DEVELOPMENTAL & IMMUNOREGULATORY EFFECTS OF TNFA LTA LTB

发展型

• 批准号: 6177633
• 负责人: HUGH O MCDEVITT
• 金额: $ 26.38万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-09-01 至 2002-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6177633
• 关键词: NOD mouse; chimeric proteins; cytokine receptors; developmental immunology; fusion gene; genetically modified animals; helper T lymphocyte; histogenesis; immunoregulation; insulin dependent diabetes mellitus; laboratory mouse; lymph nodes; spleen; thymus; tumor necrosis factor alpha; tumor necrosis factor beta

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.

描述：肿瘤坏死因子（TNF），α-光氧合酶（LTA）， 光敏素-β（LTb）对细胞的发育和功能有重要影响， 淋巴结，脾脏，胸腺，特别是对T细胞功能，在几个 自身免疫性疾病 在这项研究应用中，转基因小鼠 表达高水平可溶性TNFRp 60和LT β R的细胞将作为单一的 和双转基因株系，以探测TNF α和LT β在 淋巴结、脾脏和胸腺的胚胎发育。 在几个 小鼠自身免疫品系[（NZB x NZW）F1和NOD]， 成年生活抑制自身免疫。 巧合的是， 新生NOD小鼠增加糖尿病的发病率并加速糖尿病的发作， 而新生儿期的抗TNF完全预防了 自身免疫 本研究应用中的实验将测试 NOD小鼠和T细胞受体转基因小鼠中的新生儿TNF给药 小鼠诱导向Th 1细胞反应的转变，而抗TNF诱导 向Th 2 T细胞反应转变。 靶向TNFRp 60和TNFRp 80 重组染色体将在NOD背景上繁殖，以确定 TNF对NOD小鼠自身免疫的作用是否通过 p60或p80受体。 最后，在对照组中， 大鼠胰岛素启动子的作用，从胎儿期或8-10周开始 将测试TNF对NOD患者自身免疫的影响， 小鼠是由于TNF在胰岛中的局部作用，或 这是由于对T细胞发育和功能的系统性影响。