Giovannoni, Gavin; (1998) Urinary neopterin: An inflammatory marker of disease activity in multiple sclerosis. Doctoral thesis (Ph.D.), University College London.

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Abstract

Although inflammation probably plays a central role in the pathogenesis of multiple sclerosis (MS), suitable immunological markers of disease activity have remained elusive. Neopterin, an established pro-inflammatory marker of interferon-γ (IFNγ) induced macrophage activity, was investigated. In addition, the in vitro control of monocyte neopterin production by cytokines was studied. Urinary neopterin excretion was chosen over cerebrospinal fluid and serum neopterin, as it maximises neopterin's sensitivity and allows for frequent monitoring. High performance liquid chromatography (HPLC) methods were set-up and validated to measure neopterin in urine and cell culture supernatants. Cell culture experiments using THP-1 cells (monocytic leukaemic cell line) and monocytes (purified by centrifugal elutriation) confirmed the stimulatory effects of pro-inflammatory cytokines (IFNγ, IL1, TNFα, GMCSF) and provided some new insights with regard to the "anti-inflammatory" cytokines (IL4, IL13, IL10, TGFβ) on neopterin production. New observations with regard to the mechanisms of action of IFNγ were also observed. Baseline studies on normal subjects confirmed that urinary neopterin excretion is subject to a diurnal rhythm. Cross-sectional and longitudinal studies in patients with MS demonstrated that urinary neopterin excretion is increased in all clinical subtypes of the disease. Increased urinary neopterin excretion occurs in association with clinical relapse and correlates with the appearance of new Gd-enhancing lesions on MRI. This thesis provides new insights into the immunology of monocyte/macrophage neopterin production and the immunopathogenesis of MS. It demonstrates the potential value of neopterin as an inflammatory marker of disease activity in MS. This work has resulted in two prospective long-term studies, involving patients with early relapsing and primary progressive MS, being set-up to investigate urinary neopterin excretion as a surrogate marker of disease progression.

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