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An Increase in B cell and Cytotoxic NK cell Proportions and Increased T cell Responsiveness in Blood of Natalizumab-treated Multiple Sclerosis Patients

Background: Changes in the blood lymphocyte composition probably both mediate and reflect the effects of natalizumab treatment in multiple sclerosis, with implications for treatment benefits and risks. Methods: A broad panel of markers for lymphocyte populations, including states of activation and co-stimulation, as well as functional T cell responses to recall antigens and mitogens, were assessed by flow cytometry in 40 patients with relapsing multiple sclerosis before and after one-year natalizumab treatment. Results: Absolute numbers of all major lymphocyte populations increased after treatment, most markedly for NK and B cells. The fraction of both memory and presumed regulatory B cell subsets increased, as did CD3-CD56dim cytotoxic NK cells, whereas CD3-CD56bright regulatory NK cells decreased. The increase in cell numbers was further associated with a restored T cell responsiveness to recall antigens and mitogens in functional assays. Conclusions: Our data confirms that natalizumab treatment increases the number of lymphocytes in blood, likely mirroring the expression of VLA-4 being highest on NK and B cells. This finding supports reduction of lymphocyte extravasation as a main mode of action, although the differential effects on subpopulation composition suggests that cell-signalling may also be affected. The systemic increase in T cell responsiveness reflects the increase in numbers, and while augmenting anti-infectious responses systemically, localized responses may become correspondingly decreased. Citation: Mellergård J, Edström M, Jenmalm MC, Dahle C, Vrethem M, et al. (2013) Increased B Cell and Cytotoxic NK Cell Proportions and Increased T Cell Responsiveness in Blood of Natalizumab-Treated Multiple Sclerosis Patients. PLoS ONE 8(12): e81685. doi:10.1371/journal.pone.0081685 Editor: Markus Reindl, Innsbruck Medical University, Austria Received March 14, 2013; Accepted October 25, 2013; Published December 2, 2013 Copyright: © 2013 Mellergård et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The study was supported by grants from The Swedish Association of Persons with Neurological Disabilities, The University Hospital of Linköping, The County Council of Östergötland and Linköping University. The study was further supported by an unrestricted grant from Biogen Idec Sweden. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: J. Mellergård has received speaker honorary from Biogen Idec. M. Edström has received speaker honorary from Biogen Idec. C. Dahle has received speaker honoraria from Biogen Idec and Merck Serono. M. Vrethem has received an unrestricted grant for research from Biogen Idec and speaker honoraria from Biogen Idec and Merck Serono. This does not alter the authors' adherence to all the PLOS ONE policies on sharing data and materials. * E-mail: johan.mellergard@lio.se ☯ These authors contributed equally to this work.