Strategies of Vaccination Against MUC.1 Antigen

描述（由申请人提供）：竞争性续期申请的第二次修订是基于对耐受小鼠肿瘤保护机制的深入分析，其中保护是由CD4 T细胞免疫muc1启动的。目前还没有报道表明CD4 T细胞对muc1的耐受性可以通过特异性疫苗被打破，也没有报道表明CD4 T细胞免疫产生肿瘤保护。因此，我们的模式是新的。我们的研究基于诱导CD4 T细胞对MUC的亚免疫原性T细胞决定因子的反应，1利用一种新方法来“启动”弱Th细胞反应，Th-Th合作。免疫的方法也是新的淋巴细胞转基因基因工程与两个Th细胞的决定因素参与Th-Th合作。在过去两年半的muc1转基因小鼠中，我们已经能够证明Th-Th配合转基因淋巴细胞免疫（TLI）有效地打破自我耐受，诱导保护性免疫。在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。具体来说，我们将重新审视mu1反应性CD4 T细胞的作用，并评估CD8 T细胞的潜在贡献（目标1），包括中枢记忆和有效记忆CD4和CD8 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）和层细胞样DC （pDC）的贡献（Aim 3），并观察NK和NKT细胞的激活是否是保护的整体机制的一部分（Aim 4）。希望这些研究能够揭示免疫和保护之间的关系，并为成功干预人类表达muc1的癌症建立基本规则。

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.