Genetic Approaches to Immune Adjuvants

该项目的目标是开发有效的分子免疫佐剂，用于主动免疫。 抗癌。尽管对癌症的耐受性是可逆的，但针对癌症抗原的免疫接种面临 与耐受性和免疫调节有关的重大障碍。有效的免疫佐剂将是必要的 为了成功地对癌症抗原进行主动免疫，癌症抗原的免疫原性天生就很差。我们 应用关于调节先天和后天的生长、激活和生存的分子的最新知识 免疫细胞研究佐剂策略和潜在机制。我们使用遗传佐剂(质粒 含有免疫球蛋白Fc区的DNA)与抗癌抗原的DNA疫苗结合。脱氧核糖核酸 编码细胞因子已经根据广泛的初步结果被仔细地挑选出来进行分析 关于这些分子如何调节先天激活和生存的筛选和我们的理解 和获得性免疫细胞。具体目标1建立在我们屏幕上的实验结果上，该结果表明 编码IL-12/Fc融合分子的DNA在增强T细胞反应和肿瘤方面最有效 豁免权。建议进行I期临床试验，以评估IL-12/Fc DNA的安全性并比较相关的 酪氨酸酶DNA联合IL-12/Fc DNA佐剂免疫的免疫效果 在III期黑色素瘤患者中单独使用。特殊目的2检查为什么Fc结构域与细胞因子连接 显著增加辅助性，同时意外降低其生物利用度。遗传方法 用于解决佐剂效应通过与Fc受体相互作用而放大的假说。 先天免疫细胞。特定目标3研究DNA佐剂与疫苗联合治疗模式 黑色素瘤的治疗，包括对新发黑色素瘤的转基因模型的治疗。苏巴伊姆 研究a)NK细胞产生的干扰素γ通过细胞因子和细胞因子/Fc cDNA在佐剂作用中的作用， 和b)IL-23DNA的佐剂作用，它与炎症的发病机制密切相关 自身免疫性疾病。特定目标4研究细胞因子DNA佐剂对增强 免疫系统动态平衡恢复过程中接种疫苗引起的抗原特异性反应 非清髓性治疗。总体目标是开发最有效的DNA佐剂，可以 适用于在体内平衡恢复期间提供的疫苗。

The goal of this project is to develop effective molecularly-defined immune adjuvants for active immunization against cancer. Although tolerance to cancer is reversible, immunization against cancer antigens faces substantial hurdles related to tolerance and immune regulation. Potent immune adjuvants will be necessary for successful active immunization against cancer antigens, which are inherently poorly immunogenic. We apply recent knowledge about molecules that regulate growth, activation and survival of innate and acquired immune cells to study adjuvant strategies and underlying mechanisms. We use genetic adjuvants (plasmid DNA incorporating Fc domains of IgG) combined with DNA vaccines against cancer antigens. DNA encoding cytokines have been carefully selected for analysis based on results of extensive preliminary screening and on our understanding about how these molecules regulate activation and survival of innate and acquired immune cells. Specific aim 1 is built on experimental results from our screens showing that DNA encoding an IL-12/Fc fusion molecule is most effective at enhancing T cell responses and tumor immunity. A phase I clinical trial is proposed to assess safety of IL-12/Fc DNA and compare the relative immunologic efficacy of vaccination with tyrosinase DNA plus IL-12/Fc DNA adjuvant to tyrosinase DNA alone in patients with stage III melanoma. Specific aim 2 examines why ligation of Fc domains to cytokines markedly increases adjuvanticity while unexpectedly decreasing their bioavailability. Genetic approaches are used to address the hypothesis that adjuvant effects are amplified by interactions with Fc receptors on innate immune cells. Specific aim 3 studies DNA adjuvants combined with vaccination in treatment models of melanoma, including treatment in a transgenic model that develops de novo melanoma. Subaims investigate a) the role of IFNgamma produced by NK cells for adjuvanticity by cytokine and cytokine/Fc cDNAs, and b) adjuvant effects of IL-23 DNA, which is strongly implicated in the pathogenesis of inflammatory autoimmune diseases. Specific aim 4 investigates the role of cytokine DNA adjuvants for potentiating antigen-specific responses elicited by vaccination during homeostatic recovery of the immune system after non-myeloablative treatments. The overall goal is to develop the most potent DNA adjuvants that can be applied to vaccines delivered during homeostatic recovery.