TARGETED CTL MEDIATED IMMUNITY FOR PROSTATE CANCER

描述(改编自申请者摘要)：目前有一个 缺乏前列腺癌的动物模型。这样做的目的之一是 该项目是建立一种前列腺癌的小鼠模型。这将使 首席研究员利用遗传和生物多样性的财富 这个物种的免疫试剂，并使他能够测试潜力 免疫治疗的策略。要开发此模型，校长 研究人员将分离出人类前列腺特异性抗原(PSA)基因和 它的监管区域。然后这些监管区域将被用于驾驶 转基因技术在小鼠前列腺中的基因表达。人类 基因经常在小鼠身上复制其组织特有的表达模式。 这种方法也将被用于靶向表达SV40T抗原 对小鼠的前列腺。预期的结果是前列腺肿瘤将 发展。由此产生的肿瘤株将是有价值的试剂，作为研究 前列腺癌。此外，首席调查员将使用肿瘤 关于抗癌免疫治疗方法的实验。这个 人PSA的前列腺特异性表达将被用来研究 打破耐受性，如通过产生PSA特异性CTL来评估， 这反过来会产生有针对性的自身免疫力。自我宽容有 已被证明依赖于几种机制。即便如此，很明显， 宽容不是绝对的。首席调查员假设 有可能在特定的器官或组织中引导自身免疫反应 通过诱导对器官特异性抗原的免疫反应来流行。至 检验这一假设，目前的研究将：1)发展一种表达 将推动前列腺中基因表达的载体；2)开发 在前列腺特异表达PSA的转基因小鼠；3)研究 人类白细胞抗原A2在体内诱导PSA诱导CTL应答能力的研究 老鼠；以及4)确定有效的免疫策略是否可以增强 即使在表达PSA的动物中，CTL的发展和肿瘤排斥反应也是如此。这个 这些方法的最终临床应用将是产生特定的CTL 这将针对一个潜在的可有可无的器官，如前列腺。 例如，前列腺特异性CTL可用于消除 切除腺体后的转移性前列腺细胞。

DESCRIPTION (Adapted from the Applicant's Abstract): There is currently a paucity of animal models for prostate tumors. One of the goals of this project is to establish a mouse model of prostate tumors. This will enable the Principal Investigator to take advantage of the wealth of genetic and immunologic reagents for this species and enable him to test potential strategies for immunotherapy. To develop this model the Principal Investigator will isolate the human prostate specific antigen (PSA) gene and its regulatory regions. These regulatory regions will then be used to drive gene expression in the mouse prostate via transgenic technology. Human genes often replicate their tissue specific expression patterns in mice. This approach will also be used to target expression of the SV40 T antigen to the mouse prostate. The expected result is that prostatic tumors will develop. The resulting tumor lines will be valuable reagents as models for prostate cancer. In addition, the Principal Investigator will use the tumor lines in experiments on anti-cancer immunotherapeutic approaches. The prostate specific expression of human PSA will be used to investigate the breaking of tolerance, as assessed by the generation of PSA specific CTL, which would, in turn, generate targeted autoimmunity. Self tolerance has been shown to depend on several mechanisms. Even so, it is clear that tolerance is not absolute. The Principal Investigator hypothesizes that it is possible to direct an autoimmune response in an organ or tissue specific fashion by inducing an immune response to organ specific antigens. To examine this hypothesis the current study will: 1) develop an expression vector that will drive expression of genes in the prostate; 2) develop transgenic mice specifically expressing PSA in the prostate; 3) investigate the ability to elicit CTL responses to PSA in vivo in HLA-A2 expressing mice; and 4) determine whether potent immunization strategies can enhance CTL development and tumor rejection even in PSA expressing animals. The ultimate clinical use of these approaches will be to generate specific CTL that would target a potentially dispensable organ, such as the prostate. For example, the prostate specific CTL could be used for the elimination of metastatic prostatic cells after removal of the gland.