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Therapeutic Potency of IL2-Caspase3 Targeted Treatment in a Murine Experimental Model of Inflammatory Bowel Disease (IBD)
  1. Shimon Shteingart
  1. Hebrew University of Jerusalem, Israel
    1. Matan Rapoport
    1. Hebrew University of Jerusalem, Israel
      1. Inna Grodzovski
      1. Hebrew University of Jerusalem, Israel
        1. Ofra Sabag
        1. Hebrew University of Jerusalem, Israel
          1. Michal Lichtenstein
          1. Hebrew University of Jerusalem, Israel
            1. Ronen Eavri
            1. Hebrew University of Jerusalem, Israel
              1. Haya Lorberboum-Galski (hayag{at}ekmd.huji.ac.il)
              1. Hebrew University of Jerusalem, Israel

                Abstract

                Background: Inflammatory bowel disease (IBD) comprises primarily the two disorders ulcerative colitis (UC) and Crohn's disease (CD) that involve deregulated T cell responses. The ever-increasing incidence rate of CD and UC during recent decades, combined with the limited efficacy and potential adverse effects of current treatments, explain the real need for seeking more specific and selective methods for treating these diseases.

                Aim: To investigate the ability of IL2-Caspase3 chimeric protein, designed to target activated T lymphocytes that express the high affinity IL2 receptor, to ameliorate the clinical symptoms of acute murine experimental colitis, using the DSS-induced mouse model.

                Methods: Mice with DSS-induced colitis were treated with IL2-Caspase3 for 7 days and disease severity was assessed in parallel to control, non-treated mice, receiving only daily injections of PBS. IL2-Caspase3 was tested both for its ability to prevent the development of colitis, and for its therapeutic potential to cure on-going, active acute disease. In addition, colon tissue samples were used for MPO assays and RNA isolation followed by PCR to determine mRNA expression levels of specific genes.

                Results: Treatment with IL2-Caspase3 dose-dependently ameliorated the Disease Activity Index (DAI) of mice colitis. We achieved up to 78% improvement in DAI with i.v. injections of 15 μg/mouse/day. Furthermore, IL2-Caspase3 decreased neutrophil and macrophage infiltration to the inflamed tissue by up to 57%. IL2-Caspase3 was proven as a therapeutic reagent in another model, where treatment begins only after disease onset. Here we demonstrated a 70% decrease in DAI when compared to non-treated sick mice. A reduction in mRNA expression levels of both IL-1β and TNF-α was found in lysates of total colon tissue of treated mice, as compared to sick, untreated mice. We also found that expression levels of BCL2 were significantly decreased after treatment, while BAX was up-regulated in comparison to non-treated mice. Moreover, the BCL2/BAX ratio, which is elevated in both experimental colitis and in human Crohn's Disease, was decreased dramatically after treatment.

                Conclusions: IL2-Caspase3 chimeric protein may provide a novel approach to the therapy of human IBD, and a possible suggested treatment for other pathological conditions that involve uncontrolled expansion of activated T cells.

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