MHC Class II Restricted Tumor Antigens and CD4+T Cells

描述(申请人提供)：T细胞在 体内抑制肿瘤生长和介导肿瘤排斥反应。鉴定 几类黑色素瘤MHC-I类限制性肿瘤抗原AS 和其他癌症一样，导致了使用这些药物的临床试验的启动 确定了T细胞表位。虽然这些研究有望有效地 治疗转移性癌症患者，独家使用CD8+T细胞 可能不会产生最佳的抗肿瘤免疫力。来自两个国家的越来越多的证据 人类和动物研究表明，CD4+T(辅助)细胞在 在启动和维持宿主对癌症的免疫反应中的作用， 但缺乏对MHC-II类限制性肿瘤抗原的这种知识是一种 开发更有效的癌症疫苗的主要障碍。远景目标 本研究的目的是解剖肿瘤免疫的免疫成分，了解 CD_4~+T细胞调节免疫反应的机制 有效的预防和治疗癌症的肿瘤疫苗 癌症患者。中心假设是MHC II类受限制 肿瘤抗原诱导肿瘤反应性CD4+T细胞，这提供了至关重要的帮助 用于启动和激活肿瘤的主要效应细胞CD8T细胞 毁灭。因此，CD4+和CD8+T细胞表位的结合将 进一步增强抗肿瘤免疫反应。建议的理由是 研究表明，一旦知道MHC类物质是如何调节肿瘤免疫的 限制的CD4+T细胞、CD4+T细胞的辅助肽/抗原 有效地纳入癌症疫苗方案，以预防和 癌症患者的治疗。这项拟议的研究是建立在一部小说的基础上 我们最初开发的遗传系统。我们已经产生了独特的资源 (肿瘤特异性的CD4+T细胞系或克隆)，并建立了实验 动物模型。为了检验我们的中心假设，我们将进一步改进 MHC-II类限制性肿瘤抗原的基因克隆及鉴定 免疫靶标。我们将评估DR2限制性的免疫原性和作用 辅助肽在DR2-TG小鼠保护性免疫中的作用。我们还将发展 增强CD4+T细胞应答的新疫苗策略 根除肿瘤。预计这些研究将推动 为肿瘤的免疫治疗提供了新的发展基础 有效的癌症疫苗的方法。

DESCRIPTION (provided by applicant): T cells play an important role in controlling tumor growth and mediating tumor rejection in vivo. Identification of several classes of MHC class I-restricted tumor antigens from melanoma as well as other cancers has led to the initiation of clinical trials using these identified T cell epitopes. While these studies hold the promise of effective treatment of patients with metastatic cancer, the exclusive use of CD8+ T cells may not generate an optimal anti-tumor immunity. Increasing evidence from both human and animal studies indicates that CD4+ T (helper) cells play a central role in initiating and maintaining the host immune responses against cancer, but the lack of such knowledge of MHC class II-restricted tumor antigens is a major hurdle for developing more effective cancer vaccines. The long-range goal of this study is to dissect immune components of tumor immunity, to understand the mechanism by which CD4+ T cells regulate immune responses, and to develop effective cancer vaccines for the prevention and therapeutic treatment of patients with cancer. The central hypothesis is that MHC class II-restricted tumor antigens induce tumor-reactive CD4+ T cells, which provide critical help for priming and activation of CD8 T cells, the major effector cells for tumor destruction. Thus, the combination of CD4+ with CD8+ T cell epitopes will further augment anti-tumor immune responses. The rationale for the proposed research is that, once it is known how tumor immunity is regulated by MHC class II restricted CD4+ T cells, CD4+ T cell helper peptides/antigens will be effectively incorporated in cancer vaccine regimen for the preventive and treatment of patients with cancer. The proposed research is built on a novel genetic system we originally developed. We have generated unique resouces (tumor-specific CD4+ T cell lines or clones), and established experimental animal models. To test our central hypothesis, we will further improve the genetic cloning system and identify MHC class II-restricted tumor antigens as immune targets. We will evaluate the immunogenicity and role of DR2-restricted T helper peptides in protective immunity in DR2-Tg mice. We will also develop novel vaccine strategies to enhance CD4+ T cell responses in an attempt to eradicate tumor. It is anticipated that these studies will advance the field of immunotherapy of cancer and provide a foundation of the development of novel approaches for effective cancer vaccines.