Clinical Immunological Correlations in Patients with Multiple Sclerosis Treated with Natalizumab.

Smaranda Maier,Irina Lata,Septimiu Voidazan,Mihaela Simu,Rodica Balasa,Zoltan Bajko,Laura Barcutean,Anca Motataianu,Adina Hutanu

doi:10.3390/brainsci10110802

Abstract

Natalizumab (NAT) was the first disease modifying therapy used for the treatment of relapsing-remitting multiple sclerosis (MS) that was designed with a specific mechanism of action that targets an important step of the MS immunopathology, directly blocking the T lymphocyte intrusion in the central nervous system. Initially, it was considered that NAT carried no biological effects on the peripheral immune response. The purpose of our study was to assess the effects of NAT on the peripheral pro and anti-inflammatory cytokines and to reveal possible correlations between them and the clinical activity of the disease. We noticed a significant decrease in interleukin (IL)-17, tumor necrosis factor-alpha (TNF-α) and IL-31 serum levels in treated patients. The lack of relapses during the study was associated with low baseline IL-17 level. The patients that had an increase in the disability score during the study had significantly lower IL-17 and higher IL-1β baseline levels. IL-17 can be used as a biomarker for disease activity but also for progression assessment in NAT treated patients. NAT has a far more complex mechanism compared to what was initially believed, besides modulating lymphocyte trafficking through the blood–brain barrier, it also changes the peripheral levels of pro and anti-inflammatory cytokines in MS patients.

Highlights

This study demonstrated that, in addition to blocking activated lymphocyte migration throughout the blood–brain barrier (BBB), NAT acts as a direct co-stimulator of the T cell population, mildly shifting the balance towards a pro-inflammatory phenotype in the periphery [14]
To assess the changes induced by NAT in the periphery, we focused on IL-17, a cytokine produced by Th17 cells
Similar observations were obtained by our team in an anterior study, and other international researchers have reported the same findings [20,21]. One explanation for these results may be that the above-mentioned studies were based on cell differentiation tests of peripheral Th lymphocytes, while our study focused on protein determinations

Summary

Introduction

Concerning MS pathology, there is clear evidence that an autoimmune adaptive inflammatory response, which involves T and B lymphocytes directed against various CNS molecules, exists [2,3]. Steinman and his team of researchers from Stanford concentrated their research on the molecules that actively guide the migration of T lymphocytes from the periphery towards the blood–brain barrier (BBB), a phenomenon known as “zip code hypothesis”. Steinman and colleagues assessed a number of monoclonal antibodies directed against adhesion molecules and noted that the antibodies against α4 integrin, an essential protein necessary for lymphocyte adherence to the BBB, prevent the intrusion of inflammatory cells in the brain parenchyma [2,4]. The AFFIRM study demonstrated that over 2 years of NAT treatment significantly reduced new T2 lesions, active lesions, clinical relapses, and the progression of disability as compared to placebo [8]

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