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    A DNA aptamer prevents influenza infection by blocking the receptor binding region of the viral hemagglutinin
    (Journal of Biological Chemistry, 2004) Jeon, Sung Ho; Kayhan, Başak; Benyedidia, Tamar; Arnon, Ruth
    Influenza A virus infection is a major source of morbidity and mortality worldwide. Current means of control for influenza are based on prophylaxis by vaccines and on treatment by the available specific influenza neuraminidase inhibitor drugs. The approach taken in the present study is to prevent and/or ameliorate influenza infection by site-specific blocking of the viral binding to host cell receptors. We describe a novel oligonucleotide, known also as an aptamer, which has been designed to complement the receptor-binding region of the influenza hemagglutinin molecule. It was constructed by screening a DNA library and processing by the selective evolution of ligands by exponential enrichment (SELEX) procedure. We show that this DNA aptamer is indeed capable of inhibiting the hemagglutinin capacity of the virus, as well as in the prevention of viral infectivity in vitro, in tissue culture. Furthermore, it inhibits viral infection by different influenza strains in an animal model, as manifested by 90 –99% reduction of virus burden in the lungs of treated mice. The mode of action of this aptamer is by blocking the binding of influenza virus to target cell receptors and consequently prevention of the virus invasion into the host cells.
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    Glatiramer acetate Copaxone regulates nitric oxide and related cytokine secretion in experimental autoimmune encephalomyelitis
    (Immunology Letters, 2003) Kayhan, Başak; Aharoni, Rina; Arnon, Ruth
    Nitric oxide (NO) is an important mediator involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) and multiple sclerosis (MS). We examined the effect of glatiramer acetate (GA), an agent with suppressing effect on EAE and of therapeutic value for the treatment of MS, on the secretion of NO, as well as of the NO regulating cytokines. We observed that induction of EAE leads to 4-fold elevation in NO secretion and that treatment of the EAE mice by GA indeed leads to a significant reduction in the NO secretion by the splenocytes in response to the encephalitogen. A parallel decrease was observed in the secretion of the NO inducing cytokine IL-1b. On the other hand, the secretion level of NO modulating cytokines IL-10 and IL-13 was significantly augmented. The correlation between these findings and the therapeutic effect of GA is discussed.
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    Immunomodulatory therapeutic effect of glatiramer acetate on several murine models of inflammatory bowel disease
    (Journal of Pharmacology and Experimental Therapeutics, 2006) Aharoni, Rina; Kayhan, Başak; Brenner, Ori; Domev, Hagit; Labunskay, Galya; Arnon, Ruth
    Inflammatory bowel disease (IBD) is characterized by detrimental immune reactivity in the gut and imbalance between proinflammatory and anti-inflammatory reactivity. In an attempt to down-regulate colitis, we investigated the effect of the immunomodulator glatiramer acetate (GA, Copaxone, copolymer 1) on two murine models of IBD, chemically induced and spontaneous. Acute experimental colitis of different levels of severity was induced in C57BL/6 mice by dextran sulfate sodium (DSS) administered orally at different concentrations and frequencies. It was manifested in weight loss, intestinal bleeding, and diarrhea, as well as by macroscopic and microscopic colon damage. GA treatment led to amelioration of all of these pathological manifestations, resulting in improved long-term survival. Moreover, even when colitis was induced by three cycles of DSS in this highly susceptible mouse strain, as well as in BALB/c mice that exhibit a chronic disease pattern, a substantial reduction in disease activity and mortality was obtained. GA treatment induced a beneficial effect also in a spontaneous model of colitis developed in the C3H/HeJBir IL-10-deficient mice. The detrimental proinflammatory response manifested by proliferation, tumor necrosis factor- , and interferon- expression was modulated by GA, whereas the regulatory anti-inflammatory transforming growth factor- and IL-10 cytokines response was elevated. This was demonstrated on the level of protein secretion in splenocytes and local mesenteric lymphocytes in response to syngeneic colon extract and in the overall response to anti-CD3, as well as on the level of mRNA expression in the colon.
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    Therapeutic effect of the immunomodulator glatiramer acetate on trinitrobenzene sulfonic acid induced experimental colitis
    (Inflammatory Bowel Diseases, 2005) Aharoni, Rina; Kayhan, Başak; Arnon, Ruth
    Inflammatory bowel diseases are characterized by detrimental immune reactivity in the gut and imbalance between proinflammatory and antiinflammatory reactivity. In an attempt to downregulate inflammatory bowel disease, we tested whether the immunomodulator glatiramer acetate (GA; Copaxone®, copolymer 1), an approved drug for the treatment of multiple sclerosis, can ameliorate trinitrobenzene sulfonic acid (TNBS)-induced colitis, a murine model that resembles human Crohn's disease. Experimental colitis was induced by rectal instillation of TNBS in 3 mice strains: BALB/c, SJL/J, and (SJL/JXBALB/c)F1, and its severity was evaluated by gross colon injury, histologic damage, body weight, and survival rate. We studied the effect of GA on all these parameters as well as on lymphocyte reactivity manifested by proliferation and secretion of tumor necrosis factor-α, and transforming growth factor-β. GA treatment significantly suppressed the various manifestations of TNBS-induced colitis as demonstrated by substantial reduction in the macroscopic colonic damage, preservation of the microscopic colonic structure, reduced weight loss, and improved long-term survival, in GA treated mice compared with untreated mice. The parenteral route was more effective than the oral route. GA suppressed the proliferation of local mesenteric lymphocytes to syngeneic colon extract and the detrimental tumor necrosis factor-α secretion. In addition, it induced a beneficial secretion of transforming growth factor-β. The ability of GA to effectively modulate the clinical manifestations and the detrimental immune response involved in experimental colitis warrants further studies to determine the clinical efficacy of GA in the treatment of human inflammatory bowel diseases.
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