ArticlePloS one2012
Natalizumab exerts direct signaling capacity and supports a pro-inflammatory phenotype in some patients with multiple sclerosis.
Article in PloS one, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 48 citations in OpenAlex.
- Reversibility of the effects of natalizumab on peripheral immune cell dynamics in MS patients.Neurology · 2017Trial
- CD49d antisense drug ATL1102 reduces disease activity in patients with relapsing-remitting MS.Neurology · 2014Trial
- Outside-In Signaling as a Detonator-like Stimulus of Integrin Activation by Promoting Both Affinity and Avidity.Biomolecules · 2026Review
- Characterization of QuantiFERON-TB-Plus Results in Patients with Tuberculosis Infection and Multiple Sclerosis.Neurology international · 2025Article
- Review
- Increased level of GATA3-AS1 long non-coding RNA is correlated with the upregulation of GATA3 and IL-4 genes in multiple sclerosis patients.Molecular biology reports · 2024Article
- Alterations of Thymus-Derived Tregs in Multiple Sclerosis.Neurology(R) neuroimmunology & neuroinflammation · 2024Article
- Natalizumab Treatment of Relapsing Remitting Multiple Sclerosis Has No Long-Term Effects on the Proportion of Circulating Regulatory T Cells.Neurology and therapy · 2023Article
- Natalizumab Promotes Activation of Peripheral Monocytes in Patients With Multiple Sclerosis.Neurology(R) neuroimmunology & neuroinflammation · 2023Article
- Enhanced pathogenicity of Th17 cells due to natalizumab treatment: Implications for MS disease rebound.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Identifying CNS-colonizing T cells as potential therapeutic targets to prevent progression of multiple sclerosis.Med (New York, N.Y.) · 2021Article
- Clinical Immunological Correlations in Patients with Multiple Sclerosis Treated with Natalizumab.Brain sciences · 2020Article
- Anti-αLβ2 antibodies reveal novel endocytotic cross-modulatory functionality.British journal of pharmacology · 2020Article
- Blockade of VLA4 sensitizes leukemic and myeloma tumor cells to CD3 redirection in the bone marrow microenvironment.Blood cancer journal · 2020Article
- Immunology of IL-12: An update on functional activities and implications for disease.EXCLI journal · 2020Review
- Natalizumab promotes activation and pro-inflammatory differentiation of peripheral B cells in multiple sclerosis patients.Journal of neuroinflammation · 2019Article
- Aquaporin-4 antibodies in patients treated with natalizumab for suspected MS.Neurology(R) neuroimmunology & neuroinflammation · 2017Article
- Relapse frequency in transitioning from natalizumab to dimethyl fumarate: assessment of risk factors.Journal of neurology · 2016Article
- New insights into the pharmacokinetics and pharmacodynamics of natalizumab treatment for patients with multiple sclerosis, obtained from clinical and in vitro studies.Journal of neuroinflammation · 2016Article
- Disrupted balance of T cells under natalizumab treatment in multiple sclerosis.Neurology(R) neuroimmunology & neuroinflammation · 2016Article
Corrections and comments
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Natalizumab is a recombinant monoclonal antibody raised against integrin alpha-4 (CD49d). It is approved for the treatment of patients with multiple sclerosis (MS), a chronic inflammatory autoimmune disease of the CNS. While having shown high therapeutic efficacy, treatment by natalizumab has been linked to progressive multifocal leukoencephalopathy (PML) as a serious adverse effect. Furthermore, drug cessation sometimes induces rebound disease activity of unknown etiology. Here we investigated whether binding of this adhesion-blocking antibody to T lymphocytes could modulate their phenotype by direct induction of intracellular signaling events. Primary CD4(+) T lymphocytes either from healthy donors and treated with natalizumab in vitro or from MS patients receiving their very first dose of natalizumab were analyzed. Natalizumab induced a mild upregulation of IL-2, IFN-γ and IL-17 expression in activated primary human CD4(+) T cells propagated ex vivo from healthy donors, consistent with a pro-inflammatory costimulatory effect on lymphokine expression. Along with this, natalizumab binding triggered rapid MAPK/ERK phosphorylation. Furthermore, it decreased CD49d surface expression on effector cells within a few hours. Sustained CD49d downregulation could be attributed to integrin internalization and degradation. Importantly, also CD4(+) T cells from some MS patients receiving their very first dose of natalizumab produced more IL-2, IFN-γ and IL-17 already 24 h after infusion. Together these data indicate that in addition to its adhesion-blocking mode of action natalizumab possesses mild direct signaling capacities, which can support a pro-inflammatory phenotype of peripheral blood T lymphocytes. This might explain why a rebound of disease activity or IRIS is observed in some MS patients after natalizumab cessation.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.