IMMUNE TOLERANCE INDUCTION BY A TUMOR SPECIFIC ANTIGEN

肿瘤特异性抗原诱导免疫耐受。 显著 癌症免疫学的知识已经取得了进展。 在 在人类中，低响应率阻碍了这种方法的广泛使用 到癌症治疗 一个很可能的原因是 对肿瘤特异性抗原的免疫耐受。 能够设计 规避免疫耐受的策略，从而设计更多 有效的免疫治疗，肿瘤免疫耐受机制 需要被定义。 本研究将利用转基因技术， 小鼠技术来开发免疫耐受诱导模型， 肿瘤。 具体地，表达两种基因的转基因小鼠模型 将使用转基因，胰腺腺泡中SV 40 T抗原的基因 导致胰腺肿瘤发展的细胞;以及 对于识别SV 40 T抗原的T细胞受体（TCR）， 在90%的T细胞上表达。 对这些小鼠的初步观察 证明了相关的T细胞随着时间的推移逐渐被删除， 这就解释了为什么肿瘤不会被排斥 在这里提出的研究中 将定义造成这种消耗的机制。 初始 将进行实验以确定胸腺克隆 缺失、外周克隆缺失、克隆无反应性或TCR调节 发生。 这将通过过继转移实验来完成， FACS分析和抗原诱导的增殖和杀伤测定。 接下来，将使用T 来自TCR转基因小鼠的肿瘤细胞，以及来自 来自SV 40 T抗原转基因小鼠的肿瘤。 的存在或缺乏 相关的共刺激分子、细胞因子或细胞相互作用 将被定义。 最后，将开发一个体内模型来研究 公差，根据从 体外模型。

Immune Tolerance Induction by a Tumor Specific Antigen. Significant advances in the knowledge of the immunology of cancer have occurred. In humans, low responses rates have hampered broader usage of this approach to cancer therapy. One very likely reason for this id the presence of immune tolerance to tumor specific antigens. To be able to design strategies to circumvent immune tolerance, and thereby design more effective immunotherapy, the mechanisms of tolerance in tumor immunity need to be defined. The study proposed here will utilize transgenic mouse technology to develop a model of immune tolerance induction by neoplasms. Specifically, a transgenic mouse model which expresses two transgenes will be used, the gene for SV40 T-antigen in pancreatic acinar cells which results in the development of pancreatic tumors; and the gene for the T cell receptor (TCR) which recognizes SV40 T-antigen, which is expressed on 90% of T cells. Preliminary observations of these mice demonstrated that the relevant T cells are gradually deleted over time, which explains why tumors are not rejected. In the study proposed here the mechanisms responsible for this depletion will be defined. Initial experiments will be performed to determine whether thymic clonal deletion, peripheral clonal deletion, clonal anergy, or TCR modulation occurs. This will be accomplished with adoptive transfer experiments, FACS analyses, and antigen induced proliferation and killing assays. Next, an in vitro tolerance induction assay will be developed using T cells from the TCR transgenic mice, and a tumor cell line derived from tumors arising from SV40 T-antigen transgenic mice. The presence or lack of relevant co-stimulatory molecules, cytokines, or cellular interactions will be defined. Finally, an in vivo model, will be developed to study tolerance, applying manipulations based on the results obtained from the in vitro model.