TARGETED CTL MEDIATED IMMUNITY FOR PROSTATE CANCER

描述：(改编自研究人员摘要)：这是一个更长期的目标 我们的工作是检验这样一种假设，即一种特定于组织和发育的 调节抗原可用于前列腺癌的有效免疫治疗 癌症。前列腺癌是男性癌症死亡的第二大原因， 老年人的一种重要疾病。过去的一个严重限制是 缺乏明确和真实的肿瘤抗原，可适用于 人类，但拥有动物模型的实验优势。致信地址 研究人员已经开发出了表达这些问题的转基因小鼠 人类前列腺特异性抗原(HPSA)的模式与 人类。在这个项目中，他们将研究HPSA的具体表达如何 在前列腺中影响细胞免疫，对PSA产生反应。使用 新的分子方法，他们将确定哪些PSA表位被识别 在表达PSA的小鼠和非转基因小鼠中进行比较。这些研究将 检验PSA-CD转基因小鼠的假设，其中PSA是 自身抗原，对一个或多个免疫优势表位具有耐受性，但 能够通过识别不同的子集来对这种抗原做出反应的 PSA表位通常是次要的或隐蔽的。的PSA表位 CD4和CD8细胞都被限制为小鼠I类分子，以及 所提的人类人类白细胞抗原-A2 I类分子，将会被测定。他们 相信他们已经整合了一种方法，不仅可以识别，而且还可以 对肿瘤抗原表位的改进。改良型多肽配体 将产生MHC结合或T细胞受体的改进识别，并 测试它们刺激对肿瘤的保护性反应的能力 表达天然的HPSA。此外，使用此模型，他们将探索 对PSA的强烈反应会导致自身免疫性前列腺炎。最后，这些 结果将被纳入免疫治疗策略，使用小鼠 自发性地患上前列腺癌。

DESCRIPTION: (Adapted from investigator's abstract): A loner term goal of this work is to test the hypothesis that a tissue-specific and developmentally regulated antigen may be used for the effective immuno-therapy of prostate cancer. Prostate cancer is the second leading cause of cancer deaths in men and an important disease of the aged. A serious limitation in the past has been the lack of defined and authentic tumor antigens, which would be applicable to humans, yet have the experimental advantages of an animal model. To address these issues the investigators have developed transgenic mice that express human prostate specific antigen (hPSA) in a pattern remarkably similar to humans. In this project they will examine how the specific expression of hPSA in the prostate affects the cell-mediated immune, response to PSA. Using a novel molecular approach, they will determine which PSA epitopes are recognized in the PSA-expressing mice compared to non-transgenic mice. These studies will test the hypothesis that the PSA-CD transgenic mice, in which PSA is a self-antigen, are tolerant to one or more immuno-dominant epitopes, but are capable of responding to this antigen via recognition of a different subset of PSA epitopes that are normally subdominant or cryptic. The PSA epitopes for both CD4 and CD8 cells restricted to mouse class I molecules, as well as those presented by the human HLA-A2 class I molecule, will be determined. They believe they have incorporated a method for not only identifying, but also improving upon tumor-antigen epitopes. Altered peptide ligands with improved MHC binding or improved recognition by the T cell receptor will be created and tested for their ability to stimulate protective responses against tumors expressing native hPSA. Further, using this model they will explore if a vigorous response to PSA results in autoimmune prostatitis. Finally, these results will be incorporated into immunotherapy strategies using mice that develop prostate cancer spontaneously.