MHC Class II Restricted Tumor Antigens and CD4+T Cells

描述（由申请人提供）：T细胞在以下方面发挥重要作用： 在体内控制肿瘤生长和介导肿瘤排斥。识别 来自黑色素瘤的几类MHC I类限制性肿瘤抗原， 以及其他癌症导致了使用这些药物的临床试验的开始， 鉴定的T细胞表位。虽然这些研究承诺有效 治疗转移性癌症患者，专门使用CD 8 + T细胞 可能不会产生最佳的抗肿瘤免疫力。越来越多的证据表明， 人类和动物的研究表明，CD 4 + T（辅助）细胞发挥着中枢作用， 在启动和维持宿主对癌症的免疫应答中的作用， 但缺乏对MHC II类限制性肿瘤抗原的了解， 这是开发更有效的癌症疫苗的主要障碍。远景目标 本研究的目的是剖析肿瘤免疫的免疫成分， CD 4 + T细胞调节免疫反应的机制， 预防和治疗癌症的有效疫苗 癌症患者。核心假设是MHC II类限制性 肿瘤抗原诱导肿瘤反应性CD 4 + T细胞， 用于CD 8 T细胞的引发和活化，CD 8 T细胞是肿瘤的主要效应细胞， 杀伤性因此，CD 4+与CD 8 + T细胞表位的组合将 进一步增强抗肿瘤免疫应答。建议的理由 研究表明，一旦知道肿瘤免疫是如何由MHC类分子调节的， II限制性CD 4 + T细胞，CD 4 + T细胞辅助肽/抗原将被用于免疫调节。 有效地纳入癌症疫苗方案， 治疗癌症患者。这项拟议中的研究是建立在一本小说上的。 我们最初开发的基因系统。我们创造了独特的资源 （肿瘤特异性CD 4 + T细胞系或克隆），并建立了实验性的 动物模型为了检验我们的中心假设，我们将进一步改进 基因克隆系统和鉴定MHC II类限制性肿瘤抗原， 免疫目标。我们将评估DR 2限制性抗体的免疫原性和作用。 DR 2-Tg小鼠保护性免疫中的T辅助肽。我们还将开发 一种新的疫苗策略，以增强CD 4 + T细胞反应， 根除肿瘤。预计这些研究将推动这一领域的发展。 为肿瘤免疫治疗提供了新的基础， 有效的癌症疫苗。

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.