Cell-Mediated Immunity in Multiple Sclerosis Patients Who Discontinued Therapy with an Integrin Inhibitor

Abstract

Introduction. Natalizumab (NTZ) is a humanized monoclonal antibody (mAb) that selectively inhibits α4-integrin adhesion molecule located on the surface of lymphocytes and prevents their trafficking into the central nervous system (CNS). The aim of this study was to identify characteristics of lymphocyte population and subpopulation pattern in the peripheral blood (PB) of multiple sclerosis (MS) patients who discontinued NTZ due to an increased risk of developing developing progressive multifocal leukoencephalopathy. Materials and methods. We conducted an open-label prospective observational study in 26 MS patients. Of those, 6 patients had rapidly progressive MS, 10 patients discontinued NTZ and had confirmed relapses afterwards, and 10 patients received NTZ and had no relapses during the washout period. Ten apparently healthy individuals were used as controls. Cell-mediated immunity parameters were evaluated by flow cytometry using a panel of mAbs to differentiation antigens of PB lymphocytes. Results. Patients who discontinued NTZ had significantly decreased absolute lymphocyte counts in PB, decreased T-cytotoxic, NKT and B1 lymphocyte subpopulation levels, and decreased activated T-cell (CD3+HLA–DR+) levels, which may be related to their redistribution, passing through the blood-brain barrier, and trafficking into the central nervous system. CD20+ В-cell levels did not differ from normal. Additional immune predictors of MS relapses after NTZ discontinuation can include decreased absolute count of PB lymphocytes and decreased percentage of CD3+CD8+ T-cell, NKT-cell, and B1-cell (CD19+CD5+) subpopulations. Significantly increased levels of CD25+- and CD38+-activated B-cells compared with the normal levels in naïve patients and subjects without relapses after NTZ discontinuation may suggest a high activation potential of the circulating B-cell pool and, therefore, a high risk of MS relapses. Conclusions. The changes in the lymphocyte subpopulation pattern in the PB of MS patients after NTZ discontinuation may have a prognostic value for assessing the risk of relapses; they justified switching patients to anti-B-cell therapy.

Keywords

• natalizumab
• immune reconstitution inflammatory syndrome
• rebound phenomenon
• t-cells
• b-cells