T CELL COLLABORATION IN TUMOR SPECIFIC CTL RESPONSES

描述：（改编自申请人的摘要）抗原之间的合作 (Ag).特异性 Ic CD8 和 CD4 T 细胞对于产生有效的 蚂蚁肿瘤 I 细胞反应，但对于何时、何地以及如何反应知之甚少 出现这种情况。我们开发了一个模型，使我们能够可视化 Ag 特异性 T 细胞对体内肿瘤生长作出反应。该模型采用 来自具有转基因 TCR 的 0T-I 小鼠的 CD8 T 细胞的过继转移 对正常小鼠中的 Kb/0VA257-264 具有特异性，并用 E.G7 肿瘤进行攻击 将 OVA 表达为假肿瘤 Ag。宿主 CD4 T 细胞对 0T-I 细胞的反应已在功能上得到证实，但这些 Ag 特异性细胞无法可视化。我们现在正在开发一个模型 采用双重过继性转移 OT-1 CD8 T 细胞至正常小鼠体内 来自 0T-II 小鼠的 CD4 T 细胞具有特异性的转基因 TCR I-Ad/OVA323-339。使用该模型来可视化、量化和表征 在对 E.G7 肿瘤的反应过程中，OVA 特异性 T 细胞我们将 追求四个具体目标：（1）描述协作互动 发生在 Ag 特异性 CD8 和 CD4 T 细胞之间 肿瘤特异性反应。 (2) 确定 CTLA-4 阻断在 允许有效的抗肿瘤 T 细胞反应。 (3) 检查CD8和CD4 T 免疫中的细胞协作以预防肿瘤和 记忆反应中的协作。基于的新型免疫策略 我们实验室最近的工作将受到审查。 (4) 表征方法 通过克服T细胞耐受性进行肿瘤免疫治疗。我们预计 拟议研究中获得的结果将有助于更好的基础 了解 CD4 和 CD8 T 细胞在免疫中的协作 对癌症的反应，并可能提出新的保护和治疗方法 治疗性免疫策略。

DESCRIPTION: (Adapted from applicant's abstract) Collaboration between antigen (Ag).specific Ic CD8 and CD4 T cells is critical for generating an effective ant-tumor I cell response, yet very little is known about where, when and how this occurs. We have developed a model that has allowed us to visualize Ag-specific T cells responding to tumor growing in vivo. The model employs adoptive transfer of CD8 T cells from 0T-I mice having a transgenic TCR specific for Kb/0VA257-264 into normal mice, and challenge with E.G7 tumor expressing OVA as a pseudo-tumor Ag. A contribution of host CD4 T cells to the response of the 0T-I cells has been demonstrated functionally, but these Ag-specific cells cannot be visualized. We are now developing a model that employs double adoptive transfer into normal mice of OT-1 CD8 T cells along with CD4 T cells from 0T-II mice having a transgenic TCR specific for I-Ad/OVA323-339. Using this model to visualize, quantitate and characterize the OVA-specific T cells during the course of a response to E.G7 tumor we will pursue four specific aims: (1) To describe the collaborative interactions that occur between Ag-specific CD8 and CD4 T cells during the course of a tumor-specific response. (2) To determine the role of CTLA-4 blockade in allowing effective anti-tumor T cell responses. (3) To examine CD8 and CD4 T cell collaboration in immunization for protection against tumor and the collaboration in the memory response. Novel immunization strategies based on recent work in our laboratory will be examined. (4) To characterize approaches for tumor immunotherapy by overcoming T cell tolerance. We anticipate that the results obtained in the proposed studies will contribute to a better basic understanding of the collaboration between CD4 and CD8 T cells in the immune response to cancer, and may suggest novel approaches for protective and therapeutic immunization strategies.