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首页> 外文学位 >'Timing is everything': A differential role for cytokines in the development of experimental autoimmune thyroiditis.
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'Timing is everything': A differential role for cytokines in the development of experimental autoimmune thyroiditis.

机译：“时间决定一切”：细胞因子在实验性自身免疫性甲状腺炎发展中的不同作用。

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摘要

Many factors are likely to influence whether an individual will develop overt autoimmune disease, including genetics of the host and the method used to terminate self-tolerance. In this study we compared the immune response of two inbred strains of mice in the development of experimental autoimmune thyroiditis (EAT). CBA/J mice typically respond to immunization with mouse thyroglobulin (mTg) by developing overt thyroid disease and anti-mTg IgG titers. BALB/c mice usually respond to immunization by developing an autoantibody titer but little or no disease. Our initial hypothesis was that the difference between the susceptible CBA/J and the resistant BALB/c mice resided in the balance of cytokines incited by the immunization.; We explored the role of IL-12 in the pathogenesis of EAT using a novel disease paradigm that distinguishes three stages of disease, from the priming of disease, through its initiation in the thyroid, and leading to the progression of destruction. We found that neutralization of IL-12 during disease priming markedly suppressed the development of disease, globally suppressed autoantibody production, and resulted in long-term alterations in mTg.-specific in vitro splenocyte cytokine production. Neutralization of IL-12-during the initiation of disease significantly suppressed disease but only anti-mTg IgG2a titers were reduced. However, blocking IL-12 after disease was established did not alter the measured disease parameters in the time frame we studied. Thus there may be a shift from IL-12-dependent to IL-12-independent mechanisms as disease progresses.; We found treating resistant BALB/c mice with exogenous rmIL-12 at any time during the course of disease did not alter disease levels. Susceptible CBA/J mice showed a significant acceleration of disease and a trend toward more severe EAT when treated early in the course of disease. When treated after disease was established, CBA/J mice had a trend toward less severe disease. Differences in strain susceptibility to IL-12 may underlie important mechanisms that maintain self-tolerance in some individuals but not in others in the face of an autoimmune challenge.
机译：许多因素可能影响一个人是否会发展出明显的自身免疫性疾病，包括宿主的遗传学和终止自我耐受的方法。在这项研究中，我们比较了两种自交系小鼠在实验性自身免疫性甲状腺炎（EAT）发生过程中的免疫反应。 CBA / J小鼠通常通过发展明显的甲状腺疾病和抗mTg IgG滴度来响应小鼠甲状腺球蛋白（mTg）的免疫反应。 BALB / c小鼠通常通过产生自身抗体滴度而对免疫反应，但很少或没有疾病。我们最初的假设是，易感CBA / J和抗性BALB / c小鼠之间的差异在于免疫诱导的细胞因子平衡。我们使用一种新颖的疾病范例探索了IL-12在EAT发病机理中的作用，该范例将疾病的三个阶段从疾病的引发，通过在甲状腺中引发开始，并导致破坏的进展区分开来。我们发现在疾病引发过程中IL-12的中和作用显着抑制了疾病的发展，整体抑制了自身抗体的产生，并导致了mTg。特异性体外脾细胞因子的长期改变。在疾病发作期间中和IL-12会显着抑制疾病，但仅降低了抗mTg IgG2a滴度。但是，在疾病确定后阻断IL-12并不会改变我们研究的时间范围内测得的疾病参数。因此，随着疾病的进展，可能会从依赖IL-12的机制转变为不依赖IL-12的机制。我们发现在疾病过程中的任何时候用外源性rmIL-12治疗抗性BALB / c小鼠都不会改变疾病水平。易感的CBA / J小鼠在疾病过程的早期进行治疗时，表现出明显的疾病加速和趋于严重EAT的趋势。在确定疾病后进行治疗时，CBA / J小鼠有向严重程度降低的趋势。菌株对IL-12的敏感性差异可能是维持某些个体自我耐受的重要机制的基础，而其他个体在面对自身免疫挑战时却没有。

著录项

  • 作者

    Stafford, Elizabeth Alice.;

  • 作者单位

    The Johns Hopkins University.;

  • 授予单位 The Johns Hopkins University.;
  • 学科 Health Sciences Immunology.; Health Sciences Pathology.
  • 学位 Ph.D.
  • 年度 2001
  • 页码 435 p.
  • 总页数 435
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 预防医学、卫生学;病理学;
  • 关键词

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