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Functional and cellular studies in HTLV-I-associated myelopathy and multiple sclerosis Al-Fahim, Abdulaziz

Abstract

Multiple sclerosis (MS) and human T-lymphotropic virus type I (HTLV-I) associated myelopathy (HAM) are inflammatory demyelinating diseases of the central nervous system (CNS). Current opinion implicates immune mediated factors, particularly T cells in the pathogenesis of both diseases. Histopathological studies in HAM and MS show perivascular mononuclear cell (MNC) infiltration into the central nervous system (CNS). The mechanism by which MNC gain access the CNS involves adhesion of peripheral blood MNC to cerebral endothelial cells that constitute the blood-brain barrier (BBB). The objective of this thesis was to investigate, first, the phenotype of lymphocytes of HAM patients with a focus on T cell activation and adhesion related antigens; second, the adhesion and mechanism of adhesion of blood MNC of HAM and MS patients to endothelial cells; and third, the effects of immunomodulating drugs on lymphocyte subsets and function in MS. We utilized direct two-color flow cytometry to study lymphocyte subsets in a group of patients with HAM and compared the results with those of HTLV-I asymptomatic carriers and seronegative controls. We found that in HTLV-I carriers, lymphocytes are activated and that activation is even more profound in HAM patients. To investigate the factors regulating the entry of blood MNC into the CNS, we used human umbilical vein endothelial cells (HUVEC) as a model for endothelial function and, after growing them to confluence, studied the adhesion of 51Cr-labeled MNCs to the monolayers. Adhesion experiments indicated that MNC from HAM and from clinically active (secondary progressive) MS patients adhered significantly more to HUVEC monolayers than MNC from controls. This supports the view that infiltration of MNC across the BBB into the CNS in HAM and MS is due to increased interaction between blood MNC and endothelium. Monoclonal antibody blocking studies indicated that the adhesion molecules LFA-1/ICAM-1 pathway plays a pivotal role in adhesion both under inflammatory and non-inflammatory conditions, while the VLA-4/VCAM-1 pathway contributes to MNC-HUVEC adhesion only when HUVEC are stimulated and therefore, might be important in recruiting immune cells under inflammatory conditions as in HAM and MS. Studies of IgG secretion by peripheral blood MNC in stable relapsing-remitting (sRR) MS and healthy controls after Pokeweed mitogen (PWM) stimulation indicated that sRR-MS patients produced more immunoglobulin (lg) G and had a higher percentage of "high responders" compared with controls. This increase in IgG secretion was significantly inhibited by interferon beta (IFN-β). This inhibition was not equivalent among three commercially available preparations of IFN-β (Avonex™, Betaseron®, and Rebif®). We found that Avonex™ had the highest inhibitory effect followed by Rebif® and Betaseron® respectively. In this study, we also examined the effects of IFN-β on MNC-HUVEC adhesion and demonstrated that IFN-β pretreatment of MNC, but not HUVEC results in significant reduction in MNC-HUVEC adhesion. This might partially explain the beneficial effects of IFN-β in MS.

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