Role of NKG2D in immune responses to tumors

建议研究NKG2D免疫受体在肿瘤免疫反应中的作用 细胞。NKG2D是一种由所有自然杀伤(NK)细胞、所有激活的细胞毒T细胞表达的刺激性受体 (CTL)所有激活的巨噬细胞，以及部分γ/Delta T细胞和NK1.1+T细胞。NKG2D 识别几种相关的细胞表面蛋白(配体)，包括RAEL和H60。高水平的表达 靶细胞对NKG2D配体的结合可引起NK细胞和活化的巨噬细胞的强烈攻击，并导致 增强CTL对肿瘤特异性抗原的反应。大多数正常细胞不表达这些NKG2D 配基。相比之下，大多数肿瘤细胞株上调RAEL和其他NKG2D配体。假设是 测试表明，NKG2D及其配体代表了一种用于肿瘤免疫监控的系统。就是，它是 提出NKG2D配体通常在肿瘤细胞发育过程中上调，以此作为一种警示和 激活免疫系统，并由此产生的免疫反应用于限制发育和/或 正常动物体内肿瘤的生长。这一假设将使用几种方法进行检验。此外, 初步实验表明，转导高水平NKG2D的肿瘤细胞系 当受到辐射时，配体作为有效的治疗性癌症疫苗发挥作用，从而刺激有效的免疫。 对相同类型的已建立的肿瘤(但不是转导的)的反应。因此，研究将是 致力于确定这种方法的有效性，以及它是否可以有效地与其他 免疫疗法。 具体目标1：确定与不同接头分子相关的NKG2D亚型在 刺激和共刺激NKG2D+细胞。 特定目的2：建立和鉴定缺失NKG2D表达的GONE靶向小鼠。 具体目的3.评价NKG2D在体内肿瘤监测中的重要性。 具体目的4.确定NKG2D刺激作为一种癌症免疫疗法的疗效

The proposal is to investigate the function of the NKG2D immunoreceptor in immune responses to tumor cells. NKG2D is a stimulatory receptor expressed by all natural killer (NK) cells, all activated cytotoxic T cells (CTL) all activated macrophages, and fractions of gamma/delta T cells and NK1.1+ T cells. NKG2D recognizes several related cell surface proteins (ligands), including Rael and H60. Expression of high levels of NKG2D ligands by target cells results in a strong attack by NK cells and activated macrophages, and an enhanced response of CTL to tumor-specific antigens. Most normal cells do not express these NKG2D ligands. Most tumor cell lines, in contrast, upregulate Rael and other NKG2D ligands. The hypothesis to be tested is that NKG2D and its ligands represent a system for tumor immunosurveillance. That is, it is proposed that NKG2D ligands are normally upregulated in developing tumor cells as a means to alert and activate the immune system, and that the resulting immune response serves to limit the development and/or growth of tumors in normal animals. This hypothesis will be tested using several approaches. In addition, preliminary experiments demonstrate that tumor cell lines transduced to express high levels of NKG2D ligands, when irradiated, function as potent therapeutic cancer vaccines that stimulate an effective immune response against established tumors of the same type (but not transduced). Therefore, studies will be undertaken to establish how effective this approach is and whether it can be effectively combined with other immunotherapies. Specific Aim 1: To determine the role of NKG2D isoforms associated with different adapter molecules in stimulating and costimulating NKG2D+ cells. Specific Aim 2: To generate and characterize gone targeted mice lacking NKG2D expression. Specific Aim 3. To assess the importance of NKG2D in surveillance of tumors in vivo. Specific Aim 4. To determine the efficacy of NKG2D stimulation as a cancer immunotherapy