Strategies of Vaccination Against MUC.1 Antigen

描述(申请人提供)：竞争性续签申请的第二次修订是基于对耐受小鼠肿瘤保护机制(S)的深入分析，在耐受小鼠中，肿瘤保护是由CD4T细胞免疫抗MUC.1启动的。目前还没有报道表明CD4T细胞对MUC.1的耐受性可以通过特定的疫苗接种而被打破，也没有报道CD4T细胞免疫产生肿瘤保护作用。因此，我们的模式是新的。我们的研究是基于针对MUC的一种亚免疫原性T细胞决定簇1的CD4T细胞反应的诱导，该方法采用了一种新的方法来“启动”弱Th细胞反应，即Th-Th合作。免疫的方法也是用Th-Th协同作用中涉及的两个Th细胞决定簇基因工程的新淋巴细胞。在过去的两年半时间里，我们在MUC.1转基因小鼠身上的研究表明，Th-Th协同结合转基因淋巴细胞免疫(TLI)有效地打破了自身耐受，诱导了保护性免疫。在这次竞争性更新中提出的实验中，我们的目标是阐明和了解体内肿瘤保护的机制(S)。具体地说，我们将回顾MUC.1反应性CD4T细胞的作用，并评估CD8T细胞的潜在贡献(目标1)，包括中央记忆和有效记忆CD4和CD8T细胞的作用(目标2)。在系统的循序渐进的方法中，我们还将研究骨髓来源的树突状细胞(DC)和血小板样树突状细胞(PDC)的作用(目标3)，并看看NK和NKT细胞的激活是否是整体保护机制的一部分(目标4)。希望这些研究将阐明免疫和保护之间的关系，并将为成功干预人类表达MUC.1的癌症奠定基本规则。

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.