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

• Published in: Multiple sclerosis Vol. 17; no. 1; pp. 16 - 23
• Main Authors: Wipfler, P, Oppermann, K, Pilz, G, Afazel, S, Haschke-Becher, E, Harrer, A, Huemer, M, Kunz, A, Golaszewski, S, Staffen, W, Ladurner, G, Kraus, J
• Format: Journal Article
• Language: English
• Published: London, England SAGE Publications 01.01.2011; Sage Publications; Sage Publications Ltd
• Subjects: Adolescent; Adult; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal, Humanized; Antigens, CD - blood; Austria; Biological and medical sciences; Biomarkers - blood; Cell Adhesion Molecules - blood; Child; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Female; Flow Cytometry; Humans; Immunologic Factors - administration & dosage; Immunomodulators; Integrin alpha4 - blood; Intercellular Adhesion Molecule-1 - blood; Leukocytes, Mononuclear - drug effects; Leukocytes, Mononuclear - immunology; Lymphocyte Function-Associated Antigen-1 - blood; Male; Medical sciences; Middle Aged; Multiple Sclerosis, Relapsing-Remitting - blood; Multiple Sclerosis, Relapsing-Remitting - drug therapy; Multiple Sclerosis, Relapsing-Remitting - immunology; Natalizumab; Neurology; Pharmacology. Drug treatments; Prospective Studies; Time Factors; Treatment Outcome; Young Adult; Austria; opportunistic infections; surrogate marker; adhesion molecules; multiple sclerosis; natalizumab; Opportunistic infection; Nervous system diseases; Multiple sclerosis; Treatment; Natalizumab; Central nervous system disease; Degenerative disease; Inflammatory disease
• ISSN: 1352-4585; 1477-0970
• DOI: 10.1177/1352458510383075

Background: Natalizumab is the first monoclonal antibody therapy approved for multiple sclerosis (MS). Its therapeutic mechanism is the blockade of the α4-integrin subunit of the adhesion molecule (AM) very late activation antigen-4 (VLA-4), which leads to an inhibition of immune cell extravasation into the central nervous system (CNS). Methods: We investigated changes in the expression levels of unblocked α4-integrin and further AM (intercellular adhesion molecule-1, -2, -3 (cICAM-1, -2, -3), leukocyte function associated antigen-1 (LFA-1)) on peripheral blood mononuclear cells (PBMC) determined by flow cytometry from 25 patients with MS before the first natalizumab infusion and before the fourth infusion. In 15 MS patients AM expression was evaluated every 3 months over 1 year. Results:We found a significant decrease (p < 0.0001) of unblocked α4-integrin cell surface expression on all investigated PBMC subsets (T cells −61.7%, B cells −69.1%, monocytes/macrophages −46.4%) in the blood of MS patients after 3 months of natalizumab treatment. Moreover, a continuous decrease (p < 0.05) of unblocked α4-integrin expression levels was seen after 3, 6, 9, and 12 months. As a secondary effect, expression levels of the other investigated AM were differentially affected. Conclusions:Results show a sustained decrease of unblocked α4-integrin expression not only in all patients but also in all investigated PBMC subsets. This probably results in a continuously decreasing transmigration of PBMC into the CNS and may explain the improved clinical efficacy in the second treatment year and also the increasing risk of progressive multifocal leukoencephalopathy during long-term natalizumab therapy. We conclude that AM expression profiles are promising candidates for the development of a biomarker system to determine both natalizumab treatment response and patients at risk for opportunistic CNS infections.