Prenatal TCDD and postnatal autoimmune disease

产前 TCDD 和产后自身免疫性疾病

• 批准号: 6938788
• 负责人: Steven David Holladay
• 金额: $ 11.33万
• 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/6938788
• 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）：SNF1小鼠向TCDD的发育暴露会诱导并加剧产后自身免疫性狼疮样肾炎。将检查可能单独或统一的这种环境化学作用对免疫发育的机制，包括：胸腺中自动反应性T细胞克隆的缺失受损；控制对自抗原的不适当反应的调节T细胞减少；将T细胞分化为负效率低下的室外室；产后T细胞库的转移向T辅助型和抗体产生；和不适当的B细胞活性，包括自身抗体的产生。在SNF1小鼠中，将随后遵循表达自身反应性CD4+ VBETA 17A+和CD3+ VBETA 3+ TCR的T细胞数量，以及CD4+ 25+调节性T细胞的数量，在SNF1小鼠（自身免疫性的TCDDDDDDDDDDDDDDDDD）中，将随后遵循在snf1小鼠中的产后时间和胸膜下的时间。 C57BL/6小鼠（非自动免疫但TCDD敏感）将同时使用，以进行风险评估考虑因素，这些个人可能对TCDD敏感且对自身免疫性疾病敏感。在SNF1和C57BL/6小鼠中，将在产后时间评估刺激的脾淋巴细胞，以鉴定细胞因子产生的化学迹象转移，这可能会沉淀或加剧产后自身抗体反应。将确定与细胞因子谱和T辅助细胞活性进行比较的ssDNA，dsDNA和心磷脂的抗体水平。由适当响应基因组成的聚焦自身免疫基因阵列将用于确定介导免疫反应的信号转导途径的基本信号通路，蛋白质和下游靶标的产后完整性。基于逆转录PCR的差异显示将用于检查SNF1和C57BL/6小鼠中的胸腺MHC I和II类基因表达，在妊娠期间有或没有TCDD暴露，作为一种可能损害T细胞教育并增加外围自身反应性细胞的机制。集体实验旨在检测由TCDD引起的胎儿免疫发育的改变，这是该化学物质引起的产后（后）自身免疫性疾病的恶化。