title: Natalizumab exerts direct signaling capacity and supports a pro-inflammatory phenotype in some patients with multiple sclerosis.
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.
authors.affiliation: Department of Molecular Pathology, University of Würzburg, Würzburg, Germany.
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Benkert
authors.forename: Lena
authors.initials: L
authors.lastname: Dietz
authors.forename: Elena M
authors.initials: EM
authors.lastname: Hartmann
authors.forename: Ellen
authors.initials: E
authors.lastname: Leich
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.forename: Edgar
authors.initials: E
authors.lastname: Serfling
authors.forename: Mathias
authors.initials: M
authors.lastname: Buttmann
authors.forename: Friederike
authors.initials: F
authors.lastname: Berberich-Siebelt
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000009:adverse effects* / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D006801:Humans; D039441:Integrin alpha4 / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D007968:Leukoencephalopathy, Progressive Multifocal / Q000139:chemically induced / Q000276:immunology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D000069442:Natalizumab; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D020381:Interleukin-17; D007376:Interleukin-2; D000069442:Natalizumab; D039441:Integrin alpha4; D007371:Interferon-gamma; D020928:Mitogen-Activated Protein Kinases