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: Thomas F Benkert, Lena Dietz, Elena M Hartmann, Ellen Leich, Andreas Rosenwald, Edgar Serfling, Mathias Buttmann, Friederike Berberich-Siebelt
• Journal: PloS one (PLoS One) Vol. 7 Issue 12 Pg. e52208 ( 2012) ISSN: 1932-6203 [Electronic] United States
• PMID: 23284936 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal, Humanized
• Interleukin-17
• Interleukin-2
• Natalizumab
• Integrin alpha4
• Interferon-gamma
• Mitogen-Activated Protein Kinases

Topics

• Antibodies, Monoclonal, Humanized (adverse effects, therapeutic use)
• CD4-Positive T-Lymphocytes (drug effects, immunology)
• Cells, Cultured
• Humans
• Integrin alpha4 (immunology)
• Interferon-gamma (metabolism)
• Interleukin-17 (metabolism)
• Interleukin-2 (metabolism)
• Leukoencephalopathy, Progressive Multifocal (chemically induced, immunology)
• Mitogen-Activated Protein Kinases (metabolism)
• Multiple Sclerosis (drug therapy, immunology, metabolism)
• Natalizumab
• Phosphorylation (drug effects)
• Signal Transduction (drug effects)
• T-Lymphocytes (drug effects, immunology)