☆ 4.7 Article

Expression and regulation of IFNα/β receptor in IFNβ-treated patients with multiple sclerosis

NEUROLOGY (2008)

Journal

NEUROLOGY

Volume 71, Issue 24, Pages 1940-1947

Publisher

LIPPINCOTT WILLIAMS & WILKINS

DOI: 10.1212/01.wnl.0000327340.50284.8d

Keywords

Funding

Fondazione Italiana Sclerosi Multipla [2007/R/6]
Fondazione per la Ricerca Biomedica
ONLUS
S. Luigi Gonzaga ONLUS
European Commission [018926]

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Abstract

Background: The cytokine interferon beta (IFN beta) is successfully used in the treatment of multiple sclerosis (MS), although there is a high degree of variability in the response. A common mechanism involved in the modulation of responsiveness to cytokines is represented by regulation of their receptor expression through autocrine ligand-mediated loops. The present study is aimed at investigating the regulation of IFN alpha/beta receptor (IFNAR) during IFN beta therapy in patients with MS and at correlating it with the biologic responsiveness to the cytokine. Methods: Quantitative PCR measurements of IFNAR-1 and the three IFNAR-2 isoforms were performed in 141 patients after short-term and long-term treatment. Patients were also regularly screened for anti-IFN beta neutralizing antibodies (NAbs). IFN-inducible myxovirus resistance protein A messenger RNA was used as an indicator of bioactivity. Results: Pretreatment levels of IFNAR-2 in patients were lower overall than in controls (p = 0.038), and high levels correlated with greater bioactivity. Upon prolonged treatment, NAb-negative patients displayed a state of decreased transmembrane IFNAR-2 expression (p <= 0.025), whereas levels of soluble IFNAR-2 were slightly increased (p < 0.0001). The presence of NAbs reversed these effects (p <= 0.0056). In NAb-positive patients, pretreatment expression levels of both transmembrane IFNAR-2 isoforms were significantly lower than in NAb-negative patients (p <= 0.0089). Conclusions: Findings show that interferon-alpha/beta receptor (IFNAR)-2 isoforms are important regulators of the responsiveness to endogenous and systemically administered interferon beta (IFN beta). They show a dual action, agonistic and antagonistic, that influences both the magnitude and the nature of the biologic response to IFN beta. Levels of IFNAR-2 are regulated with the aim of keeping the body in a state of equilibrium, even when nonphysiologic stimuli are present.

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IL-21 and IFNα therapy rescues terminally differentiated NK cells and limits SIV reservoir in ART-treated macaques

Justin Harper, Nicolas Huot, Luca Micci, Gregory Tharp, Colin King, Philippe Rascle, Neeta Shenvi, Hong Wang, Cristin Galardi, Amit A. Upadhyay, Francois Villinger, Jeffrey Lifson, Guido Silvestri, Kirk Easley, Beatrice Jacquelin, Steven Bosinger, Michaela Muller-Trutwin, Mirko Paiardini

Summary: The study demonstrated that sequential interleukin-21 and interferon alpha therapy can generate terminally differentiated natural killer cells with potent activity in SIV-infected rhesus macaques, reducing SIV dissemination in lymph nodes. This suggests that the differentiation profiles of natural killer cells seen in African green monkeys can be rescued in rhesus macaques to promote viral clearance in tissues.

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