TARGETED CTL MEDIATED IMMUNITY FOR PROSTATE CANCER

描述（改编自申请人的摘要）：目前有一种 缺乏前列腺肿瘤的动物模型。 其中一个目标是 项目是建立小鼠前列腺肿瘤模型。 这将使 首席研究员利用丰富的遗传和 免疫试剂，使他能够测试潜在的 免疫治疗的策略。 为了开发这个模型， 研究者将分离人前列腺特异性抗原（PSA）基因， 其监管区域。 这些监管区域将用于驱动 通过转基因技术在小鼠前列腺中的基因表达。 人类 基因通常在小鼠中复制其组织特异性表达模式。 该方法也将用于靶向SV 40 T抗原的表达 老鼠的前列腺。 预期结果是前列腺肿瘤将 开发. 由此产生的肿瘤细胞系将是有价值的试剂，作为模型， 前列腺癌 此外，主要研究者将使用肿瘤 在抗癌免疫方法的实验中。 的 人PSA的前列腺特异性表达将用于研究 耐受性的破坏，如通过PSA特异性CTL的产生所评估的， 从而产生针对性自身免疫 自我宽容 它取决于几种机制。 即便如此，很明显， 宽容不是绝对的。 主要研究者假设， 有可能在器官或组织特异性中引导自身免疫应答， 通过诱导对器官特异性抗原的免疫反应来形成。 到 为了验证这一假设，本研究将：1）开发一个表达式， 将驱动前列腺中基因表达的载体; 2）开发 前列腺特异性表达PSA的转基因小鼠; 3）研究 在表达HLA-A2的小鼠中， 小鼠;以及4）确定有效的免疫策略是否可以增强 甚至在PSA表达动物中的CTL发展和肿瘤排斥。 的 这些方法的最终临床应用将是产生特异性CTL 针对潜在的前列腺器官，比如前列腺 例如，前列腺特异性CTL可用于消除前列腺癌细胞。 切除腺体后转移的前列腺细胞。

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.