Abstract
Cladribine (CLAD) is a deoxyadenosine analogue prodrug which is given in multiple sclerosis (MS) as two short oral treatment courses 12 months apart. Reconstitution of adaptive immune function following selective immune cell depletion is the presumed mode of action. In this exploratory study, we investigated the impact of CLAD tablets on immune cell surface molecules for adhesion (CAMs) and costimulation (CoSs) in people with MS (pwMS). We studied 18 pwMS who started treatment with CLAD and 10 healthy controls (HCs). Peripheral blood mononuclear cells were collected at baseline and every 3 months throughout a 24-month period. We analysed ICAM-1, LFA-1, CD28, HLADR, CD154, CD44, VLA-4 (CD49d/CD29), PSGL-1 and PD-1 with regard to their expression on B and T cells (T helper (Th) and cytotoxic T cells (cT)) and surface density (mean fluorescence intensity, MFI) by flow cytometry. The targeted analysis of CAM and CoS on the surface of immune cells in pwMS revealed a higher percentage of ICAM-1 (B cells, Th, cT), LFA-1 (B cells, cT), HLADR (B cells, cT), CD28 (cT) and CD154 (Th). In pwMS, we found lower frequencies of Th and cT cells expressing PSGL-1 and B cells for the inhibitory signal PD-1, whereas the surface expression of LFA-1 on cT and of HLADR on B cells was denser. Twenty-four months after the first CLAD cycle, the frequencies of B cells expressing CD44, CD29 and CD49d were lower compared with the baseline, together with decreased densities of ICAM-1, CD44 and HLADR. The rate of CD154 expressing Th cells dropped at 12 months. For cT, no changes were seen for frequency or density. Immune reconstitution by oral CLAD was associated with modification of the pro-migratory and -inflammatory surface patterns of CAMs and CoSs in immune cell subsets. This observation pertains primarily to B cells, which are key cells underlying MS pathogenesis.
Highlights
IntroductionThe interaction between cell-bound adhesion molecules (CAMs) expressed by activated leukocytes and their cognate ligands present on the endothelial cells of the blood–brain barrier (BBB) plays a central role in the transmigration of immune cells to and within the central nervous system (CNS) [2,3]
We assessed the expression of cell surface molecules for adhesion (CAMs) and Costimulatory signals (CoSs) on CD4+, CD8+ and CD19+ lymphocytes from healthy controls (HCs) and compared them with the baseline (BL) values of people with MS (pwMS)
We found that the frequencies of ICAM-1+ lymphocytes were significantly increased in pwMS, and the differences were most pronounced among B cells
Summary
The interaction between cell-bound adhesion molecules (CAMs) expressed by activated leukocytes and their cognate ligands present on the endothelial cells of the BBB plays a central role in the transmigration of immune cells to and within the CNS [2,3]. The IS optimizes pathogen control, while dysregulation is central to the proliferation of autoreactive T helper cells and the subsequent autoimmune processes [5,6]. Costimulatory signals (CoSs) involved in the pathogenesis of MS are CD80/CD86 on antigen-presenting cells (APCs) and their cognate ligand CD28 (on naïve lymphocytes), as well as the binding of CD154 (on Th cells) to CD40 (on APCs) [9,10]
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