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.

/pdf/immune-response-associated-production-of-neopterin-release-28pw8ix4bp.pdf

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

The pathogenesis of central nervous system (CNS) disease in acquired immunodeficiency syndrome (AIDS) is poorly understood but may be related to specific effects of the immune system. Cytokines such as tumor necrosis factor and interleukin-1 may have toxic effects on CNS cells and have been postulated to contribute to the pathogenesis of the neurological complications of human immunodeficiency virus (HIV) infection. To characterize viral and immunological activity in the CNS, frozen specimens taken at autopsy from the cerebral cortex and white matter of HIV-seropositive and -seronegative individuals were stained immunocytochemically for mononuclear cells, major histocompatibility complex (MHC) antigens, HIV, astrocytes, and the cytokines interleukin-1 and -6, tumor necrosis factor-α and -β, and interferon γ. Levels of soluble CD4, CD8, and interleukin-2 receptor, as well as interferon γ, tumor necrosis factor-α, β2-microglobulin, neopterin, and interleukin-6 and -1 β were assayed in the cerbrospinal fluid and plasma of many of these individuals during life. The HIV-seropositive group included individuals without neurological disease, those with CNS oppotunistic infections, and those with HIV encephalopathy. Perivascular cells, consisting primarily of macrophages with some CD4+ and CD8+ T cells and rare B cells, were consistently MHC class II positive. MHC class II antigen was also present, on microglial cells, which were frequently positive for tumor necrosis factor-α. HIV p24 antigen, when present, was found on macrophages and microglia. Endothelial cells were frequently positive for interleukin-1 and interferon γ and less frequently for tumor necrosis factor and interleukin-6. There were gliosis and significant increases in MHC class II antigen, interleukin-1, and tumor necrosis factor-α in HIV-positive patients compared to HIV-negative brains. Cerebrospinal fluid from most of the patients tested had increased levels of tumor necrosis factor, β2-microglobulin, and neopterin. There was no correlationin HIV-positive individuals between levels of cytokines and the presence or absence of CNS disease. These data indicate that there is a relative state of “immune activation” in the brains of HIV-positive compared to HIV-negative individuals, and suggest a potential role for the immune system in the pathogenesis of HIV encephalopathy.

Cytokine expression in the brain during the acquired immunodeficiency syndrome.

Publisher Summary This chapter focuses on the immunological basis and clinical experiences with neopterin as an indicator for activation of the cell-mediated immune system. Neopterin was isolated from larvae of bee, worker bees, and royal jelly. Comprehensive information on the chemistry of pteridines is provided. Synthetic methods for some natural pteridines are reviewed, and the reactivity of pteridines is examined. The chapter discusses some reactions that are important for measurement of neopterin in biological specimens. The low-weight metabolite neopterin is biosynthetically derived from guanosine triphosphate via 7, 8-dihydroneopterin triphosphate. In vitro, human monocytes/macrophages produce neopterin when stimulated by interferon-γ released from activated T cells. High neopterin levels were observed in clinical settings recognized to involve activation of cell-mediated immunity in acute allograft rejections, viral infections, infections by intracellular parasites and bacteria, autoimmune diseases, and certain malignancies. Studies of neopterin levels in groups at high risk for AIDS and in patients infected with HIV have demonstrated that activation of T lymphocytes and macrophages represents a crucial event for HIV production. In malignant diseases, the degree of neopterin elevation is a measure of the clinical activity and in some tumor types, serves as a measure of the extent of disease. In ovarian cancer, cancer of the uterine cervix, prostatic tumor, and carcinoma of the lung, neopterin is of predictive value.

Neopterin as marker for activation of cellular immunity: immunologic basis and clinical application.

THERE is an obvious need for a marker that will differentiate one type of lymphocyte from another. The need has become urgent in view of recent evidence suggesting that there are at least two populations of lymphocytes, one thymus-derived and one bone marrow-derived, which participate in different ways in the immune response1. The theta (θ) isoantigen (θ is determined by a single locus with two alleles: θAKR found in AKR and RF mice and θC3H present in most other inbred strains of mice tested), described by Reif and Allen2,3, which is found chiefly in thymus lymphocytes and brain, and to a lesser extent in peripheral lymphocytes in mice, seemed a possible antigenic marker of thymus-derived lymphocytes. To establish that θ is such a marker, it is necessary to demonstrate that there is a discrete population of peripheral lymphocytes which carry the antigen and that these cells are thymus-dependent.

Theta isoantigen as a marker of thymus-derived lymphocytes in mice (Reprinted from Nature vol 224, pg 378-379, 1969)

Nitric oxide synthase (NOS) has received immense interest as an antimicrobial and antitumoral effector system of mononuclear phagocytes from rodents. Because there is increasing doubt that an analogous system exists in human macrophages, NOS was reexamined in these cells. Under tightly controlled conditions, with murine macrophages as positive controls, human macrophages failed to secrete nitric oxide (< 0.1 mumol/10(6) cells/24 h), even after activation with endotoxin, interferon-gamma, granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, bacteria, or proliferating lymphocytes. The discrepancy between murine and human macrophages depended on neither the anatomic source (blood, peritoneum), the agent used for activation, nor the duration of activation. NOS activity was paralleled by metabolization of L-arginine to L-citrulline. Exogenous tetrahydrobiopterin, an essential cofactor of NOS not synthesized by human macrophages, did not support NOS activity in human macrophages. Also, no NOS activity was found in cellular subfractions of human macrophages. It appears that in humans, the inducible high-output NOS is not conserved as an antimicrobial system of macrophages.

