Ph.D Thesis

Ph.D StudentGalboiz Yanina
SubjectInterferon-Gamma and Beta-Mediated Modulation of Matrix-
Metalloproteinases (MMPs), Their Endogenous Tissue
Inhibitors (TIMPs) and Co-Stimulatory
Molecules in Human Monocytic C
DepartmentDepartment of Medicine
Supervisor PROF. Ariel Miller


Activated T helper (Th)-1 cells and monocytes, expressing elevated levels of co-stimulatory molecules, associated with increased interferon (IFN )-  secretion are characteristic of multiple sclerosis (MS), an immune-mediated disease of the central nervous system. Elevated levels of MMPs, implicated in blood brain barrier disruption, immune-cell infiltration and myelin degradation, are also observed in MS. MMPs’ inhibitors as well as inhibitors of co-stimulatory signals are reported to suppress disease activity in the experimental MS model, while clinical efficacy has been shown for IFN- treatment. We therefore evaluated the in-vitro effects of IFN- and - on monocytes` mRNA (Northern blot) and protein expression (ELISA, flow-cytometry, Western blot) of MMP-2, its activator MT1-MMP, and its inhibitor TIMP-2. In addition, peripheral blood leukocytes from relapsing-remitting (R-MS) and secondary-progressive (P-MS) MS patients were evaluated, prior to and at 3 months intervals, during the 1st year of IFN- treatment, for: MMP-2, -7, -9, MT1-MMP, TIMP-1 and TIMP-2 mRNA expression (semi-quantitative RT-PCR) and for co-stimulatory molecules expression (flow-cytometry) by monocytes (CDs: 11b, 40, 54, 80, 86, HLA-DR) and T cells (CDs: 28, 40L, CTLA-4). In-vitro experiments showed that IFN-b, in contrary to IFN-g, led to an anti-proteolytic pattern of MMPs and TIMPs expression. These results were supported by the ex-vivo studies showing that IFN-b treatment of R-MS patients led to a significant reduction in MMP-7 and MMP-9 mRNA expression. Furthermore, changes observed in co-stimulatory molecules expression, down-regulation of CD80, CD28 and CD54 while up-regulation of CD86, are in keeping with postulated IFN-b induced Th-1 to Th-2 immune-deviation. Our results also support the existence of differences in the immune mechanisms underlying R-MS and P-MS and suggest that MMPs, TIMPs and co-stimulatory molecules may serve as potential biomarkers as well as targets for immune-modulation and therapy in MS.