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）是一种临床表现多样的系统性自身免疫性疾病 演示和可变结果；肾小球肾炎（GN）是SLE的严重表现。 SLE 患者和易患狼疮的小鼠表现出 B 细胞和 T 细胞耐受性及其反应状态的异常。它们产生针对多种自身抗原 (Ag) 的自身抗体 (autoAb) 反应，并在组织中具有免疫复合物（IQ 沉积物）。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。本文中，我们通过研究胸腺切除术第 3 天 (d3tx) 对狼疮易感小鼠的影响来研究调节性 T 细胞在 SLE 中的作用。d3tx 狼疮易感小鼠 NZM2328 小鼠表现出较早的自身抗体反应，积累更多的肾小球 IC，并加速发生急性肾小球肾炎。 值得注意的是，90% 的雄性 NZM2328 小鼠出现了严重的急性肾小球肾炎，这些小鼠通常对狼疮肾小球肾炎的抵抗力更强。这些结果引出了以下假设。首先，调节性 T 细胞会对 SLE 的发展产生负面影响。二、急性狼疮GN是T型 针对肾小球的细胞介导的自身免疫性疾病。 CD4+CD25效应T细胞通过靶向肾Ag或肾小球1C提供的Ag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) 直接引发急性肾小球肾炎。第三， 急性肾小球肾炎是狼疮肾小球肾炎的一个检查点，雄性小鼠从急性肾小球肾炎开始消退，而雌性小鼠则进展为慢性肾小球肾炎。因此，雄性 NZM2328 小鼠可能具有不太有效或更多的调节性 T 细胞功能。该模型还将允许研究导致狼疮肾炎进展和消退的因素。我们将在我们提案的目标 I 中研究这些假设。对易患狼疮的雌性 SNF1 小鼠的研究得出了一个截然不同的结果。 d3tx 后，还注意到自身抗体反应加速，但这与致命性 GN 的显着减少有关。对他们的血清和肾小球自身抗体同种型的分析揭示了具有强烈 Th2 偏好的自身免疫反应。在目标 2 中，我们将测试 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，它们的 Ag 特异性 Th1 反应降低，而这是致病性自身抗体产生和狼疮 GN 所需的。最后，我们将寻求对两只狼疮易感小鼠之间对 d3tx 的不同反应的解释。因此，我们将通过 d3tx 以外的方法确定 SNF1 小鼠中 CD4+CD25+ T 细胞耗竭的结果。