Adhesion molecules are promising candidates to establish surrogate markers for natalizumab treatment

Wipfler, Peter; Oppermann, Katrin; Pilz, Georg; Afazel, Shahrzad; Haschke-Becher, Elisabeth; Harrer, Andrea; Huemer, Marlies; Kunz, Alexander; Golaszewski, Stefan; Staffen, Wolfgang; Ladurner, G.; Kraus, Jörg

doi:10.1177/1352458510383075

Cited by 31 publications

(32 citation statements)

References 25 publications

(36 reference statements)

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“…Its mechanism of action is thought to be mediated through the block of the binding between the α4 subunit of the α4β1 (very late antigen-4; VLA-4) and α4β7 integrins on the lymphocytes of systemic circulation with their ligand, the vascular cell adhesion molecule 1 (VCAM-1), on vascular endothelium. Natalizumab also induces a continuous decrease of α4 expression [3] that results in a reduced transmigration of inflammatory cells across the bloodbrain barrier (BBB) into the central nervous system (CNS) and in an enhancement of the number of B cells, in particular immature B lymphocytes, CD8 + , CD4 + and NK cells in peripheral blood [4][5][6][7]. In treated patients, the increase of CD34 + precursor cells [8], together with the transient increase of nucleated immature red cells [9] and immature B lymphocytes [4] has suggested that natalizumab can preferentially mobilize immature cell subsets, probably because of its interference with the binding between VLA-4 and the VCAM-1 on the bone marrow (BM) stromal cells [8].…”

Section: Introductionmentioning

confidence: 99%

Peripheral accumulation of newly produced T and B lymphocytes in natalizumab-treated multiple sclerosis patients

Zanotti

Chiarini

Serana

et al. 2012

Clinical Immunology

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The anti-α4 monoclonal antibody natalizumab inhibits lymphocyte extravasation into the central nervous system and increases peripheral T and B lymphocytes in multiple sclerosis patients. To investigate whether the lymphocyte accumulation was due to a higher lymphocyte production, an altered homeostasis, or a differential transmigration of lymphocyte subsets through endothelia, T-cell receptor excision circles and kappa-deleting recombination excision circles were quantified before and after treatment, T-cell receptor repertoire was analyzed by spectratyping, and T-and B-lymphocyte subset migration was studied using transwell coated with vascular and lymphatic endothelial cells. We found that the number of newly produced T and B lymphocytes is increased because of a high release and of a low propensity of naïve subsets to migrate across endothelial cells. In some patients this resulted in an enlargement of T-cell heterogeneity. Because new lymphocyte production ensures the integrity of immune surveillance, its quantification could be used to monitor natalizumab therapy safety.

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Section: Introductionmentioning

confidence: 99%

Peripheral accumulation of newly produced T and B lymphocytes in natalizumab-treated multiple sclerosis patients

Zanotti

Chiarini

Serana

et al. 2012

Clinical Immunology

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“…Naïve B cells express low levels of LFA-1 and a4b1 integrin and are not retained within the splenic MZ. It has been shown that natalizumab, in addition to block the interaction of a4 integrins with their cognate receptors, reduces the expression of both a4b1 and LFA-1 adhesion molecules, and that the relative decrease on B cells was more pronounced than on T cells [12,36]. Natalizumab may thus impede retention of memory-and MZ-like B cells in the splenic MZ of spleen and Peyer's patches by downregulating LFA-1 and a4b1 expression in addition to blocking a4b1/VCAM-1 interaction.…”

Section: /Cd8mentioning

confidence: 99%

Natalizumab treatment perturbs memory‐ and marginal zone‐like B‐cell homing in secondary lymphoid organs in multiple sclerosis

