JC Virus-DNA Detection Is Associated with CD8 Effector Accumulation in Peripheral Blood of Patients with Multiple Sclerosis under Natalizumab Treatment, Independently from JC Virus Serostatus.

Maria A Zingaropoli,Marco Frontoni,Maria R Ciardi,Manuela Morreale,Valeria Pietropaolo,Alessandra D’Abramo,Marco Iannetta,Donatella Maria Rodio,Simona Pontecorvo,Vincenzo Vullo,Antonio Cortese,Claudio M Mastroianni,Miriam Lichtner,Ada Francia,Elena Anzivino,Alessandra Oliva,Carla Prezioso

doi:10.1155/2018/5297980

Abstract

Although natalizumab (anti-α4 integrin) represents an effective therapy for relapsing remitting multiple sclerosis (RRMS), it is associated with an increased risk of developing progressive multifocal leukoencephalopathy (PML), caused by the polyomavirus JC (JCV). The aim of this study was to explore natalizumab-induced phenotypic changes in peripheral blood T-lymphocytes and their relationship with JCV reactivation. Forty-four patients affected by RRMS were enrolled. Blood and urine samples were classified according to natalizumab infusion number: 0 (N0), 1–12 (N12), 13–24 (N24), 25–36 (N36), and over 36 (N > 36) infusions. JCV-DNA was detected in plasma and urine. T-lymphocyte phenotype was evaluated with flow cytometry. JCV serostatus was assessed. Ten healthy donors (HD), whose ages and sexes matched with the RRMS patients of the N0 group, were enrolled. CD8 effector (CD8 E) percentages were increased in natalizumab treated patients with detectable JCV-DNA in plasma or urine compared to JCV-DNA negative patients (JCV−) (p < 0.01 and p < 0.001, resp.). Patients with CD8 E percentages above 10.4% tended to show detectable JCV-DNA in plasma and/or urine (ROC curve p = 0.001). The CD8 E was increased when JCV-DNA was detectable in plasma or urine, independently from JCV serology, for N12 and N24 groups (p < 0.01). As long as PML can affect RRMS patients under natalizumab treatment with a negative JCV serology, the assessment of CD8 E could help in the evaluation of JCV reactivation.

Highlights

More than 2.3 million people worldwide are living with multiple sclerosis (MS) [1], a chronic inflammatory demyelinating disease of the central nervous system (CNS) [2] with 85–90% of cases presenting as a relapsing remitting (RR)form [1]
Ten healthy donors (HD) (5 females, 5 males), whose ages and sexes matched with relapsing remitting multiple sclerosis (RRMS) patients of the number: 0 (N0) group, were enrolled as control group
In a previous work in which 26 RRMS patients under natalizumab treatment were longitudinally followed up for 24 months, we showed that CD8 effector (CD8 E) is increased in patients with detectable John Cunningham polyomavirus (JCV)-DNA in plasma or urine [17]

Summary

Introduction

More than 2.3 million people worldwide are living with multiple sclerosis (MS) [1], a chronic inflammatory demyelinating disease of the central nervous system (CNS) [2] with 85–90% of cases presenting as a relapsing remitting (RR)form [1]. Lymphocyte migration through the blood brain barrier (BBB) represents a crucial step in the process that leads to inflammation and demyelination in the CNS [3]. The adhesion and subsequent migration of leukocytes into the CNS are regulated by the molecular interaction between membrane receptors and their cognate ligands, which are BioMed Research International expressed on endothelial cell surface. Lymphocyte migration into the CNS is regulated by the interaction of the α4β1 integrin (very late antigen [VLA]-4), expressed on their surface, with the vascular-cell adhesion molecule (VCAM), expressed on the vascular endothelial cell surface of CNS blood vessels [4, 5]. Natalizumab (Tysabri; Biogen Idec, Cambridge, MA, USA), a humanized monoclonal antibody targeting the α4 integrin (CD49d), was developed to inhibit leukocyte adhesion to the vascular endothelium of the CNS [4, 6]. Natalizumab limits leukocyte recruitment in the CNS, reducing the inflammation responsible for MS lesions [7]

Objectives

Methods

Results

Conclusion