ANTITUMOR AND COSTIMULATORY ACTIVITY OF B7 ON T CELLS

B7 对 T 细胞的抗肿瘤和共刺激活性

• 批准号: 6137614
• 负责人: VIJAY K. KUCHROO
• 金额: $ 18.97万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-01-01 至 2002-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6137614
• 关键词: CD28 molecule; CD44 molecule; T lymphocyte; antigen presenting cell; antineoplastics; biological signal transduction; cell adhesion molecules; cell population study; cytotoxic T lymphocyte; gene expression; gene mutation; gene targeting; genetically modified animals; glycosylation; immunosuppression; interleukin 10; interleukin 4; laboratory mouse; lymphoma; neoplasm /cancer immunology; neoplasm /cancer remission /regression; posttranslational modifications; protein isoforms; suppressor T lymphocyte; tissue /cell culture

DESCRIPTION: (Applicant's Abstract) Suppression of immunologic reactivity is one of the major mechanisms by which tumors are thought to escape host defense mechanisms. However, how tumors suppress immune responses is not clear. Recent studies have shown that for the induction of T cell responses two signals are required from the antigen presenting cell, one that is antigen specific and is provided by the antigen-MHC complex and a second non-specific costimulatory signal which is provided by the B7 molecules. In the absence of a costimulatory signal, T cells are inactivated or anergized. The B7 family consists of two molecules (B7.1 and B7.2) both of which can interact with two counter-receptors CD28 and CTLA4 on T cells. Engagement of B7 molecules with CD28 induces a positive signal leading to T cell proliferation whereas interaction with CMA4 induces a negative signal and turns off the T cell response. Expression of B7.1 and B7.2 in tumor cells has led to the generation of immunocompetent tumor cells that induce anti-tumor immunity and tumor regression. The applicant expressed either B7.1 or B7.2 molecules in a T lymphoma cell line, EL-4. While EL4-B7.1 cells induced T cell costimulation and tumor regression, surprisingly the ELA-B7.2 or EL-4-B7.1 plus B7.2 double transfectants did not induce tumor regression but progressively grew in syngeneic mice. To further understand the biochemical and molecular basis for this surprising result, the applicant proposes the following specific aims: He will 1) determine whether lack of induction of anti-tumor immunity by B7.2 expressed on T cells is because of quantitative differences in the expression of B7.2 on the surface of T cells. Furthermore he will test whether B7.2 affects expression/upregulation of other accessory molecules critical in the induction of T cell response; 2) determine whether lack of induction of antitumor immunity is because B7-2 expressed on T cells is qualitatively different. He will test whether B7.2 expressed on T cells is altered by post-translational modifications (glycosylation) or by splicing or introduction of mutations, which affects its ability to bind CD28. Since different isoforms of B7.2 have been isolated he will also test the effect of expression of other isoforms of B7.2 on the induction of anti-tumor immunity 3) Determine the nature and type (including CTL activity, cytokine profile and function upon adoptive transfer) of T cell response induced against B7.2 and B7.1 plus B7.2 transfected EL-4 cells and test the mechanism by which they inhibit anti-tumor immunity.

描述：（申请人摘要） 免疫反应性的抑制是免疫抑制的主要机制之一。 这些肿瘤被认为可以逃脱宿主的防御机制。但如何 肿瘤抑制免疫反应尚不清楚。最近的研究表明 为了诱导T细胞反应，需要两个信号， 抗原呈递细胞是抗原特异性的， 由抗原-MHC复合物和第二非特异性抗原提供。 共刺激信号由B7分子提供。在 在缺乏共刺激信号的情况下，T细胞失活或无反应。 B7家族由两种分子（B7.1和B7.2）组成， 可以与T细胞上的两种反受体CD 28和CTLA 4相互作用。 B7分子与CD 28的结合诱导正信号， 而与CMA 4的相互作用诱导了T细胞增殖的负性。 信号并关闭T细胞反应。B7.1和B7.2的表达 导致了免疫活性肿瘤细胞的产生 诱导抗肿瘤免疫和肿瘤消退。申请人 在T淋巴瘤细胞系EL-4中表达B7.1或B7.2分子。 虽然EL 4-B7.1细胞诱导T细胞共刺激和肿瘤消退， 令人惊讶的是，ELA-B7.2或EL-4-B7. 1加B7. 2双转染子 不诱导肿瘤消退，但在同基因组中进行性生长。 小鼠为了进一步了解其生物化学和分子基础， 鉴于这一令人惊讶的结果，申请人提出了以下具体目标： 他将1）确定是否缺乏诱导抗肿瘤免疫 B7.2在T细胞上的表达是因为在 T细胞表面B7.2的表达。此外，他将 测试B7.2是否影响其他辅助因子的表达/上调 在诱导T细胞应答中起关键作用的分子; 2）确定 是否B7-2缺乏抗肿瘤免疫的诱导作用 在T细胞上表达的是质的不同。他将测试是否 T细胞上表达的B7.2通过翻译后修饰而改变 （糖基化）或通过剪接或引入突变， 影响其结合CD 28的能力。由于B7.2的不同亚型具有 被孤立的他也将测试其他表达的效果 B7.2同种型对诱导抗肿瘤免疫的作用 性质和类型（包括CTL活性、细胞因子谱和 过继转移后的功能）诱导的针对B7.2的T细胞应答 和B7.1 + B7.2转染EL-4细胞，并通过 它们抑制抗肿瘤免疫。