Dendritic Cell Biology and Therapy

该项目是前项目1和2所进行研究的延续。我们获得了证据 辅助性T细胞应答和对MUC 1肿瘤抗原肽的抗体应答降低， MUCITg小鼠与WT小鼠相比，但是当肽携带0-连接的GalNac残基时，代表 对于低糖基化肿瘤形式的MUC 1，MUCITg小鼠的反应与WT小鼠一样好。我们 假设对DC呈递的MUC 1肽与糖肽的应答差异是 由于耐受性，因为MUC 1肽被认为是“自身”，而肿瘤特异性糖肽代表了 不正常的自我，因此被视为外国人。类似的耐受状态可以表征MUC 1肽 因此，相关的假设是MUC 1糖肽是更好的疫苗 候选人比已经使用的肽。我们的第三个假设是免疫参数 有效性的生物标志物作为DC和T细胞免疫激活的复杂特征存在，我们的目标是 以鉴定那些可以预测MUC 1疫苗的抗肿瘤功效的基因。我们建议测试这些假设 在人MUC 1转基因小鼠和MUC 1肽和糖肽特异性TCR转基因小鼠中， 如在恒河猴中使用恒河猴MUC 1序列。我们提出以下具体目标： 目的1：我们将确定是什么控制了对自身/肿瘤抗原MUC 1的免疫应答的差异， 当MUC 1肽（自身？）与MUC 1糖肽（外源？）用作抗原， 针对的是被杀虫剂激活的DC具体目标2：我们将在恒河猴中测试不同的MUC 1疫苗 拟议的实验将借鉴项目1和项目3中已经或将要进行的观察 识别T细胞和DC活化重要参数。项目2的最终目标是定义 下一代MUC 1疫苗，能够引发具有预定特征的免疫应答 抗肿瘤的功效。

This project is a continuation of studies performed in the previous Projects 1 and 2. We obtained evidence that helper T cell responses and antibody responses to the MUC1 tumor antigen peptide are reduced in MUCITg mice compared to WT mice but when the peptide carried 0-linked GalNac residues, representing hypoglycosylated tumor form of MUC1, MUCITg mice responded equally well as the WT mice. We hypothesize that the difference in responses to the MUC1 peptide versus glycopeptide presented by DC is due to tolerance because MUC1 peptide is perceived as "self," while tumor-specific glycopeptide represents abnormal self and thus is perceived as foreign. Similar state of tolerance may characterize MUC1 peptide specific T cells in patients and thus a related hypothesis is that MUC1 glycopeptide is a better vaccine candidate than the peptide that has been used to date. Our third hypothesis is that immune parameters (biomarkers) of efficacy exist as complex signatures of immune activation of DC and T cells and our goal is to identify those that can predict anti-tumor efficacy of MUC1 vaccines. We propose to test these hypotheses in human MUC1 transgenic mice and MUC1 peptide and glycopeptide specific TCR transgenic mice, as well as in rhesus macaques using rhesus MUC1 sequences. We propose the following specific aims: Specific Aim 1: We will determine what controls differences in immune responses to the self/tumor antigen MUC1 in MUCITg mice when MUC1 peptide (self?) versus MUC1 glycopeptide (foreign?) are used as antigens and targeted to adjuvant-activated DC. Specific Aim 2: We will test different MUC1 vaccines in rhesus macaques The proposed experiments will draw on observations already made or to tte made in the Projects 1 and 3 that identify important parameters of T cell and DC activation. The ultimate goal of Project 2 is to define the next generation of MUC1 vaccines.capable of eliciting an immune response with a predetermined signature of anti-tumor efficacy.