Ill Samsonov MY, Nassonov EL, Tilz GP, Geht BM, 122Frick B, Rudzite V, Schroecksnadel K, Kalnins U, Demel U, Gurkina GT, Shtutman VZ, Guseva AG, Erglis A, Trusinskis K, Fuchs D. Homocysteine, Β Wächter H, Fuchs D. Elevated serum levels of vitamins and immune activation in coronary heart neopterin in adult patients with polymyositis/der- disease. Pteridines 2003; 14: 82-87. matomyositis. Brit J Rheumatol 1997; 36: 656-660. 123 Schumacher M, Halwachs G, Tatzber F, Fruhwald 112Prior C, Bollbach R, Fuchs D, Hausen A, Judmaier FM, Zweiker R, Watzinger Ν, Eber B, Wilders- G, Niederwieser D, Reibnegger G, Rotthauwe HW, Truschnig M, Esterbauer H, Klein W. Increased

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neopterin in patients with chronic and acute coro- Transm 2000; 107: 1469-1474. nary syndromes. J Am Coll Cardiol 1997; 30: 703- 136Wirleitner B, Neurauter G. Schröcksnadel K, Frick 707. Β, Fuchs D. Interferon-y-induced conversion of 124Garcia-Moll X. Coccolo F, Cole D, Kaski JC. tryptophan: immunologic and neuropsychiatrie Serum neopterin and complex stenosis morphology aspects. Curr Med Chem 2003; 10: 1581-1591. in patients with unstable angina. J Am Coll Cardiol 137Schennach H, Murr C, Larcher C, Streif W, Pastner 2000; 35: 956-962. E, Zaknun D, Schönitzer D, Fuchs D. Neopterin 125 Ridker PM, Hennekens CH, Buring JE, Rifai Ν. C concentrations in cord blood: a single-cohort study reactive protein and other markers of inflammation of paired samples from 541 pregnant women and in prediction of cardiovascular disease in women. their newborns. Clin Chem 2002; 48: 2059-2061. Ν Engl J Med 2000; 342: 836-843. 138Winkler C, Wirleitner B, Werner ER, Fuchs D. 126Avanzas Ρ, Arroyo-Espliguero R, Cosin-Sales J, Urinary neopterin concentrations in healthy indi- Quiles J, Zouridakis E, Kaski JC. Prognostic value viduals with household contact. Pteridines 2003; of neopterin levels in treated patients with hyper- 14: 35-38. tension and chest pain but without obstructive 139Frick B, Schroecksnadel K, Neurauter G, coronary artery disease. Am J Cardiol 2004; 93: Leblhuber F, Fuchs D. Increasing production of 627-629. homocysteine and neopterin and degradation of 127Fuchs D. Jaeger M, Widner B, Wirleitner B, tryptophan with older age. Clin Biochem 2004; 37: Artner-Dworzak E, Leblhuber F. Is hyperhomocys- 684-687. teinemia due to oxidative depletion of folate rather 140Reibnegger G. Huber LA, Jürgens G, Schönitzer D, than insufficient dietary intake. Clin Chem Lab Werner ER, Wächter H, Wick G, Traill ΚΝ. Med 1991; 39: 691- 694. Approach to define "normal ageing" in man 128Fredrikson S, Link H, Eneroth P. CSF neopterin as immune function serum lipids lipoproteins and marker of disease activity in multiple sclerosis. neopterin levels. Mech Ageing Dev 1988; 46: 67- Acta Neurol Scand 1987; 75: 352-355. 82. 129Giovannoni G, Lai M, Kidd D, Thorpe JW, Miller 141 Diamondstone LS, Tollerud DJ, Fuchs D, Wächter DH, Thompson AJ, Keir G, Feldmann M, H, Brown LM, Maloney E, Kurman CC, Nelson Thompson EJ. Daily urinary neopterin excretion as DL, Blattner WA. Factors influencing serum an immunological marker of disease activity in neopterin and ß2-microglobulin levels in healthy multiple sclerosis. Brain 1997; 120: 1-13. diverse population. J Clin Immunol 1994; 14: 368- 130 Westarp ME. Fuchs D, Bartmann Ρ, Hoff- 374. Jörgensen R, Clausen J, Wächter H, Kornhuber 142Ledochowski M, Murr C, Widner Β, Fuchs D. HH. Amyotrophic lateral sclerosis - an enigmatic- Association between insulin resistance body mass disease with B-cellular and anti-retroviral immune and neopterin concentrations. Clin Chim Acta responses. Eur J Med 1993; 2: 327-332. 1999; 282: 115-123. 13 1 Leblhuber F, Walli J, Demel U, Tilz GP, Widner B, 143Ledochowski M, Murr C, Jäger M, Fuchs D. Fuchs D. Increased serum neopterin concentrations Dehydroepiandrosterone ageing and immune acti- in patients with Alzheimer's disease. Clin Chem vation. Exp Gerontol 2001; 36: 1739-1747. Lab Med 1999; 37: 429-431. 144Reibnegger G, Aichberger C, Fuchs D, Hausen A, 1 32Leblhuber F, Walli J, Jellinger K, Tilz GP, Widner Spielberger M, Werner ER, Margreiter R, Wächter B, Laccone F, Fuchs D. Activated immune system H. Posttransplant neopterin excretion in renal allo- in patients with Huntington's disease. Clin Chem graft recipients - a reliable diagnostic aid for acute Lab Med 1998; 36: 747-750. rejection and a predictive marker of long-term graft 133Frick B, Neurauter G, Diez-Ruiz A, survival. Tranplantation 1991; 52: 58-63. Schroecksnadel K, Wirleitner B, Leblhuber F. 145Müller Τ, Keuchel M, Schindler S, Steinmetz A, Fuchs D. Neopterin and oxidation products in the Feiber H, Lange H. Differential diagnosis of trans- blood of patients with various forms of dementia. plant function disorders in therapy with monoclon- Pteridines 2003; 14: 88-93. al antibodies OKT3. Helv Chir Acta 1991; 58: 271- 134Widner B, Leblhuber F, Fuchs D. Increased 275. neopterin production and tryptophan degradation in 146Grebe SO, Mueller TF. Immune monitoring in advanced Parkinson's disease. J Neural Transm organ transplantation using neopterin. Curr Drug 2002; 109: 181-189. Metab. 2002; 3: 189-202. 135Leblhuber F, Walli J, Artner-Dworzak E, Vrecko K. 147Hausen A, Aichberger C, Königsrainer A, Weiss G, Widner B, Reibnegger R, Fuchs D. Margreiter R, Wächter H. Biliary and urinary Hyperhomocysteinemia in dementia. J Neural neopterin concentrations in monitoring liver-allo-

