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Title: Differential Regulation of Cytokine Secretion in Multiple Sclerosis
Author: Fragkoulis, Nikolaos D.
ISNI:       0000 0001 3481 0560
Awarding Body: University of Central Lancashire
Current Institution: University of Central Lancashire
Date of Award: 2007
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Multiple sclerosis (MS) is the most common autoimmune inflammatory demyelinating disorder of the human nervous system affecting nearly 1 million people worldwide every year. Current treatments for first-line nontoxic therapy of the relapsing-remitting form of the disease are two forms of recombinant IFNp, la and lP and glatiramer acetate. The pathogenesis of MS is highlighted by an inflammatory response and myelin destruction. Several recent studies have reported alterations in immune variables such as cytokine concentrations, immune-related molecules such as MHC and adhesion molecules and chemokines; which may contribute to an imbalance between Thl and Th2 T ceIlmediated immune response. The aims of the present study were to characterize the cytokinetic profile of MS patients through investigating the secretion of the main pro- and anti-inflammatory cytokines from peripheral blood mononuclear ceIls of MS patients compared to controls, and to investigate cytokine receptor expression levels in T and NK ceIls. In addition, the induction of apoptosis and the involvement of adhesion molecules and metalloproteinases in oligodendrocyte destruction are examined. Finally, the effect of IFNp treatment on cytokine secretion levels as well as on the aforementioned immunoregulatory molecules was evaluated. The study population consisted of 60 MS patients (20 untreated, 20 treated with IFNP-l a and 20 treated with IFNP-l P) in paraIlel with 25 controls. Serum/plasma samples and peripheral blood mononuclear ceIls (PBMCs) were isolated from each participant. Using the enzyme linked immunospot (ELISPOT) assay the numbers of cytokine-secreting PBMCs were measured for the following cytokines: IFN-y, TNF-a, IL-12, IL-IO and IL-4. The expression levels of the cytokine receptors IL-12RPl, IFN-y, IL-IOR, TNFaR were estimated in the surface of lymphocytes using flow cytometry and serum levels of soluble CD95, ICAM-l, VCAM-l, metaIloproteinase-9 (MMP-9) and the tissue inhibitor, metalloproteinase-l (TIMP-l) were evaluated in all samples. The ELISPOT assay proved a very sensitive and valuable tool for characterisation of the cytokine profile ofMS patients. Decreased numbers ofPBMCs secreting IL-l 0 and IL-4, and increased numbers ofPBMCs secreting TNF-a, IL-12 and IFN-y were observed in MS patients compared to healthy controls. Treatment with IFNp elevated IL-IO and IL-4 levels, and decreased TNF-a, IL-12 and IFN-y levels in these patients. IFNp/la was more efficient in decreasing IL-12 secreting cells and IFNp/lP in decreasing IFN-y, and TNF-a secreting cells and elevating IL-4 and IL-l 0 secreting cells Increased expression ofIL-12RPl and TNF-aR was observed in NK cells and decreased expression of IFN-yR and IL-IOR was shown in T cells of MS patients compared to controls. IFNp therapy reduced IL-12RP i levels in T and NK cells (IFNP-l a. was more effective), and TNF-aR levels in T cells (IFNP- lP was more effective), but it increased IFN-yR and IL-IOR in T and NK cells ofMS patients. Increased levels of the soluble CD95 apoptosis marker were observed in serum of MS patients compared to controls, which further increased after IFNp treatment (IFNP-l P was more efficient). Increased levels of soluble ICAM-l and VCAM-l were observed in serum of MS patients compared to controls, which were further increased after treatment with IFNp (lFNP-l a was more efficient in increasing sICAM-1 and IFNP-I P in increasing sVCAMI levels) Increased levels of MMP-9, decreased levels of TIMP-l, and increased MMP-9/TIMP-l ratio was found in serum of MS patients compared to controls, and treatment with IFNp decreased MMP-9 levels, increased TIMP-l levels and decreased MMP-9/TIMP-l levels (lFNp-la was more effective). These results indicate an over expression ofThl type cytokines in MS accompanied by a concomitant suppression of Th2 type immune response as well as by alterations in the expression of cytokine receptors. A consequent activation of other immunoregulatory elements (sCD95, adhesion molecules, metalloproteinases) was also observed which was partly modified by IFNp treatment. This study provides important evidence on the role of cytokines and of other inflammatory molecules in MS pathogenesis and highlights possible mechanisms of action of IFNp treatment, offering new perspectives for novel, more efficient, diagnostic, and therapeutical approaches for the disease.
Supervisor: Not available Sponsor: Not available
Qualification Name: University of Central Lancashire, 2007 Qualification Level: Doctoral
EThOS ID:  DOI: Not available