IMMUNITY TO MELANOMA VIA DENDRITIC CELLS

通过鉴定抗原和相应的肿瘤特异性淋巴细胞，特别是杀伤和辅助T细胞，人类肿瘤免疫学已经得到了发展。该计划将利用树突状细胞[DC]来增强黑色素瘤抗原向T细胞的呈递，主要在人类中，但也在小鼠模型中。我们在DC上的MHC I类和II类产物可以通过喂养凋亡和坏死细胞而被加载一系列肿瘤抗原; 3]携带抗原的DC可以通过喂养凋亡和坏死细胞而被加载一系列肿瘤抗原; 3]携带抗原的DC可以原位快速增强人类免疫系统。因此，一个综合方案在达拉斯和纽约可以开始积极免疫系统原位。因此，在达拉斯和纽约的一个综合项目可以开始主动免疫患者黑色素瘤抗原，同时进行实验室研究，学习如何增强DC对肿瘤抗原的加工，评估不同DC亚群和成熟状态的作用，并原位观察DC在肿瘤和淋巴结中的功能。该项目强调黑色素瘤，因为已知小鼠和人类的肿瘤特异性T细胞，并且现在很明显，DC存在源自凋亡细胞的体外黑色素瘤抗原。人类肿瘤特异性免疫的记录已经变得更容易与定量测定，包括：MHC四聚体的结合，ELISPOTS的生产，并召回测定，以引发特定的杀伤T细胞。该计划将包括双中心随机试验。在第一部分中，我们将比较两种类型的DC在引发对黑色素瘤肽的免疫中的作用，并寻找对其他抗原的免疫应答，作为体内交叉呈递的指标。在第二部分中，我们将比较负载有肽的DC与垂死的肿瘤细胞在扩增肿瘤特异性CD 4和CD 8 T细胞中的作用。用于管理、DC生产和免疫监测的共享持续核心设施将激发和标准化相互作用。总之，我们假设DC，自然界的佐剂，将增强对肿瘤抗原的免疫力，从而可以追求癌症疫苗接种和治疗的临床结果。

Human tumor immunology has been advanced by the identification of antigens and the corresponding tumor specific lymphocytes, particularly killer and helper T cells. This program will exploit the dendritic cell [DC] to enhance presentation of melanoma antigens to T cells, primarily in humans but also in mouse models. Our MHC class I and II products on DCs can be charged with an array of tumor antigens by feeding apoptotic and necrotic cells; 3] antigen-bearing DCs can be charged with an array of tumor antigens by feeding apoptotic and necrotic cells; 3] antigen-bearing DCs can rapidly boost the human immune system in situ. Therefore an integrated program in Dallas and New York can begin to actively immune system in situ. Therefore an integrated program in Dallas and New York can begin to active immunize patients to melanoma antigens, concomitant with laboratory studies to learn to enhance DC processing of tumor antigens, to evaluate the roles of distinct DC subsets and maturation states, and to observe DC function in tumors and lymph nodes in situ. This program emphasizes melanoma, because tumor-specific T cells are known for mice and humans, and it is now evident that DCs an present in vitro melanoma antigens derived from apoptotic cells. Documentation of tumor-specific immunity in humans has become more accessible with quantitative assays that are in place and include: binding of MHC tetramers, production of ELISPOTS, and recall assays to elicit specific killer T cells. The program will include dual center randomized trials. In the first we will compare two types of DC in eliciting immunity to melanoma peptides, and look for speaking of the immune response to other antigens, as an index of cross presentation in vivo. In the second, we will compare DCs loaded with peptides vs. dying tumor cells in expanding tumor specific CD4 and CD8 T cells. Shared ongoing core facilities for administration, DC production, and immune monitoring will energize and standardize interactions. Together, we hypothesize that DCs, nature's adjuvant, will enhance immunity to tumor antigens so that the clinical consequences for cancer vaccination and therapy can be pursued.