Prenatal TCDD and postnatal autoimmune disease

产前 TCDD 和产后自身免疫性疾病

• 批准号: 7059477
• 负责人: Steven David Holladay
• 金额: $ 14.75万
• 依托单位: VIRGINIA POLYTECHNIC INST AND ST UNIV
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7059477
• 关键词: antinuclear autoantibody; apoptosis; autoantibody; autoimmune disorder; cardiolipins; cytokine; developmental immunology; differential display technique; dioxins; disease /disorder etiology; embryo /fetus toxicology; environmental toxicology; gene expression profiling; helper T lymphocyte; immune response; laboratory mouse; lupus nephritis

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）：SNF 1小鼠在发育过程中暴露于TCDD可诱导并加重出生后自身免疫性狼疮样肾炎。可能单独或共同的免疫发育的环境化学效应的基础机制，将被检查，包括：受损的删除自身反应性T细胞克隆在胸腺减少调节T细胞控制不适当的反应，以自身抗原，T细胞分化到胸腺外的隔间，其中负选择是无效的强迫;出生后T细胞库向辅助性T细胞分布和抗体产生的转变;以及不适当的B细胞活性，包括自身抗体产生。在出生后的SNF 1小鼠（自身免疫易感但TCDD不敏感）中，将跟踪胸腺外和胸腺隔室中表达自身反应性CD 4 + V β 17 a+和CD 3 + V β 3+ TcR的T细胞数量以及CD 4 +25+调节性T细胞数量，并与疾病进展相关。C57 Bl/6小鼠（非自身免疫但对TCDD敏感）将平行用于可能对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SNF 1和C57 Bl/6小鼠中：将在出生后时间内评价Con A刺激的脾淋巴细胞，以确定可能沉淀或加剧出生后自身抗体应答的细胞因子产生的化学印迹变化。将测定ssDNA、dsDNA和心磷脂的抗体水平，以与细胞因子谱和T辅助细胞活性进行比较。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传导途径、蛋白质和信号转导途径的下游靶点的出生后完整性。逆转录PCR为基础的差异显示将被用来检查胸腺MHC I类和II类基因的表达SNF 1和C57 B1/6小鼠，或没有TCDD暴露在妊娠期间，作为一种机制，可能会损害T细胞教育和增加外周自身反应细胞。集体实验的目的是检测TCDD引起的胎儿免疫发育的变化，这种变化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。