GAMMA/DELTA T CELLS IN TOLERANCE AND TUMOR IMMUNITY

描述(摘自研究人员摘要)：这一新应用的长期目标是确定伽马/德尔塔T细胞和非细胞溶解的α/βT细胞如何调节对OVA作为外源性抗原、内源性抗原和肿瘤抗原的耐受性。在CD8 T细胞(TCR-1)或CD4T细胞(OT-11)上表达OVA特异性TCR的转基因小鼠以及各种基因敲除小鼠将被用来探索控制耐受发展的生理信号。第一个目的是鉴定来自B6小鼠的非细胞溶解的CD8 T细胞，这些T细胞表达转基因TCR-1 T细胞和从上皮内淋巴细胞克隆的伽马/Delta T细胞。通过过继转移到γ/deltaTCR缺陷小鼠体内，研究γ/deltaT细胞与非溶细胞性CD8T细胞之间的相互作用。表达转基因OT-11T细胞的受者将被用来确定非溶细胞性CD8T细胞如何抑制抗体反应。第二个目的是利用TCR-1小鼠对OVA转基因小鼠体内的γ/Delta T细胞和非溶细胞性CD8 T细胞的功能进行评估。E.G7-OVA诱导肿瘤特异性耐受的假设将在第三个目标中得到验证。如果发现耐受性，研究人员将确定CD8 T细胞是否被删除、无能或显示功能改变。将测试共刺激分子转染的E.G7-OVA肿瘤逆转耐药的能力。诺斯汀对肿瘤特异性耐受性和免疫的细胞和分子效应将被确认。这些研究的结果应该为开发诺伐他汀在人类的临床试验提供基础。

DESCRIPTION (Adapted from Investigator's Abstract): The long-term goal of this renewal application is to determine how gamma/delta T cells and non-cytolytic alpha/beta T cells regulate tolerance to OVA as an exogenous antigen, an endogenous antigen and as a tumor antigen. Transgenic mice expressing OVA-specific TCR on CD8+ T cells (TCR-1) or CD4+ T cells (OT-11) and a variety of knockout mice will be used to explore the physiological signals that control development of tolerance. The first aim is to characterize non- cytolytic, CD8+ T cells from B6 mice expressing transgenic TCR-1 T cells and gamma/delta T cells cloned from intra-epithelial lymphocytes. Interactions between gamma/delta T cells and non- cytolytic, CD8+ T cells will be studied by adoptive transfer into gamma/delta TCR deficient mice. Recipients expressing transgenic, OT-11 T cells will be used to determine how non-cytolytic CD8+ T cells inhibit antibody responses. In the second aim, the function of gamma/delta T cells and non-cytolytic CD8+ T cells in OVA transgenic mice will be evaluated using TCR-1 mice. The hypothesis that E.G7-OVA induces tumor-specific tolerance will be tested in the third aim. If tolerance is found, the investigator will determine whether CD8+ T cells are deleted, anergic or display altered functions. The ability of E.G7-OVA tumors transfected with a co-stimulatory molecule to reverse tolerance will be tested. The cellular and molecular effects of noscapine on tumor-specific- tolerance and immunity will be identified. Results from these studies should provide the basis for developing clinical trials of noscapine in humans.