Therapy - immunomodulation - Part IIFriday, September 30, 2005, 15:30 - 17:00
Mechanisms of statins in multiple sclerosis – inhibition of activated T lymphocytes by dual action: impaired isoprenylation of guanosinetriphosphate-binding proteins and disruption of lipid microdomainsO. Neuhaus, V.S. Manda, O. Stüve, J.J. Archelos, H.-P. Hartung (Dusseldorf, D; Graz, A)
Objective: To investigate the effects of statins on human T and B lymphocytes.
Background: It has recently been demonstrated that statins, 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, have immunomodulatory properties and ameliorate disease severity in experimental allergic encephalomyelitis. Evidence is emerging that statins reduce magnetic resonance imaging (MRI) disease activation markers in multiple sclerosis (MS) patients.
Design/Methods: Mitogen-activated, antigen-specific, and naïve peripheral blood leukocytes obtained from patients with relapsing-remitting MS or from healthy donors were treated with various statins. The proliferative responsiveness and the presence of surface markers, including activation markers and adhesion molecules were evaluated. For assessment of the molecular mode of action of statins, control agents affecting crucial steps of the cholesterol biosynthesis pathway downstream of HMG-CoA reductase were further applied.
Results: Statins reduced proliferative activity of mitogen-activated and antigen-stimulated T cells in a dose-dependent manner. Proliferation of B cells was virtually not affected. There was a marked alteration in the surface marker expression of activated T cells, with a decrease in the ratio of CD45RO+ cells. Following statin-treatment, the phenotype of activated T cells approached that of non-activated T cells. Statins affected both the isoprenylation of guanosinetriphosphate (GTP)-binding proteins (i.e. the posttranslational lipid attachment of intracellular proteins that regulate the activation of lymphocytes) and the integrity of lipid microdomains that contain important immune molecules.
Conclusions: The activation of autoreactive encephalitogenic T cells may be affected by statin treatment in MS patients by a dual mode of action.