Cladribine Alters Immune Cell Surface Molecules for Adhesion and Costimulation: Further Insights to the Mode of Action in Multiple Sclerosis

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 inv...

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Autores principales:	Tobias Moser, Lena Hoepner, Kerstin Schwenker, Michael Seiberl, Julia Feige, Katja Akgün, Elisabeth Haschke-Becher, Tjalf Ziemssen, Johann Sellner
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	cladribine multiple sclerosis adhesion molecules costimulatory molecules immune cells LFA-1 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/0b07cf9a9e294919a8cd3066783f1727
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spelling	oai:doaj.org-article:0b07cf9a9e294919a8cd3066783f17272021-11-25T17:11:37ZCladribine Alters Immune Cell Surface Molecules for Adhesion and Costimulation: Further Insights to the Mode of Action in Multiple Sclerosis10.3390/cells101131162073-4409https://doaj.org/article/0b07cf9a9e294919a8cd3066783f17272021-11-01T00:00:00Zhttps://www.mdpi.com/2073-4409/10/11/3116https://doaj.org/toc/2073-4409Cladribine (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.Tobias MoserLena HoepnerKerstin SchwenkerMichael SeiberlJulia FeigeKatja AkgünElisabeth Haschke-BecherTjalf ZiemssenJohann SellnerMDPI AGarticlecladribinemultiple sclerosisadhesion moleculescostimulatory moleculesimmune cellsLFA-1Biology (General)QH301-705.5ENCells, Vol 10, Iss 3116, p 3116 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	cladribine multiple sclerosis adhesion molecules costimulatory molecules immune cells LFA-1 Biology (General) QH301-705.5
spellingShingle	cladribine multiple sclerosis adhesion molecules costimulatory molecules immune cells LFA-1 Biology (General) QH301-705.5 Tobias Moser Lena Hoepner Kerstin Schwenker Michael Seiberl Julia Feige Katja Akgün Elisabeth Haschke-Becher Tjalf Ziemssen Johann Sellner Cladribine Alters Immune Cell Surface Molecules for Adhesion and Costimulation: Further Insights to the Mode of Action in Multiple Sclerosis
description	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.
format	article
author	Tobias Moser Lena Hoepner Kerstin Schwenker Michael Seiberl Julia Feige Katja Akgün Elisabeth Haschke-Becher Tjalf Ziemssen Johann Sellner
author_facet	Tobias Moser Lena Hoepner Kerstin Schwenker Michael Seiberl Julia Feige Katja Akgün Elisabeth Haschke-Becher Tjalf Ziemssen Johann Sellner
author_sort	Tobias Moser
title	Cladribine Alters Immune Cell Surface Molecules for Adhesion and Costimulation: Further Insights to the Mode of Action in Multiple Sclerosis
title_short	Cladribine Alters Immune Cell Surface Molecules for Adhesion and Costimulation: Further Insights to the Mode of Action in Multiple Sclerosis
title_full	Cladribine Alters Immune Cell Surface Molecules for Adhesion and Costimulation: Further Insights to the Mode of Action in Multiple Sclerosis
title_fullStr	Cladribine Alters Immune Cell Surface Molecules for Adhesion and Costimulation: Further Insights to the Mode of Action in Multiple Sclerosis
title_full_unstemmed	Cladribine Alters Immune Cell Surface Molecules for Adhesion and Costimulation: Further Insights to the Mode of Action in Multiple Sclerosis
title_sort	cladribine alters immune cell surface molecules for adhesion and costimulation: further insights to the mode of action in multiple sclerosis
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/0b07cf9a9e294919a8cd3066783f1727
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Cladribine Alters Immune Cell Surface Molecules for Adhesion and Costimulation: Further Insights to the Mode of Action in Multiple Sclerosis

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