/pdf/nitric-oxide-synthase-is-not-a-constituent-of-the-yrdnmb3vu4.pdf

Nitric Oxide Synthase Is Not a Constituent of the Antimicrobial Armature of Human Mononuclear Phagocytes

In a recent publication, evidence was presented that cellular immune responses are associated with increased in vivo and in vitro excretion of neopterin. Our study aimed at investigating the biosynthesis of unconjugated pterins in highly purified human macrophages and T lymphocytes before and during stimulation with supernatants of activated T cells or with recombinant human interferon-gamma (IFN-gamma) by monitoring the following parameters: substrate concentration (GTP, guanosine triphosphate), activity of the enzyme initiating the biosynthesis of pterins (GTP-cyclohydrolase I) and product concentrations of total neopterin, biopterin, and pterin. In contrast to T cells and other tissues, macrophages were unable to produce tetrahydrobiopterin. This was indicated by our failure to detect biopterin and pterin. Instead, products of the first biosynthetic step accumulated, which were measured as total neopterin. We concluded that in macrophages the other enzymes required for biosynthesis of tetrahydrobiopterin are limiting. GTP concentration correlated with GTP cyclohydrolase I activity. An increase in both was induced by IFN-gamma and suppressed by neutralization of T-cell supernatants with monoclonal antibodies having specificity for IFN-gamma. Addition of tetrahydrobiopterin to the culture medium only led to a suppressed increase in GTP cyclohydrolase I activity and neopterin, but not in GTP concentration. Thus, it appears that IFN-gamma selectively stimulates the early steps of pterin biosynthesis in macrophages, thereby leading to accumulation and excretion of dihydroneopterin and neopterin. Although the physiological role of this phenomenon remains obscure, the fact that it seems to reflect endogenous release of IFN-gamma deserves particular attention.

Interferon-γ Enhances Biosynthesis of Pterins in Peripheral Blood Mononuclear Cells by Induction of GTP-Cyclohydrolase I Activity

Zirkulierende Lymphocyten setzen sich aus funktionell heterogenen Zellen zusammen, welche mit morphologischen Methoden allein nur ungenugend differenziert werden konnen. Unter Verwendung immunologischer und autoradiographischer Methoden wurden Lymphocyten mit Determinanten leichter (kappa) Ketten, Lymphocyten mit Membranreceptoren fur Immun-Komplement-Komplexe, lymphatische Zellen mit cytoplasmatischem Immunglobulingehalt und Lymphocyten in DNS-Synthese bestimmt. Gegenuber Normalpersonen waren bei Patienten mit chronischer Lymphadenose Abweichungen an mehreren dieser Lymphocytenpopulationen nachweisbar. Die Ergebnisse werden im Hinblick auf das Konzept thymus- und knochenmarkabhangiger Lymphocyten diskutiert, deren Differenzierung mit immunologischen Methoden erleichtert wird.

Die Differenzierung menschlicher Blutlymphocyten mit immunologischen und autoradiographischen Methoden

The object of this study was to investigate the effects of different single doses of recombinant interferon-γ (rIFN-γ) on white blood cell counts, differential blood counts, and the relative composition of T-cell subsets in the peripheral blood of cancer patients. Sixteen patients suffering from metastasizing renal cell carcinoma received 10, 100, or 500 μg of rIFN-γ three times at weekly intervals. After a therapy-free interval of 2 weeks, the next dose level was applied. The order of dose levels was assigned randomly to each patient. White blood cells, differential blood counts, and the number of Leu1, Leu3, Leu2a, Leu7, and HLA DR+ cells were measured immediately before and at 4, 24, 48, 72, 96, and 168 h after the administration of single doses of rIFN-γ. Results indicated that white blood cells were transiently removed from the blood circulation after administration of IFN-γ. Monocytes, HLA DR+ cells, and Leu7+ cells were reduced to below 50% of pretreatment values 4 h after application of t...

Acute Effects of Single Doses of Recombinant Interferon-γ on Blood Cell Counts and Lymphocyte Subsets in Patients with Advanced Renal Cell Cancer

Activated T-lymphocytes represent crucial effector cells. They are pathogenetically involved into various disease states such as allograft rejection or viral infection. So far their assessment is laborious and rarely possible in clinical routine. In this review article we present the compount neopterin as a new biochemical marker for the in vivo and in vitro detection of activated T-lymphocytes. Our main finding was that in vitro as well as in vivo stimulation of T-lymphocytes with foreign and chemically or virally modified autologous cells in invariably associated with increased neopterin production. It thus appeared that neopterin might represent a potential marker for biochemical monitoring of diseases caused by or associated with T-lymphocyte activation. Our clinical experience with neopterin determination in allograft rejection and in infectious or autoimmune states strongly support this view. We conclude that evaluation of neopterin represents a useful and simple tool for the biochemical monitoring of immunological and/or malignant states.

Neopterin, ein neuer biochemischer Marker zur klinischen Erfassung zellulärer Immunreaktionen

Although cachexia is a common feature of cytomegalovirus infection, little is known about its cause. To explore any contributory role that tumour necrosis factor-alpha (TNF) might have the serum concentrations of TNF in eight patients who developed CMV disease after liver transplantation were investigated. All patients exhibited pronounced and long lasting increases in TNF serum concentrations. Increased endogenous TNF concentrations were associated with weight loss and anorexia. In contrast, liver transplant recipients without CMV disease showed no weight loss.

https://jcp.bmj.com/content/jclinpath/44/6/519.full.pdf

Cachexia and tumour necrosis factor-alpha in cytomegalovirus infection.

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