Novel Immunological Modifer as a Tissue Protector

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DESCRIPTION (provided by applicant): Novel Immunological Modifier as a Tissue Protector Tissues in the body can be damaged by a wide variety of events. Protecting these tissues after the damaging stimulus has been applied is a worthy goal. Several reports in the literature have shown that mice lacking the APOE gene (APOE knockout mice) and therefore lacking apolipoprotein-E (apoE protein), are more susceptible to death after a bacterial challenge than their wild-type, apoE-containing counterparts. We now report herein that APOE knockout mice lacking apoE protein are significantly more sensitive to total body irradiation and die at doses of radiation where their wild-type, apoE containing counterparts live. This opens the possibility that apoE protein, or mimetics of apoE protein, might be used to protect tissues from the damaging effects of radiation. We are developing COG133, a peptide based on residues 133-149 of apolipoprotein-E (apoE). COG133 displays anti-inflammatory activities in cell-based models of inflammation and in whole animal models of inflammation. We recently reported that C57Bl/6 mice treated with lipopolysaccharide plus COG133 has significantly less cytokine release than mice treated with lipopolysaccharide alone (Lynch et al. JBC 2003). We report new data in which wild-type mice exposed to 10 Gy of total body irradiation and then treated with COG133, survive significantly longer than their saline treated counterparts. Together with our new data on sensitivity of APOE knockout mice to ionizing radiation, we will fully test the hypothesis that COG133 may protect mice from the harmful and lethal effects of total body irradiation on mortality. Novel Immunological Modifier as a Tissue Protector: Exposure of the whole body to high levels of ionizing radiation typically constitutes a life-ending event (Hall 2000). Exposure to even limited levels of ionizing radiation can cause significant morbidity and may lead to mortality. Controlled total body irradiation (TBI) in a medical setting is beneficial in certain cancer therapeutic modalities, but is none-the- less associated with severe and unwanted side effects. Whether from an accident, from a tragic attack with a Radiological Dispersion Device (NIAID Panel White Paper, 2003), from space travel or from a scheduled medical procedure; there is a great medical need for treatments that can significantly decrease or eliminate the morbidity and mortality associated with Total Body Irradiation (TBI).