Strategies of Vaccination Against MUC.1 Antigen

描述（由申请人提供）：竞争性更新申请的第二次修订是基于对耐受小鼠中肿瘤保护机制的深入分析，其中保护是由针对MUC.1的CD 4 T细胞免疫启动的。目前，没有报道显示针对MUC.1的CD 4 T细胞耐受性可以通过特异性疫苗接种被打破，也没有报道显示CD 4 T细胞免疫产生肿瘤保护。因此，我们的模式是新的。我们的研究是基于对MUC的亚免疫原性T细胞决定簇1的CD 4 T细胞应答的诱导，其利用了“跳跃启动”弱Th细胞应答的新方法，即Th-Th合作。免疫的方法也是新的淋巴细胞转基因的基因工程与两个Th细胞决定因素参与Th-Th合作。在过去的两年半中，我们在MUC.1转基因小鼠中的工作已经能够表明，Th-Th合作与转基因淋巴细胞免疫（TLI）相结合，有效地打破自身耐受，诱导保护性免疫。在这项竞争性更新中提出的实验中，我们的目标是阐明和理解体内肿瘤保护的机制。具体而言，我们将重新审视MUC.1反应性CD 4 T细胞的作用，并评估CD 8 T细胞的潜在贡献（目标1），包括中枢记忆和有效记忆CD 4和CD 8 T细胞的作用（目标2）。在系统的逐步方法中，我们还将研究骨髓来源的树突状细胞（DC）和浆细胞样DC（pDC）的贡献（目的3），并观察NK和NKT细胞的活化是否是整体保护机制的一部分（目的4）。希望这些研究将阐明免疫和保护之间的关系，并将建立成功干预人类表达MUC.1的癌症的基本规则。

DESCRIPTION (provided by applicant): This second revision of a competitive renewal application is based on an in-depth analysis of the mechanism(s) of tumor protection in tolerant mice where protection is initiated by CD4 T cell immunity against MUC.1. At the present time there are no reports showing that CD4 T cell tolerance against MUC.1 can be broken by specific vaccination, nor that CD4 T cell immunity generates tumor protection. Therefore, our model is new. Our studies are based on the induction of CD4 T cell responses against a sub-immunogenic T cell determinant of MUC,1 that exploits a new method to "jump-start" weak Th cell responses, Th-Th cooperation. The method of immunization is also new lymphocytes transgenic for a gene engineered with the two Th cell determinants involved in Th-Th cooperation. Working in MUC.1 transgenic mice during the past two and half years we have been able to show that Th-Th cooperation combined with transgenic lymphocyte immunization (TLI) effectively breaks self tolerance and induce protective immunity. In the experiments proposed in this competitive renewal our goal is to elucidate and understand the mechanism(s) of tumor protection in vivo. Specifically, we will revisit the role of MUC.1 reactive CD4 T cell and assess a potential contribution of CD8 T cells (Aim 1), including the role of central memory and effective memory CD4 and CD8 T cells (Aim 2). In a systematic step-wise approach, we will also study the contribution of bone marrow-derived dendritic cells (DC) and plamacytoid DC (pDC) (Aim 3), and see if activation of NK and NKT cells is part of the overall mechanism of protection (Aim 4). It is hoped that these studies will shed light on the relationship between immunity and protection, and will establish the ground rules for successful intervention against cancer expressing MUC.1 in humans.