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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. Natalizumab blocks leukocyte extravasation across the blood-brain barrier by inhibiting the molecular interaction between integrin alpha-4/beta-1 heterodimers expressed on leukocytes and VCAM-1 on inflammatory-activated CNS endothelium. Here we investigated whether binding of this adhesion-blocking antibody to T lymphocytes modulated their phenotype by direct induction of intracellular signaling events. Natalizumab induced a mild upregulation of IL-2, IFN-gamma 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. Overall, the relative effect of natalizumab was more pronounced in less than in fully activated T cells. 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-gamma 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 may support a pro-inflammatory phenotype of peripheral blood T lymphocytes. This might explain why a rebound of disease activity is observed in some MS patients after natalizumab cessation. Human CD4+ T cells from healthy donors were stimulated in the absence or presence of natalizumab for 10 days. To recall the developed program and induce cytokine expression, half of the cells were restimulated for a further 8 h.

ORGANISM(S): Homo sapiens  

SUBMITTER: Andreas Rosenwald   Lena Dietz  Elena M Hartmann  Edgar Serfling  Thomas F Benkert  Friederike Berberich-Siebelt  Ellen Leich  Mathias Buttmann 

PROVIDER: E-GEOD-37783 | ArrayExpress | 2015-05-02



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