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Forschungsdatenbank PMU-SQQUID

Adhesion molecules are promising candidates to establish surrogate markers for natalizumab treatment.
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;
Mult Scler. 2011; 17(1):16-23
Originalarbeiten (Zeitschrift)

PMU-Autor/inn/en

Golaszewski Stefan
Harrer Andrea
Haschke-Becher Elisabeth
Huemer Michael
Kraus Jörg
Kunz Alexander
Oppermann Katrin
Pilz Georg
Staffen Wolfgang
Wipfler Peter

Abstract

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).
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.
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.
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.


Useful keywords (using NLM MeSH Indexing)

Adolescent

Adult

Antibodies, Monoclonal/administration*

dosage*

Antibodies, Monoclonal, Humanized

Antigens, CD/blood

Austria

Biomarkers/blood

Cell Adhesion Molecules/blood*

Child

Female

Flow Cytometry

Humans

Immunologic Factors/administration*

dosage*

Integrin alpha4/blood

Intercellular Adhesion Molecule-1/blood

Leukocytes, Mononuclear/drug effects*

Leukocytes, Mononuclear/immunology

Lymphocyte Function-Associated Antigen-1/blood

Male

Middle Aged

Multiple Sclerosis, Relapsing-Remitting/blood

Multiple Sclerosis, Relapsing-Remitting/drug therapy*

Multiple Sclerosis, Relapsing-Remitting/immunology

Natalizumab

Prospective Studies

Time Factors

Treatment Outcome

Young Adult


Find related publications in this database (Keywords)

adhesion molecules
multiple sclerosis
natalizumab
opportunistic infections
surrogate marker