DEVELOPMENTAL & IMMUNOREGULATORY EFFECTS OF TNFA LTA LTB

描述：肿瘤坏死因子(TNF)、淋巴毒素-α(LTA)和 淋巴毒素-β(LTB)在卵巢癌的发生和功能中具有重要作用。 淋巴、脾、胸腺尤其对T细胞功能的影响 自身免疫性疾病。在本研究应用中，转基因小鼠 高水平表达可溶性TNFRp60和LTbetaR将作为单项使用 和双转基因株系，以探讨肿瘤坏死因子α和脂蛋白β在细胞周期调控中的作用 淋巴结、脾和胸腺的胚胎发育。在几个月内 小鼠自身免疫品系[(NZB X NZW)F1和NOD]，肿瘤坏死因子在体内的应用 成年人的生活抑制了自身免疫力。矛盾的是，对肿瘤坏死因子的管理 新生的NOD小鼠增加了糖尿病的发病率并加速了糖尿病的发生， 而新生儿生活中的抗肿瘤坏死因子完全阻止了所有的表现 自身免疫力。在这项研究应用中的实验将测试 新生肿瘤坏死因子在NOD小鼠和T细胞受体转基因小鼠中的应用 小鼠诱导向Th1细胞反应转变，而抗肿瘤坏死因子诱导 向Th2 T细胞反应转变。靶向TNFRp60和TNFRp80 重组染色体将被培育到结节背景上以确定 肿瘤坏死因子对NOD小鼠自身免疫的影响是否通过 P60或p80受体。最后，控制下的肿瘤坏死因子的表达 从胎儿期或8-10周开始的大鼠胰岛素启动子 的年龄，将测试肿瘤坏死因子对节点自身免疫的影响 小鼠的死亡是由于肿瘤坏死因子在朗格汉斯胰岛的局部作用，或者 由于对T细胞发育和功能的全身性影响。

DESCRIPTION: Tumor necrosis factor (TNF), lymphotoxin-alpha (LTA), and lymphotoxin-beta (LTb) have major effects on the development and function of lymph nodes, spleen, thymus and particularly on T-cell function in several autoimmune diseases. In this research application, transgenic mice expressing high levels of soluble TNFRp60 and LTbetaR will be used as single and double transgenic lines to probe the function of TNFalpha and LTbeta on the embryologic development of lymph nodes, spleen and thymus. In several autoimmune strains of mice [(NZB x NZW)F1 and NOD], TNF administration in adult life suppresses autoimmunity. Paradoxically, TNF administration to neonatal NOD mice increases the incidence and hastens the onset of diabetes, while anti-TNF in neonatal life completely prevents all manifestations of autoimmunity. Experiments in this research application will test whether neonatal TNF administration in NOD mice and in T-cell receptor transgenic mice induces a shift towards a Th1 cell response while anti-TNF induces a shift towards a Th2 T-cell response. TNFRp60 and TNFRp80 targeted recombination chromosomes will be bred onto the NOD background to determine whether the effect of TNF on autoimmunity in the NOD mouse is mediated via the p60 or the p80 receptor. Finally, expression of TNF under the control of the rat insulin promoter, beginning either in fetal life or at 8-10 weeks of age, will test whether the effects of TNF on autoimmunity in the NOD mouse are due to the local effects of TNF in the islets of Langerhans, or due to a systemic effect on T cell development and function.