The role of CD4+ T cells in melanoma immunotherapy

描述（由申请人提供）： 这位候选人是一位最近晋升的 研究助理教授，他一直在研究树突状细胞的使用 细胞激活CD 8 + T细胞对黑色素瘤的反应 V. Engelhard医生 作为走向独立的一部分，候选人是 发展他自己的研究项目， 调查事务所 候选人的意图是将特明奖作为一个 在导师制下发展智力和科学的基础 由恩格尔哈德博士提供，随后成功过渡到完全 肿瘤免疫治疗的独立研究。 弗吉尼亚大学 提供了一个理想的环境，这一建议，由于卓越的 基础科学教师和与医生合作的潜力 对在临床环境中应用免疫疗法感兴趣。 研究 该提案是基于几个团体积累的数据，这些数据表明 CD 4 + T细胞在指导适应性免疫反应中起着不可或缺的作用， 针对肿瘤，通过为专业抗原提供激活刺激， 呈递细胞、细胞因子支持效应和记忆CD 8+的产生 不 细胞和直接抗肿瘤活性。 因此，疫苗 引发针对肿瘤的CD 8 + T细胞和CD 4 + T细胞应答的方案是 可能比那些针对自适应机器人的任何一个手臂的机器人更有效。 免疫反应。 基于CD 4 + T细胞的产生 能够对MHC II类限制性表位特异性应答的细胞 来自黑素细胞分化蛋白质将增强生成 肿瘤特异性CD 8 + T细胞应答，以及记忆性CD 8 + T细胞的产生。 细胞对黑色素瘤，我们建议：1。 识别和比较HLA-DR*0401 来自酪氨酸酶的限制性肽呈现在树突状细胞上， 细胞、黑素瘤细胞或两者。 2. 表征CD 4 + T细胞对 DR 4/IEd转基因小鼠中酪氨酸酶衍生的HLA-DR*0401限制性肽 在外周表达或不表达酪氨酸酶。 3. 定义 酪氨酸酶特异性CD 4 + T细胞及其表位在酪氨酸酶产生中的作用 酪氨酸酶特异性CD 8 + T细胞和抗黑色素瘤反应。 结果 预计这项建议所产生的影响将立即对我们的 了解对外周表达的自身抗原的免疫应答 与黑色素瘤相关，免疫抑制剂的设计 针对黑色素瘤的干预措施。

DESCRIPTION (provided by applicant): The candidate is a recently promoted Research Assistant Professor who has been investigating the use of dendritic cells to activate CD8+ T cell responses against melanoma in the laboratory of Dr. V. Engelhard. As part of a move towards independence, the candidate is developing his own research project that extrapolates from his postdoctoral investigations. It is the candidate's intention to use the Temin Award as a foundation to advance intellectually and scientifically under the mentorship provided by Dr. Engelhard, followed by a successful transition to completely independent research in tumor immunotherapy. The University of Virginia provides an ideal environment for this proposal due to the excellence of the basic science faculty and the potential for collaboration with physicians interested in applying immunotherapy in a clinical setting. The research proposal is based on the accumulated data from several groups that suggests that CD4+ T cells play an integral role in directing adaptive immune responses against tumors, by providing activation stimuli for professional antigen presenting cells, cytokine support the generation of effector and memory CD8+ T cells and direct anti-tumoricidal activity. Therefore, vaccination protocols that elicit CD8+ T cell and CD4+ T cell responses against tumors are likely to be more effective than those that target either arm of the adaptive immune response alone. Based on the hypothesis that the generation of CD4+ T cells that can respond specifically to MHC class II-restricted epitopes derived from melanocyte differentiation proteins will enhance the generation of tumor-specific CD8+ T cell responses, and the generation of memory CD8+ T cells against melanoma, we propose to: 1. Identify and compare HLA-DR*0401- restricted peptides derived from tyrosinase that are presented on dendritic cells, melanoma cells, or both. 2. Characterize the CD4+ T cell response to tyrosinase-derived HLA-DR*0401-restricted peptides in DR4/IEd transgenic mice that either do or do not express tyrosinase in the periphery. 3. Define the role of tyrosinase-specific CD4+ T cells and their epitopes in the generation of tyrosinase-specific CD8+ T cells and anti-melanoma responses. The results derived from this proposal are expected to have immediate impact on our understanding of the immune response to peripherally expressed self-antigens t h a t are relevant to melanoma, and the design of immunotherapeutic interventions against melanoma.