et al. 2011

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Natalizumab, an antibody against the a4 subunit of a4 integrins, has been approved for multiple sclerosis (MS) therapy based on its high efficacy and safety profile. However, natalizumab has been associated with the development of progressive multifocal leukoencephalopathy (PML), a disorder caused by JC virus (JCV) infection. In order to improve our understanding of the mechanism of action of natalizumab and to identify possible risk factors for PML development, we have characterized in detail the cell blood composition in MS patients treated with natalizumab for more than 30 months. Natalizumab induced the release of lymphoid-but not myeloid precursor cells, which resulted in a chronic increase of T-, NK-and particularly B cells. While the percentage of recent thymic emigrants (RTE), naïve, effector or memory T cells remained unchanged during treatment, a higher percentage of memory-and marginal zone (MZ)-like, but not of naïve B cells, was observed, which most likely is due to a decreased retention of these cells within the splenic MZ. The ability of natalizumab to influence B-cell migration and homeostasis through the splenic MZ, where JCV has been detected, adds to the list of natalizumab effects and may contribute to PML development by disseminating JCV.Key words: B cells . Multiple sclerosis . Natalizumab . Progressive multifocal leukoencephalopathy Supporting Information available online Introduction Natalizumab, a monoclonal antibody against the a4 subunit (CD49d) of a4 integrins (a4b1 and a4b7), has been approved for multiple sclerosis (MS) therapy based on its high efficacy and good safety profile. The a4b1 integrin is expressed by all leukocytes except neutrophils and serves as an adhesion molecule mediating attachment to endothelial cells. Natalizumab prevents transmigration of leukocytes across the blood-brain barrier by blocking a4b1 integrin/vascular cell adhesion molecule-1 (VCAM-1) interaction [1][2][3][4][5]. a4b1 integrin also serves as a retention signal for hematopoietic precursor cells in the BM, and consequently it has been demonstrated that natalizumab mobilizes hematopoietic precursor cells from the BM [6][7][8]. Natalizumab treatment also induces significant phenotypic changes in the immune cell composition of peripheral blood such as an increase Eur. J. Immunol. 2012. 42: 790-798 790 in T-, NK-and especially B cells and a decrease in monocytes [9][10][11][12]. These changes have been attributed to a higher release of hematopoietic precursor cells from the BM as well as a reduced migration of leukocytes into the central nervous system (CNS). However, since a4 integrin ligands are also expressed in secondary lymphoid tissues, such as spleen and gut-associated lymphoid tissue, natalizumab may influence the immune cell composition in the blood by affecting homeostasis, homing and migration of leukocytes through secondary lymphoid organs as well.Natalizumab treatment can lead to progressive multifocal leukoencephalopathy (PML), a demyelinating disorder of the CNS caused by JC virus (JCV...

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“…The antibody is directed against the α4 subunit of the α4β1 (very late antigen-4, VLA-4) integrin on the lymphocytes [2]. It prevents the binding between VLA-4 and the vascular endothelium cell adhesion molecule 1 (VCAM-1) which, over time, decreases α4 expression [2].…”

Section: Introductionmentioning

confidence: 99%

Long-term follow-up of peripheral lymphocyte subsets in a cohort of multiple sclerosis patients treated with natalizumab

Koudriavtseva¹,

Sbardella²,

Trento

et al. 2014

Clinical and Experimental Immunology

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SummaryNatalizumab, an anti-alpha4 integrin monoclonal antibody inhibiting the adhesion of lymphocytes to the endothelium, is a widely accepted drug treatment for relapsing-remitting multiple sclerosis (RRMS). A peripheral increase of T and B lymphocytes has already been observed as an early treatment effect. This retrospective observational study was aimed to evaluate the peripheral lymphocyte subsets during a long-term treatment follow-up. We included 23 RRMS patients treated with natalizumab for at least 24-48 months who had pretreatment lymphocyte evaluation. Baseline values of lymphocyte subsets and CD4/CD8 ratio did not differ significantly from the 23 matched healthy subjects. The periodic (every 3-6 months) assessment of immune cell subsets was performed by flow cytometry on peripheral blood collected before drug injection. Therapy with natalizumab was confirmed to be effective during the observational period. For all patients, the increase in lymphocytes during natalizumab therapy compared to baseline at every assessment was significantly higher compared to that of overall white blood cells (2·1-and 1·3-fold, respectively, P < 0·0001). Both T cell subsets were proportionally modified and the CD4/CD8 ratio did not change significantly, while B cells increased significantly compared to T and NK cells (3·2-, 1·88-and 1·92-fold, respectively, P < 0·0001). These changes remained constant throughout the 25-48-month period of therapy. In conclusion, effective natalizumab treatment of RRMS patients was associated with the persistence of its biological effects through a stable increase of peripheral lymphocytes, mainly B cells, and an unchanged proportion of T cell subsets in long-term follow-up.

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Adhesion molecules are promising candidates to establish surrogate markers for natalizumab treatment

Cited by 31 publications

References 25 publications

Peripheral accumulation of newly produced T and B lymphocytes in natalizumab-treated multiple sclerosis patients

Peripheral accumulation of newly produced T and B lymphocytes in natalizumab-treated multiple sclerosis patients

Natalizumab treatment perturbs memory‐ and marginal zone‐like B‐cell homing in secondary lymphoid organs in multiple sclerosis

Long-term follow-up of peripheral lymphocyte subsets in a cohort of multiple sclerosis patients treated with natalizumab

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