ANTI AKR/GROSS MULV CTL--MECHANISMS OF NONRESPONSIVENESS

ANTI AKR/GROSS MULV CTL--无反应机制

• 批准号: 6514145
• 负责人: WILLIAM R GREEN
• 金额: $ 27.43万
• 依托单位: DARTMOUTH COLLEGE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514145
• 关键词: CD95 molecule; apoptosis; cellular immunity; cytotoxic T lymphocyte; gene induction /repression; genetically modified animals; helper T lymphocyte; immune tolerance /unresponsiveness; laboratory mouse; leukemia; microorganism immunology; murine leukemia virus; neoplasm /cancer genetics; neoplasm /cancer immunology; viral carcinogenesis

DESCRIPTION: (Adapted from the Investigator's abstract): This is a revised application from Dr. William Green to study anti-AKR/Gross MuLV CTL: Mechanisms of nonresponsiveness. The development of immunological strategies that will ensure the generation of sufficient immunity towards transformed cells is one of the major unresolved issues in the field of cancer research. In this proposal we intend to extend our ongoing studies which utilize weakly immunogenic, AKR/Gross murine leukemia virus (MULV) induced tumor cells as a model system for examining cell-mediated anti-tumor immunity. In particular, the generation of cytolytic T lymphocytes (CTL), an effector cell type generally considered to be especially beneficial against virus-infected cells and tumor cells, will be emphasized. This proposal will focus on the inability of two congenic strains of mice, AKR.H-2b and AKR.H-2b:Fv-lb, to mount AKR/Gross MULV specific CTL responses. Our focus on these congenic mouse strains is part of our general approach towards dissecting the importance of antiviral CTL in this system by sequentially moving from our earlier studies with low leukemic/high CTL responder C57BL/6 (B6, H-2b) mice to high leukemic/low responder AKR (H-2k) mice. For B6 prototypic anti-AKR/Gross MULV CTL, we have shown that the type-specific viral TM 134-141 peptide, KSPWFTTL, represents the immunodominant epitope. In contrast, AKR.H-2b mice, despite the presence of a responder H-2b haplotype, fail to mount such antiviral CTL responses. Young AKR.H-2b:Fvlb mice, whose additional differential locus (Fv-1b) retards the expression and spread of endogenous N-ecotropic proviruses such as EMV- II, are able to generate anti-AKR/Gross virus CTL. As mice of this latter double congenic strain age, however, viral antigen expression increases, and beginning at about 9 weeks of age they become specifically unable to generate such antiviral CTL. Our findings indicate that clonal deletion of the precursors of antiviral CTL is not operative in these strains. Furthermore, moderately-aged AKR.H-2b:Fv-lb mice contain antigen specific CD8+ inhibitory T cells in adoptive transfer experiments. CD8+ T cell and other lymphoid inhibitory cells have also been demonstrated in vitro and in vivo in the AKR.H-2b strain. Similarly, CTL responder B6 or B6.Fv-ln mice infected exogenously with certain MuLV become specifically unable to generate AKR/Gross MuLV-specific CTL. This proposal seeks to characterize the mechanisms of action of the inhibitory cells which are responsible for CTL peripheral nonresponsiveness, specifically focussing on the common mechanism in these systems which we have recently shown is FasL/Fas mediated activation- induced cell death (AICD) induced by viral antigen and FasL expressing normal lymphoid cells. The experimental approach will be to use the previously defined and easily manipulated in vitro system in which the secondary restimulation of primed responder B6 antiviral pCTL/CTL is inhibited by normal AKR.H-2b spleen cells, as well as to selectively employ the in vivo systems. It is hoped that these studies will add to our understanding of the factors controlling responsiveness to weakly-immunogenic tumors and how retroviruses interact with and modulate the immune system by establishing peripheral tolerance mechanisms.

描述：（根据调查员的摘要进行了改编）：这是一个修订版 William Green博士的申请进行研究反对ANTI-AKR/GROSS MULV CTL：机制 无反应。免疫策略的发展将 确保产生足够的对转化细胞的免疫力是一个 癌症研究领域的主要未解决问题。在这个 提案我们打算扩展我们正在进行的研究，这些研究利用薄弱 免疫原性，AKR/GROSS鼠白血病病毒（MULV）诱导肿瘤细胞作为一种 用于检查细胞介导的抗肿瘤免疫力的模型系统。尤其， 效应细胞类型的细胞溶解T淋巴细胞（CTL）的产生 通常认为对感染病毒的细胞特别有益 和肿瘤细胞将被强调。该建议将集中于无能 在两只小鼠的两只同类菌株中，AKR.H-2B和AKR.H-2B：FV-LB AKR/GROSS MULV特异性CTL响应。我们专注于这些友善的老鼠 菌株是我们剖析重要性的一般方法的一部分 该系统中的抗病毒CTL通过依次从我们的早期研究中移动 较低的白血病/高CTL响应者C57BL/6（B6，H-2B）至高 白血病/低响应者AKR（H-2K）小鼠。对于B6原型抗AKR/GROSS MULV CTL，我们已经表明，特异性的病毒TM 134-141肽kspwfttl， 代表免疫主流表位。相反，尽管有 响应者H-2B单倍型的存在，无法安装这种抗病毒CTL 回答。年轻的AKR.H-2B：FVLB小鼠，其其他差异基因座 （FV-1B）延迟内源性N-核心病毒的表达和传播 例如EMV-II能够生成抗AKR/GROSS病毒CTL。作为这个老鼠 然而，后一种双同类菌株年龄增加，病毒抗原表达增加， 从大约9周龄开始，它们变得明确无法 产生这种抗病毒CTL。我们的发现表明克隆删除 在这些菌株中，抗病毒CTL的前体不起作用。此外， 中等年龄的AKR.H-2B：FV-LB小鼠含有抗原特异性CD8+抑制性T 收养转移实验中的细胞。 CD8+ T细胞和其他淋巴样 抑制细胞在体外和体内也已证明 AKR.H-2B菌株。同样，CTL响应者B6或B6.FV-LN小鼠感染了 某些MULV外源无法产生AKR/GROSS MULV特异性CTL。该建议旨在表征行动机制 负责CTL周围的抑制细胞的 无反应性，特别关注这些共同机制 我们最近显示的系统是FASL/FAS介导的激活诱导的系统 病毒抗原和FASL诱导的细胞死亡（AICD）表达正常淋巴样 细胞。实验方法将是使用先前定义的，并且 轻松操纵体外系统 正常AKR.H-2B脾脏抑制启动响应者B6抗病毒PCTL/CTL 细胞以及选择性地采用体内系统。希望 这些研究将增加我们对控制因素的理解 对弱免疫原性肿瘤的反应性以及逆转录病毒如何与 并通过建立外围耐受性机制来调节免疫系统。