Neopterin production and tryptophan degradation during 24-months therapy with interferon beta-1a in multiple sclerosis patients

Abstract

BackgroundIncreased synthesis of neopterin and degradation of tryptophan to kynurenine, measured as kynurenine/tryptophan ratio (kyn/trp ratio), are considered in vitro markers of interferon beta-1a (IFNβ-1a) activity. The aim of the study was to investigate the dynamic profile of neopterin and kyn/trp ratio in patients with relapsing remitting multiple sclerosis (RRMS) treated with two different doses of IFNβ-1a over a period of 24 months.MethodsRRMS patients (n = 101) received open-label IFNβ-1a 22 mcg (low dose, LD) or 44 mcg (high dose, HD) subcutaneously (sc), three times weekly for 24 months. Serum measurements of neopterin, kyn/trp ratio and neutralizing antibodies (NAbs) were obtained before treatment (i.e., at baseline) and 48 hours post-injection every 3 months thereafter. Clinical assessments were performed at baseline and every 6 months. Changes in biomarkers over time were compared between LD- and HD-group as well as between patients with/without relapses and with/without NAbs using Analysis of Variance and Mann-Whitney tests.ResultsNeopterin (p < 0.001) and kyn/trp ratio (p = 0.0013) values increased over time vs baseline in both treatment groups. Neopterin values were higher (p = 0.046) in the HD-compared to the LD-group at every time point with the exclusion of months 21 and 24 of therapy. Conversely, there were no differences between the two doses groups in the kyn/trp ratio with the exclusion of month 6 of therapy (p < 0.05). Neopterin levels were significantly reduced in NAb-positive patients starting from month 9 of therapy (p < 0.05); the same result was observed for kyn/trp ratio but only at month 9 (p = 0.02). Clinical status did not significantly affect neopterin production and tryptophan degradation.ConclusionsAlthough differences in serum markers concentration were found following IFNβ administration the clinical relevance of these findings needs to be confirmed with more detailed studies.

Kynurenines in CNS disease: regulation by inflammatory cytokines

“…Therapeutically relevant concentrations of IFN-β, a standard fist-line immunomodulatory treatment for MS, leads to induction of IDO mRNA and a significant increase in the production of QUIN by human monocyte-derived macrophages (Guillemin et al, 2001 ). In MS patients, treatment with IFN-β leads to significant acute elevations in plasma or serum L-KYN levels and K/T ratio compared to baseline measurements, consistent with the induction of IDO in response to IFN-β (Amirkhani et al, 2005 ; Durastanti et al, 2011 ). Given the hypothesized role of KP metabolism in the mechanism underlying the depressive side-effects associated with IFN-α-based immunotherapy (Bonaccorso et al, 2002a ), KP activation may be similarly involved in the depressive side-effects often reported for MS patients undergoing IFN-β treatment (Goeb et al, 2006 ).…”

HELZ2 Is an IFN Effector Mediating Suppression of Dengue Virus

“…Interestingly, a role for type I IFNs in tryptophan degradation has been well described, but has not previously included FICZ. IFN beta induces indoleamine 2,3-dioxygenase (IDO), the enzyme responsible for tryptophan degradation into kynurenine and other metabolites (not FICZ), which have been implicated in IFN immune response, including that observed during IFN treatment of multiple sclerosis (Meyer et al, 1992 ; Durastanti et al, 2011 ). Furthermore, IDO activity induced by IFN gamma has been described to have antiviral properties against the DNA virus HSV-2 (Adams et al, 2004 ).…”

Effect of immune activation on the kynurenine pathway and depression symptoms – A systematic review and meta-analysis

“…A total of 315 patients (200 men and 152 women; mean age: 47 standard deviation (SD): 4.3) that received IFN-α and took part in the prospective follow up. Data from the other five studies are summarized in Table 1(one IFN-α (Raison et al, 2010), two IFN-β (Amirkhani et al, 2005;Durastanti et al, 2011), two LPS (Kruse et al, 2019;Padberg et al, 2012) (Figure 2). Also, due to limitations on QUIN and KYNA data, full quantitative analysis was not possible.…”