• 主题
高级搜索  >
历史搜索 清空历史
首页> 美国卫生研究院文献>other >Breaking Tolerance in Transgenic Mice Expressing the Human TSH Receptor A-Subunit: Thyroiditis Epitope Spreading and Adjuvant as a ‘Double Edged Sword’
【2h】

Breaking Tolerance in Transgenic Mice Expressing the Human TSH Receptor A-Subunit: Thyroiditis Epitope Spreading and Adjuvant as a ‘Double Edged Sword’

机译：在转基因小鼠打破容忍表达人TsH受体α亚单位：甲状腺炎表位扩展和辅助作为双刃剑

代理获取
本网站仅为用户提供外文OA文献查询和代理获取服务，本网站没有原文。下单后我们将采用程序或人工为您竭诚获取高质量的原文，但由于OA文献来源多样且变更频繁，仍可能出现获取不到、文献不完整或与标题不符等情况，如果获取不到我们将提供退款服务。请知悉。
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Transgenic mice with the human thyrotropin-receptor (TSHR) A-subunit targeted to the thyroid are tolerant of the transgene. In transgenics that express low A-subunit levels (Lo-expressors), regulatory T cell (Treg) depletion using anti-CD25 before immunization with adenovirus encoding the A-subunit (A-sub-Ad) breaks tolerance, inducing extensive thyroid lymphocytic infiltration, thyroid damage and antibody spreading to other thyroid proteins. In contrast, no thyroiditis develops in Hi-expressor transgenics or wild-type mice. Our present goal was to determine if thyroiditis could be induced in Hi-expressor transgenics using a more potent immunization protocol: Treg depletion, priming with Complete Freund's Adjuvant (CFA) + A-subunit protein and further Treg depletions before two boosts with A-sub-Ad. As controls, anti-CD25 treated Hi- and Lo-expressors and wild-type mice were primed with CFA+ mouse thyroglobulin (Tg) or CFA alone before A-sub-Ad boosting. Thyroiditis developed after CFA+A-subunit protein or Tg and A-sub-Ad boosting in Lo-expressor transgenics but Hi- expressors (and wild-type mice) were resistant to thyroiditis induction. Importantly, in Lo-expressors, thyroiditis was associated with the development of antibodies to the mouse TSHR downstream of the A-subunit. Unexpectedly, we observed that the effect of bacterial products on the immune system is a “double-edged sword”. On the one hand, priming with CFA (mycobacteria emulsified in oil) plus A-subunit protein broke tolerance to the A-subunit in Hi-expressor transgenics leading to high TSHR antibody levels. On the other hand, prior treatment with CFA in the absence of A-subunit protein inhibited responses to subsequent immunization with A-sub-Ad. Consequently, adjuvant activity arising in vivo after bacterial infections combined with a protein autoantigen can break self-tolerance but in the absence of the autoantigen, adjuvant activity can inhibit the induction of immunity to autoantigens (like the TSHR) displaying strong self-tolerance.
机译：具有靶向甲状腺的人促甲状腺激素受体（TSHR）A亚基的转基因小鼠可耐受转基因。在表达低A-亚基水平的转基因（Lo-表达子）中，在用编码A-亚基（A-sub-Ad）的腺病毒免疫之前，使用抗CD25进行调节性T细胞（Treg）耗竭会破坏耐受性，从而引起广泛的甲状腺淋巴细胞浸润，甲状腺损害和抗体扩散到其他甲状腺蛋​​白。相反，在Hi-expressor转基因或野生型小鼠中没有甲状腺炎发生。我们目前的目标是确定是否可以使用更有效的免疫方案在Hi-expressor转基因产品中诱发甲状腺炎：Treg清除，完全弗氏佐剂（CFA）+ A-亚基蛋白引发的Treg清除以及进一步的Treg清除，再用A-sub两次加强免疫-广告。作为对照，在A-sub-Ad加强免疫之前，分别用CFA +小鼠甲状腺球蛋白（Tg）或CFA灌注抗CD25处理的Hi-和Lo表达子以及野生型小鼠。 Lo表达转基因中CFA + A-亚基蛋白或Tg和A-sub-Ad增强后发展为甲状腺炎，而Hi-表达者（和野生​​型小鼠）对甲状腺炎的诱导有抵抗力。重要的是，在Lo表达子中，甲状腺炎与A亚基下游小鼠TSHR抗体的发展有关。出乎意料的是，我们观察到细菌产物对免疫系统的作用是一把“双刃剑”。一方面，用CFA（在油中乳化的分枝杆菌）加A-亚基蛋白引发的表达破坏了Hi-expressor转基因基因对A-亚基的耐受性，从而导致高TSHR抗体水平。另一方面，在不存在A-亚基蛋白的情况下，用CFA预先治疗抑制了对随后用A-sub-Ad免疫的反应。因此，细菌感染与蛋白自身抗原结合后在体内产生的佐剂活性可以破坏自身耐受性，但是在缺乏自身抗原的情况下，佐剂活性可以抑制对自身抗原（如TSHR）的免疫诱导，表现出很强的自我耐受性。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
代理获取

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号