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Department of Cell Biology Faculty
Foroozan Mokhtarian Ph.D., M.P.H., Pharm.D.
Adjunct Associate Professor
Director of Immunology Research at Maimonides Medical Center
Tel: (718) 283-8432 • Fax: (718) 635-7895
Mechanisms of Demyelination and Remyelination in Multiple Sclerosis
To study the autoimmune etiology of multiple sclerosis (MS), We have developed a system in which chronic relapsing experimental autoimmune encephalomyelitis (EAE) can be induced in mice by adoptive transfer of T cells sensitized to myelin basic protein (MBP) (Mokhtarian et al Nature, 309:356 1984, Mokhtarian et al, Lab. Invest. 51:534, 1984). This animal model which is now widely used, is clinically and histologically the best available model for MS. Using this system, my laboratory was able to isolate a T cell clone with ability to suppress EAE in mice, upon adoptive transfer (Ofosu-Appiah and Mokhtarian, Cell Immunol. 135:143, 1991). The adoptive transfer model of EAE has been ideal for examining the various therapeutic protocols such as anti I A antibody treatment (Mokhtarian, Clin. Immunol. Immunopath. 49:308, 1988) and oral MBP treatment (Miller et al., Proc. Natl. Acad. Sci.89:421,1992 and Mokhtarian et al., Annal. N.Y. Acad. Sci.,778:414,1996) in my laboratory and others.
To investigate the natural mechanisms by which MS patients may become sensitized to MBP, viral infections of the CNS and their potential to trigger such sensitization was investigated, using Semliki Forest virus (SFV), as a model. This study was initially based on the hypothesis that viruses capable of causing acute inflammatory disease of the CNS, with demyelination, may prime the host to respond immunologically to components of its own myelin, thereby predisposing it to develop autoimmune disease of the CNS (Mokhtarian and Swoveland, J. Immunol. 138:3264, 1987, Mokhtarian et al, J. Immunol. 143:633, 1989). The role of pro- and anti- inflammatory cytokines in the susceptibility of different strains of mice to SFV-induced encephalomyelitis and to utoimmune CNS disease, was studied, using Northern blot technique (Mokhtarian et al, Cell. Immunol, 157:195, 1994). Using RT-PCR to determine the mRNA induction of these cytokines in the meningeal exudate cells and CNS has revealed that some strains of mice are deficient in the induction of anti-inflammatory cytokines (Mokhtarian et al, J. Neuroimmunol. 66:11, 1996). Molecular approaches such as transfection of lymphocytes with TGF-b gene and adoptive transfer to EAE-prone strains of mice were used to correct these deficiencies (Shi &Mokhtarian, Unpublished).
In search of a more suitable model for multiple sclerosis (MS), we have investigated the role of epitope mimicry in the induction of autoimmune response and demyelinating disease following a CNS viral infection. We have aligned, located and synthesized peptides, which fall within the T and B cell epitopes of SFV, and have molecular mimicry with peptides of myelin (MBP, PLP, and MOG). Furthermore, cross recognition of two mimicked sequences by T and B cells of immunized mice caused autoimmune response and demyelination in these mice (Mokhtarian F, et al 1999). At this time we are studying the role of g/d T cells in de- and remyelination following SFV.
The immunoregulatory mechanisms in patients with autoimmune diseases; Multiple Sclerosis (MS) and Myasthenia Gravis (MG) were investigated by the preparation of T lymphocyte clones from the peripheral blood of these patients, in the presense of IL-2 and in the absence of autoantigen. While some of these clones were responsive to myelin basic protein (only from MS patients), and to acetylcholine receptor (only from MG patients), the putative autoantigens of these diseases, none of the similarly obtained clones from the control subjects responded to these autoantigens (Ofosu-Appiah, et al, 1991, Clin. Immunol. Immunopath. 58: 46-55, Mokhtarian et al 1990, J. Clin. Invest. 8: 2099-2108.). To understand the pathogenesis of these diseases, production and molecular expression of the cytokines; interleukin-2( IL-2), interferon gamma (IFN-_) lymphotoxin and TGF-§ were investigated in MS, MG and other autoimmune controls. Lymphocytes from MS patients, while producing higher concentration of pro-inflammatory cytokines than normal controls and other autoimmune diseases, were defective in the production of TGF-§ 1(Mokhtarian et al J. Immunol. 124:231-244, 1994).
My lab has also studied MS patients undergoing treatment with oral myelin or myeloral and placebo (July 1994-March 1997), and followed the effect of treatment by analyzing their lymphocyte surface markers, T-cell, B cell and macrophage activation markers and the production of pro- and anti inflammatory cytokines by IL-2 activated T cell lines from these myeloral and placebo treated MS patients. Also, treated and untreated MG patients and normal controls were used in this study. The clinical and laboratory results of this comprehensive study is being prepared for publication.
Using a similar system, my lab has also investigated a newly described T cell activation marker (LAG-3) on the lymphocytes of our patients with autoimmune disease such as MS and MG, and compared with normal controls.
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