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.

Anti-retroviral effects of interferon-α in AIDS associated Kaposi's sarcoma

Neopterin was discovered in bee larvae, in worker bees and in royal jelly. The compound was termed "neopterin" to denote that it might start a new (Greek, neo) epoch in pteridine research. Increased concentrations of neopterin were reported in patients with viral infections, suggesting that increased neopterin may originate from the immune response of patients to the infections. In vitro studies revealed that human monocytes/macrophages produce neopterin when stimulated by interferon-gamma. Neopterin can easily be detected in serum and urine. The most important clinical applications for the determination of neopterin are prognostic indicator of malignant diseases, follow-up control of chronic infections, monitoring of immune-stimulatory therapy, differential diagnosis of acute viral and bacterial infections, prognostic indicator in HIV infections and early indications of complications in allograft recipients. In recent years new physiological functions of neopterin have been discovered such as inducing or enhancing cytotoxicity, inducing apoptosis and the role of a chain breaking antioxidant. This review will focus on the immunological and physiological properties of neopterin.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1600-0625.1999.tb00367.x

Neopterin: a review.

Elevated serum neopterin levels in atherosclerosis

Endogenous release of interferon-gamma and diminished response of peripheral blood mononuclear cells to antigenic stimulation

We have recently shown that interferon-gamma is capable of activating the key enzyme of pterin biosynthesis in macrophages. This leads to excretion of the stable degradation product neopterin. In this article we present experimental evidence suggesting that stimulation of T cells by alloantigens is associated with release of interferon-gamma--which, in the case of rejection, is locally restricted and not always detectable in the bloodstream. Neopterin induced by this lymphokine, however, readily penetrates tissue barriers and is detectable in the serum. This conclusion is based on two different sets of observations: (1) If supernatants of MLCs are compared with sera from patients with documented acute rejection episodes for their interferon-gamma and neopterin levels, a marked gradient is observed to exist between interferon levels measured in vitro and in vivo; this is not the case for neopterin for which comparable levels were seen. (2) Detection of interferon-gamma in sera of allograft recipients invariably precedes an increase of neopterin; on the other hand, increasing neopterin counts are also seen in the absence of detectable interferon-gamma levels in the serum. It thus appears that although interferon-gamma release during allograft rejection is primarily restricted to the tissue, evaluation of certain metabolites of interferon-dependent metabolic pathways enables definition of its endogenous release. Whereas interferon gamma represents a less reliable marker in the monitoring of rejection episodes, it might offer an additional means to differentiate rejection from systemic infections. Such a discrimination can not be achieved with the neopterin marker.

Relationship of interferon-gamma and neopterin levels during stimulation with alloantigens in vivo and in vitro.

The number of large granular lymphocytes (LGL) and the capacity of peripheral blood mononuclear cells (PBMC) to lyse K 562 target cells in a natural killer (NK)-like fashion was evaluated in seven hairy cell leukemia (HCL) patients undergoing treatment with recombinant interferon-alpha-2 (rIFN-alpha-2) In HCL patients, whose peripheral blood showed high numbers (≧15×103/μl) of leukemic cells the number of LGL and their capacity to lyse K 562 tumor target cells were very low prior to treatment but increased significantly (p<005) following interferon (IFN) therapy In patients with low numbers of hairy cells (HC) in their peripheral blood, both these parameters were higher and remained largely unaffected throughout IFN treatment In vitro, HC proved to be completely insensitive to natural killing when tested against unstimulated and IFN-activated LGL from healthy donors These results fail to support the concept of IFN-mediated enhancement of host antitumor actions, responsible for the favourable clinical results in HCL

Alpha-interferon induces remission in hairy cell leukemia without enhancement of natural killing

This study aimed to investigate high molecular weight surface glycoprotein (S-GP) patterns on various types of human leukocytes. S-GP were externally labelled by the Galactose-oxidase-NaB3H4 technique. Results based on the analysis of 120 samples derived from different types of normal and malignant leukocytes indicate that (i) the relative expression of high molecular weight S-GPs changes during haemopoietic cell differentiation and (ii) to some extent these changes enable the classification of human leukocytes.

Surface glycoproteins (S-GP) on normal and malignant human leukocytes.

Evaluation of spontaneous lymphocyte proliferation by single cell autoradiography in human allograft recipients

Influence of ethylene-2,2'-bis (dithio)bis(ethanol) on certain human in vitro and in vivo lymphocyte functions.

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