Proefschrift

The aims of the study

The accumulated knowledge about the organization and function of the human immune system contributes to a better understanding of the pathogenesis of many diverse disorders and is opening new avenues for therapeutic regimens. In this thesis one component of the immune system, neopterin, has been studied to determine the status of the immune system in different inflammatory diseases and to evaluate the use of it in monitoring therapeutic efficacy.

Chapter 1

In chapter 1 an up-to-date review is presented of the literature focused on the immunological and physiological properties of neopterin. 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 pro duce neopterin when stimulated by interferon-y. 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 allo graft 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 ant.ioxidant. Ample evidence has been presented that in psoriatic skin immune activation takes place leading to interferon-yproduction by T lymphocytes.

Chapter 2

In chapter 2 untreated patients suffering from mild to severe psoriasis, immune activation was monitored by serum IL-2 receptor, soluble CD27 and neopterin levels.

Chapter 3

In chapter 3 of this thesis the serum neopterin concentration was evaluated as an additional marker for disease activity in the primary cutaneous T cell lymphomas: mycosis fungoides and Sézary syndrome. The diagnosis was made on clinical and histological criteria according to the classification of the European Organization for Research and Treatment of Cancer (EORTC). Results we re compared with those of patients with psoriasis, atopic dermatitis and healthy controls.

Reactions, a common phenomenon among leprosy patients under treatment, require early detection and proper management to prevent serious nerve damage.

It is generally accepted that these reactional states are immunologically mediated, and as such, improve with treatment with immunomodulatory drugs such as corticosteroids.

Chapter 4

In chapter 4 we studied the relationship between the occurrence of leprosy reactions and serum neopterin concentrations, as well as the influence of treatment with corticosteroids. We used banked sera obtained from leprosy patients before, during, and af ter reaction. We compared neopterin levels in single serum samples from leprosy patients on treatment with and without reaction, with untreated controls, and when available, serial samples from patients with and without reaction. Sarcoidosis is an inflammatory multiorgan disorder of unknown origin, characterized by the infiltration of T lymphocytes and mononuclear phagocytes and by the formation of noncaseating granulomas in the affected organs. So far, prognostic parameters predicting deterioration are missing in untreated sarcoidosis. Current concepts of the immuno-pathogenesis of the disease include local stimulation and replication of activated T lymphocytes and macrophages via a complex cytokine network

Chapter 5

In chapter 5 serum neopterin concentrations were compared with two other serum parameters, angiotensin converting enzyme and lysozyme to evaluate the value of this parameters before, during and after treatment of (sub)acute and chronic sarcoidosis. Serum neopterin, angiotensin converting enzyme and lysozyme concentrations were measured in untreated patients with pulmonary tuberculosis and compared to those in patients with sarcoidosis to determine the usefulness of these serum parameters in an another granulomatous condition.

Chapter 6

In chapter 6 patients with visceralleishmaniasis and cutaneous leishmaniasis were studied. The diagnosis was confirmed by demonstration of parasites in samples from skin, aspirates of lymph node, bone marrow or spleen. Serum neopterin levels were determined during a longitudinal study of a population of visceralleishmaniasis patients treated with sodium stibogluconate. The aim of the study was to investigate the value of the serum neopterin concentration as a marker of disease activity and as a parameter of the efficacy of the treatment. There is a need for a simple test for field use which allows early detection of an infection and a fast determination for an useful treatment. The extent and activity of infections with intracellular microorganisms e.g. Mycobacterium tuberculosis, MIeprae and Leishmaniasis correlate significantly with elevated neopterin levels.

Chapter 7

In chapter 7 a rapid and simple semi-quantitative dip stick assay for the determination of the serum neopterin concentration is described which may be valuable as a diagnostic tool and to monitor the effectiveness of therapy.

Samenvatting en conclusies

Stellingen behorende bij het proefschrift

SERUM NEOPTERIN AS AN IMMUNOLOGICAL MARKER OF DISEASE ACTIVITY IN INFLAMMATORY DISEASES

1. Neopterine waarden geven een beter beeld dan het bepalen van de bezinking (BSE) als parameter voor de activiteit van een ziektebeeld bij infectie ziekten daar de waarde in het serum snel daalt en normaliseert in navolging van een behandeling.
2. Achtereenvolgende bepaling van het serum neopterine waarden bij een patiënt kunnen nuttig zijn voor het bepalen van het beleid bij de behandeling van onstekingsziekten.
3. Om de ziekteactiviteit bij een patiënt met sarcoidose te vervolgen is de bepaling van de serum neopterine waarde beter dan de bepaling van het Angiotensin Converting Enzyme (ACE) in het serum.
4. De hypothese dat cel gemedieerde immuniteit (CMI) een rol speelt in Erythema Nodosum Leprosum (ENL) wordt gesteund door verhoogde serum neopterine waarde.
5. De waarde van neopterine in het serum bij patiënten met borderline lepra kan nuttig zijn voor het differentiëren tussen enerzijds, onbehandelde patiënten en patiënten met een recidief en anderzijds patiënten met een Reversal Reaction (RR).
6. Tolerantie betekent niet zich willoos laten overtroeven door andersdenkenden, maar wel samen met andersdenkenden de grens definiëren.
7. De ene cultuur is niet beter dan de andere cultuur .Ze is alleen anders. De meerwaarde van een multiculturele samenleving is gelegen in de herkenning en de erkenning van het anders zijn.
8. De inzet van welgestelden voor het verrichten van verpleegkundige en andere zorg taken, in de geest van de uitspraken van Mgr. M. Muskens, zal leiden tot een hogere waardering van de beroepen van verpleegkundige en verzorgende.
9. Ondanks verbeterende diagnostiek in de bestrijding van lepra staat menselijke zorg centraal.
10. Man must not play God.

F.FV. Hamerlinck, september 1999.