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CD4T细胞对于产生有效的 抗肿瘤I细胞反应，但对地点、时间和方式知之甚少 这种情况就会发生。我们已经开发了一种模型，使我们能够可视化 对体内生长的肿瘤有反应的银特异性T细胞。该模型采用了 TCR转基因0T-I小鼠CD8 T细胞过继转移 KB/0VA257-264感染正常小鼠及对E.G7肿瘤的攻击 将OVA表达为假性肿瘤抗原。宿主CD4T细胞对机体免疫功能的影响 已经从功能上证明了OT-I细胞的反应，但这些 银特异的细胞不能被可视化。我们现在正在开发一种模型， OT-1 CD8 T细胞在正常小鼠体内的双向过继转移 用来自0T-II小鼠的CD4T细胞获得转基因的TCR I-Ad/OVA323-339。使用此模型来可视化、量化和表征 卵子特异性T细胞在对E.G7肿瘤的应答过程中我们将 追求四个具体目标：(1)描述 发生在抗原特异的CD8和CD4T细胞之间 肿瘤特异性反应。(2)确定CTLA-4封锁在 允许有效的抗肿瘤T细胞反应。(3)检测CD8、CD4T 肿瘤免疫中的细胞协同作用及其机制 记忆反应中的协作。新的免疫策略基于 我们实验室最近的工作将被检查。(4)确定方法的特点 通过克服T细胞耐受进行肿瘤免疫治疗。我们预计， 拟议研究中获得的结果将有助于更好地 对免疫中CD4和CD8 T细胞协同作用的认识 对癌症的反应，并可能提出新的预防和治疗方法 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.