Prenatal TCDD and postnatal autoimmune disease

产前 TCDD 和产后自身免疫性疾病

基本信息

项目摘要

DESCRIPTION (provided by applicant): Developmental exposure of SNF1 mice to TCDD induces and exacerbates postnatal autoimmune lupus-like nephritis. Mechanisms that may singly or collectively underlie this environmental chemical effect on immune development will be examined, including: impaired deletion of autoreactive T cell clones in the thymus; diminished regulatory T cells that control inappropriate responses to self antigen; the forcing of T cell differentiation into extra-thymic compartments where negative selection is inefficient; a shift in the postnatal T cell repertoire toward a T helper profile and antibody production; and inappropriate B cell activity including autoantibody production. Numbers of T cells expressing autoreactive CD4+ Vbeta 17a+ and CD3+ Vbeta 3+ TcR, and numbers of CD4+25+ regulatory T cells, in extrathymic and thymic compartments, will be followed over postnatal time in SNF1 mice (autoimmune-predisposed but TCDD insensitive) and correlated to disease progression. C57Bl/6 mice (non-autoimmune but TCDD sensitive) will be used in parallel for risk assessment considerations in individuals who may be both sensitive to TCDD and genetically predisposed to autoimmune disease. In both SNF1 and C57Bl/6 mice: Con A stimulated splenic lymphocytes will be evaluated over postnatal time to identify chemical-imprinted shifts in cytokine production that may precipitate or exacerbate the postnatal autoantibody response. Antibody level to ssDNA, dsDNA and cardiolipin will be determined for comparison to cytokine profile and T helper cell activity. A focused autoimmunity gene array consisting of appropriate response genes will be used to determine the postnatal integrity of fundamental signaling pathways, proteins and downstream targets of signal transduction pathways that mediate the immune response. A reverse transcription PCR-based differential display will be used to examine thymic MHC class I and II gene expression in SNF1 and C57Bl/6 mice, with or without TCDD exposure during gestation, as a mechanism that may impair T cell education and increase peripheral autoreactive cells. The collective experiments are designed to detect alterations in fetal immune development caused by TCDD that underlie the worsened postnatal (postpubertal) autoimmune disease caused by this chemical.
描述(由申请人提供):SNF1小鼠在发育过程中暴露于TCDD可诱导并加剧出生后自身免疫性狼疮样肾炎。将研究可能单独或共同构成这种环境化学作用对免疫发育的机制,包括:胸腺中自身反应性T细胞克隆的受损缺失;控制对自身抗原不适当反应的调节性T细胞减少;迫使T细胞分化到胸腺外区室,在那里负选择是无效的;出生后T细胞库向辅助性T细胞和抗体产生的转变;和不适当的B细胞活性,包括自身抗体的产生。在SNF1小鼠(自身免疫易感性但TCDD不敏感)出生后,将跟踪胸腺外腔和胸腺室中表达自身反应性CD4+ Vbeta 17a+和CD3+ Vbeta 3+ TcR的T细胞数量,以及CD4+25+调节性T细胞数量,并与疾病进展相关。C57Bl/6小鼠(非自身免疫性但TCDD敏感)将同时用于可能对TCDD敏感且遗传上易患自身免疫性疾病的个体的风险评估考虑。在SNF1和C57Bl/6小鼠中,将在出生后对Con A刺激的脾淋巴细胞进行评估,以确定细胞因子产生的化学印记变化,这些变化可能会沉淀或加剧出生后自身抗体反应。将测定对ssDNA、dsDNA和心磷脂的抗体水平,以比较细胞因子谱和T辅助细胞活性。由适当的应答基因组成的聚焦自身免疫基因阵列将用于确定介导免疫应答的基本信号通路、蛋白质和信号转导通路下游靶点的出生后完整性。基于逆转录pcr的差异显示将用于检测SNF1和C57Bl/6小鼠胸腺MHC I类和II类基因的表达,无论妊娠期间是否暴露于TCDD,作为一种可能损害T细胞教育和增加外周自身反应性细胞的机制。这些集体实验旨在检测TCDD引起的胎儿免疫发育的改变,这种改变是由这种化学物质引起的出生后(青春期后)自身免疫性疾病恶化的基础。

项目成果

期刊论文数量(4)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Developmental exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin alters postnatal T cell phenotypes and T cell function and exacerbates autoimmune lupus in 24-week-old SNF1 mice.
  • DOI:
    10.1002/bdra.20603
  • 发表时间:
    2009-10
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Mustafa, Amjad;Holladay, Steven D.;Goff, Matthew;Witonsky, Sharon;Kerr, Richard;Weinstein, Danielle A.;Karpuzoglu-Belgin, Ebru;Gogal, Robert M., Jr.
  • 通讯作者:
    Gogal, Robert M., Jr.
Prenatal TCDD in mice increases adult autoimmunity.
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Steven David Holladay其他文献

Steven David Holladay的其他文献

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{{ truncateString('Steven David Holladay', 18)}}的其他基金

Prenatal TCDD and postnatal autoimmune disease
产前 TCDD 和产后自身免疫性疾病
  • 批准号:
    7059477
  • 财政年份:
    2005
  • 资助金额:
    $ 10.74万
  • 项目类别:
Prenatal TCDD and postnatal autoimmune disease
产前 TCDD 和产后自身免疫性疾病
  • 批准号:
    6938788
  • 财政年份:
    2005
  • 资助金额:
    $ 10.74万
  • 项目类别:
IMMUNOTOXICITY OF DERMAL PERMETHRIN & CIS UROCANIC ACID
皮肤氯菊酯的免疫毒性
  • 批准号:
    6178738
  • 财政年份:
    1998
  • 资助金额:
    $ 10.74万
  • 项目类别:

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