Genetic Approaches to Immune Adjuvants

本项目的目标是开发有效的分子定义的免疫佐剂用于主动免疫 对抗癌症虽然对癌症的耐受性是可逆的，但针对癌症抗原的免疫面临着 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 用于针对固有免疫原性差的癌抗原的成功主动免疫。我们 运用最新的知识，调节生长，激活和生存的先天和后天的分子 免疫细胞来研究佐剂策略和潜在机制。我们使用遗传佐剂（质粒 掺入IgG Fc结构域的DNA）与针对癌抗原的DNA疫苗组合。DNA 根据广泛的初步研究结果， 筛选和我们对这些分子如何调节先天性巨噬细胞的激活和存活的理解， 和获得性免疫细胞。具体目标1是建立在我们屏幕的实验结果上的， 编码IL-12/Fc融合分子的DNA在增强T细胞应答和肿瘤免疫方面最有效。 免疫力建议进行I期临床试验，以评估IL-12/Fc DNA的安全性，并比较其相对 酪氨酸酶DNA联合IL-12/Fc DNA免疫效果观察 III期黑色素瘤患者中单独使用。具体目标2检查了为什么Fc结构域与细胞因子的连接 显著增加了佐剂性，同时出乎意料地降低了它们的生物利用度。遗传方法 用于解决佐剂效应通过与Fc受体的相互作用而放大的假设， 先天免疫细胞具体目标3研究DNA佐剂与疫苗接种联合治疗模型 黑色素瘤，包括在一个转基因模型，发展从头黑色素瘤治疗。苏拜姆斯 研究a）NK细胞产生的IFN γ对细胞因子和细胞因子/Fc cDNA的佐剂性的作用， 和B）IL-23 DNA的佐剂作用，其强烈地涉及炎性细胞因子的发病机制。 自身免疫性疾病具体目的4研究细胞因子DNA佐剂对于增强细胞因子表达的作用。 免疫后免疫系统稳态恢复期间疫苗接种引起的抗原特异性应答 非清髓性治疗。总的目标是开发最有效的DNA佐剂， 应用于体内平衡恢复期间递送的疫苗。

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.