TARGETED CTL MEDIATED IMMUNITY FOR PROSTATE CANCER

描述：（改编自研究者的摘要）：这个的一个单独的目标 工作是检验以下假设：组织特异性和发育 调节抗原可用于前列腺的有效免疫治疗 癌症。前列腺癌是男性和女性癌症死亡的第二大原因 老年人的重要疾病。过去的一个严重限制是 缺乏明确的和真实的肿瘤抗原，这将适用于 人类，但具有动物模型的实验优势。致地址 研究人员开发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 前列腺中的细胞因子会影响细胞介导的免疫、对 PSA 的反应。使用 新颖的分子方法，他们将确定哪些 PSA 表位被识别 与非转基因小鼠相比，表达 PSA 的小鼠。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，对一种或多种免疫显性表位具有耐受性，但 能够通过识别不同的子集来响应该抗原 通常是次显性或隐性的 PSA 表位。 PSA表位为 CD4 和 CD8 细胞仅限于小鼠 I 类分子，以及那些 由人类 HLA-A2 I 类分子呈递，将被确定。他们 相信他们已经采用了一种方法，不仅可以识别，还可以 改进肿瘤抗原表位。改变的肽配体具有改进的 将产生 MHC 结合或增强 T 细胞受体的识别能力， 测试了它们刺激针对肿瘤的保护性反应的能力 表达天然 hPSA。此外，他们将利用这个模型探索是否 对 PSA 的强烈反应会导致自身免疫性前列腺炎。最后，这些 结果将被纳入使用小鼠的免疫治疗策略中 自发地发展为前列腺癌。

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.