Regulatory and effector T cells in SLE

SLE 中的调节性 T 细胞和效应性 T 细胞

• 批准号: 6663943
• 负责人: KENNETH S.K. TUNG
• 金额: $ 21.7万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-27 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6663943
• 关键词: B lymphocyte; T lymphocyte; autoantibody; autoimmunity; epitope mapping; gender difference; gene expression; genetic strain; genetic susceptibility; genetically modified animals; glomerulonephritis; helper T lymphocyte; immunopathology; immunoregulation; laboratory mouse; medical complication; newborn animals; systemic lupus erythematosus

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a systemic autoimmune disease with protean clinical presentation and variable outcome; and glomerulonephritis (GN) is a serious manifestation of SLE. SLE patients and lupus prone mice exhibit abnormalities in B cell and T cell tolerance and their responsive state. They produce autoantibody (autoAb) response to multiple self antigens (Ag) and have immune complex (IQ deposits in tissues. The CD4+CD25+ regulatory T cells normally prevent organ specific autoimmune disease occurrence. Herein we investigate the role of the regulatory T cells in SLE by studying the effect of thymectomized on day 3 (d3tx) in lupus prone mice. The d3tx lupus prone NZM2328 mice exhibited earlier autoAb response, accumulated more glomerular IC, and developed accelerated acute GN. Remarkably, severe acute GN occurred in - 90% of male NZM2328 mice that are normally more resistant to lupus GN. These results have led to the following hypotheses. First, regulatory T cells can negatively influence development of SLE. Second, acute lupus GN is a T cellmediated autoimmune disease that targets the renal glomerulus. The CD4+CD25effector T cells participate in renal glomerular injury by targeting either renal Ag or Ag provided by the glomerular 1C. Thus, in SLE, autoreactive T cells: 1) drive an autoAb response, and 2) directly elicit acute GN. Third, acute GN is a checkpoint in lupus GN, from which the male mice regress and the female mice progress to chronic GN. Thus male NZM2328 mice may have less effective or more regulatory T cell function. The model will also permit the study on factors responsible for the progression and regression of lupus GN. We will investigate these hypotheses in Aim I of our proposal. A very different story emerged from the study on the lupus prone female SNF1 mice. Following d3tx, an accelerated autoAb response was also noted but this was associated with significant reduction in fatal GN. Analysis of their serum and glomerular autoAb isotypes revealed an autoimmune response with a strong Th2-bias. In Aim 2, we will test the hypothesis that d3tx of the SNF1 mice retains the nonpathogenic neonatal Th2 responsiveness. At the same time, they had a reduced Ag specific Th1 response that is required for pathogenic autoAb production and for lupus GN. Finally, we will seek an explanation for the different responses to d3tx between the two lupus prone mice. Accordingly, we will determine the outcome of CD4+CD25+ T cell depletion by methods other than d3tx in SNF1 mice.

描述(由申请人提供)： 系统性红斑狼疮(SLE)是一种临床多变的系统性自身免疫性疾病 而肾小球肾炎(GN)是SLE的一种严重表现。SLE患者和狼疮易感小鼠表现出B细胞和T细胞耐受性及其反应状态的异常。它们对多种自身抗原(Ag)产生自身抗体(AutoAb)，并在组织中沉积免疫复合体(IQ)。CD4+CD25+调节性T细胞通常可以预防器官特异性自身免疫性疾病的发生。在此，我们通过研究狼疮易感小鼠第3天(D3tx)胸腺切除对SLE的影响，探讨调节性T细胞在SLE中的作用。D3tx狼疮易感NZM2328小鼠表现出较早的自身抗体应答，积聚更多的肾小球IC，并发展为加速性急性GN。值得注意的是，在正常情况下对狼疮GN更具抵抗力的雄性NZM2328小鼠中，-90%发生了严重的急性GN。这些结果导致了以下假设。首先，调节性T细胞会对SLE的发展产生负面影响。其次，急性狼疮性肾炎是一种以肾小球为靶点的T细胞介导的自身免疫性疾病。CD4+CD25效应T细胞通过靶向肾小球抗原或肾小球1C提供的抗原参与肾小球损伤。因此，在SLE中，自身反应性T细胞：1)驱动自身抗体反应，2)直接引发急性GN。第三, 急性肾小球肾炎是狼疮性肾小球肾炎的一个关卡，雄性小鼠退行性变，雌性小鼠进展为慢性肾小球肾炎。因此，雄性NZM2328小鼠可能具有较低的有效T细胞功能或更多的调节T细胞功能。该模型还将允许对狼疮肾炎进展和消退的因素进行研究。我们将在我们提案的目标I中调查这些假设。在对易患狼疮的雌性SNF1小鼠的研究中，出现了一个非常不同的故事。在d3tx后，也注意到加速的自身抗体反应，但这与致命性GN的显著减少有关。对他们的血清和肾小球自身抗体亚型的分析显示，他们的自身免疫反应具有强烈的Th2偏向。在目标2中，我们将检验SNF1小鼠的d3tx保留非致病性新生儿Th2反应性的假设。与此同时，他们的抗原特异性Th1反应减少，这是病原性自身抗体产生和狼疮GN所必需的。最后，我们将寻求解释两个狼疮易感小鼠对d3tx的不同反应。因此，我们将确定在SNF1小鼠中用d3tx以外的方法去除CD4+CD25+T细胞的结果。