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graft recipients. Clin Chem 1993; 39: 45-47. 157Zvetkova E, Wirleitner B, Tram NT, Schennach H, 148 Königsrainer A, Reibnegger G, Ofner D, Klima G, Fuchs D. Aqueous extracts of Crinum latifolium Tauscher T, Margreiter R. Pancreatic juice (L.) and Camellia sinensis show immunomodulato- neopterin excretion: reliable marker for detection ry properties in human peripheral blood mononu- of pancreatic allograft rejection. Transplant Proc clear cells. Intern Immunopharmacol 2001; 1: 1990;22:671-672. 2143-2150. 149Niederwieser D. Huber C, Gratwohl A, Bannert P, 158Winkler C, Wirleitner B, Schroecksnadel K. Puchs D, Hausen A, Reibnegger G, Speck B, Schennach H, Mur E, Fuchs D. In vitro effects of Wächter H. Neopterin as a new biochemical mark- two extracts and two pure alkaloid preparations of er in the clinical monitoring of bone marrow trans- Uncaria tomentosa on peripheral blood mononu- plant recipients. Transplantation 1984; 38: 497- clear cells. Planta Med 2004; 70: 205-210. 500. 159Neurauter G, Wirleitner B, Schroecksnadel K. 1 50Reissigl H, Rosmanith P, Schönitzer D. HIV anti- Schennach H, Ueberall F. Fuchs D. PADMA 28 gen study. Beitr Infusionsther 1989; 24: 14-17. modulates interferon-y-induced tryptophan degra- 151 Hönlinger M, Fuchs D, Hausen A, Reibnegger G, dation and neopterin production in human PBMC Schönitzer D, Werner ER, Reissigl H, Dierich MP, in vitro. Intern Immunopharmacol 2004; 4: 833- Wächter H. Serum neopterin determination for the 839. add itional safeguarding of blood transfusions. Our 160Neurauter G, Wirleitner Β, Schroecksnadel Κ. experiences with 76587 blood donors. Dtseh Med Schennach Η, Fuchs D. Wine and grape juice mod- Wochenschr 1989; 114: 172-176. ulate interferon-y-induced neopterin production 152Schennach H. Hessenberger G, Mayersbach P, and tryptophan degradation in human PBMC. Schönitzer D. Fuchs D. Acute cytomegalovirus Pteridines 2004; 15: 1-9. infections in blood donors are indicated by lólNeurauter G. Wirleitner Β, Laich A, Schennach Η. increased serum neopterin concentrations. Med Weiss G, Fuchs D. Atorvastatin suppresses inter- Microbiol Immunol 2002; 191: 115-118. feron-γ- induced neopterin formation and trypto- 153 Schcnnach H. Lanthaler AJ. Mayersbach P, Ulmer phan degradation in human peripheral blood H. Müll Κ, Schönitzer D, Fuchs D, Larcher C. mononuclear cells and in monocytic cell lines. Clin Human parvovirus Β 19 detection in asymptomatic Exp Immunol 2003; 131: 264-267. blood donors: association with increased neopterin 162Waller RB, Fuchs D, Weiss G. Walter TR. concentration. J Infect Dis 2002 ; 168: 1494-1497. Reinhard WH. HMG-CoA reductase inhibitors arc I 54Schennach H. Schoenitzer D, Fuchs D. Association associated with decreased serum neopterin levels in between chronic hepatitis C virus infection and stable coronary artery disease. Clin Chem Lab Med increased neopterin concentrations in blood dona- 2003;41: 1314-1319. tions. Clin Chem 1998; 44: 2225-2226. 163 Werner-Felmayer G, Baier-Bitterlich G, Fuchs D, 155Altindag ZZ, Werner-Felmayer G. Sahin G, Hausen A, Murr C, Reibnegger G, Werner ER. Wächter H, Fuchs D. Colchicine derivatives inhib- Wächter H. Detection of bacterial pyrogens on the it neopterin production in human peripheral blood basis of their effects on gamma interferon-mediat- mononuclear cells (PBMC). Clin Exp Immunol ed formation of neopterin or nitrite in cultured 1997; 107: 574-577. monocyte cell lines. Clin Diagn Lab Immun 1995; 156Gruber A, Murr C. Wirleitner B, Werner-Felmayer 2:307-313. G, Fuchs D. Histamine suppresses neopterin pro- duction in the human myelomonocloma cell line 'ΓΗΡ-1. Immunol Lett 2000; 72: 133-136.

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