Novel Immunological Modifer as a Tissue Protector

描述(申请人提供)：新型免疫调节剂作为组织保护剂，可在多种情况下对体内组织造成损害。在实施破坏性刺激后保护这些组织是一个有价值的目标。一些文献报道表明，缺乏apoE基因的小鼠(apoE基因敲除小鼠)因此缺乏apoE蛋白(apoE蛋白)，比含有apoE的野生型小鼠更容易在细菌攻击后死亡。我们现在在这里报告，缺乏apoE蛋白的apoE基因敲除小鼠对全身照射明显更敏感，并在其野生型、含有apoE的同龄人生活的辐射剂量下死亡。这开启了apoE蛋白或apoE蛋白的模拟物可能被用来保护组织免受辐射损伤的可能性。我们正在开发一种基于载脂蛋白-E(ApoE)133-149残基的多肽COG133。COG133在基于细胞的炎症模型和整个动物炎症模型中显示出抗炎活性。我们最近报道，C57BL/6小鼠在脂多糖加COG133的治疗下，细胞因子的释放明显少于仅用脂多糖治疗的小鼠(Lynch等人。JBC 2003)。我们报道了新的数据，野生型小鼠受到10Gy全身照射，然后用COG133治疗，存活时间明显长于生理盐水治疗的小鼠。结合我们关于APOE基因敲除小鼠对电离辐射敏感性的最新数据，我们将全面检验这一假设，即COG133可能保护小鼠免受全身照射对死亡率的有害和致命影响。作为组织保护剂的新型免疫调节剂：全身暴露在高水平的电离辐射下通常构成生命终结事件(Hall 2000)。即使暴露在有限水平的电离辐射下，也会导致严重的发病率，并可能导致死亡。受控全身照射(TBI)在某些癌症治疗方法中是有益的，但仍然与严重的和不想要的副作用有关。无论是事故、辐射弥散装置的悲剧性攻击(NIAID专家组白皮书，2003)、太空旅行还是预定的医疗程序；医学上都非常需要能够显著降低或消除与全身照射(TBI)相关的发病率和死亡率的治疗。

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).