MATERNAL IMMUNE TOLERANCE TO THE ALLOGENEIC FETUS

母体对异体胎儿的免疫耐受

• 批准号: 6168763
• 负责人: Adrian Erlebacher
• 金额: $ 8.14万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-07-01 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6168763
• 关键词: CD28 molecule; CD40 molecule; CD95 molecule; T cell receptor; T lymphocyte; gene mutation; genetic mapping; genetically modified animals; immune tolerance /unresponsiveness; interleukin 10; interleukin 4; laboratory mouse; leukocyte activation /transformation; monoclonal antibody; nucleic acid sequence; ovalbumin; pregnancy immunology; tryptophan

The mechanism whereby the allogeneic fetus avoids immune rejection during pregnancy is unknown. Until recently, it was thought that the implanted fetus escaped rejection either because it was antigenically immature, or because it was sequestered in an immunologically privileged site. Current evidence, however, suggests that the fetus and placenta actively suppress the alloreactive components of the maternal immune system. leading to a special case of peripheral tolerance. We propose to evaluate this possibility using a genetic approach in mice. These studies have implications for several reproductive disorders and autoimmune diseases, the mechanisms used by cancer cells to avoid immune surveillance, and may have applications in organ transplantation and the prevention of graft-versus-host disease. The aims of the proposal are as follows: l) Using known mouse mutations and blocking monoclona1 antibodies, we will evaluate the reproductive requirements for interleukin A and interleukin-10, two key cytokines that regulate the mode of T cell differentiation associated with pregnancy, as well as the requirements for Fas and CTLA-4, two factors required for peripheral tolerance. 2) We will generate transgenic mice that express ovalbumin on placental tissues, and then use these mice to study the T cell responses to placental antigens and the pathways of fetal antigen presentation to the maternal immune system. These studies will take advantage of genetic techniques and T cell receptor transgenic mice that have been previously used to study similar issues outside the placenta. 3) We will test whether diminished cytotoxic T cell activity towards the fetus is due to a specific inhibition of helper T cell function. These experiments will rely upon the ability of activating monoclonal antibodies towards CD40 expressed by antigen presenting cells to substitute for helper cell function in vivo. 4) We will take advantage of the ability of methyl-tryptophan to induce the immune rejection of allogeneic but not syngeneic concepti in order to isolate genes expressed by placental tissues that might induce maternal immune tolerance. Genes will be isolated by cDNA representational difference analysis and DNA microchip array analysis. and will be functionally evaluated by their ability to modulate tumor immunogenicity in vivo.

同种异体胎儿避免怀孕期间免疫排斥的机制尚不清楚。直到最近，人们认为植入的胎儿逃脱了排斥，要么是因为它是抗原不成熟的，要么是因为它是在免疫学特权部位隔离的。但是，目前的证据表明，胎儿和胎盘可积极抑制母体免疫系统的同种异体作用成分。导致特殊的外围耐受性。我们建议在小鼠中使用遗传方法评估这种可能性。这些研究对几种生殖疾病和自身免疫性疾病有影响，癌细胞用来避免免疫监测的机制，并且可能在器官移植和预防移植物抗旋转疾病中应用。该提案的目的如下：l）使用已知的小鼠突变并阻止MonoClona1抗体，我们将评估白介素A和白介素10的生殖要求，这是两个关键的细胞因子，这些细胞因子调节与怀孕相关的T细胞分化模式，例如以及对FAS和CTLA-4的要求，外围耐受性所需的两个因素。 2）我们将产生在胎盘组织上表达卵蛋白的转基因小鼠，然后使用这些小鼠研究T细胞对胎盘抗原的反应以及胎儿抗原对母体免疫系统的途径。这些研究将利用遗传技术和T细胞受体转基因小鼠，这些小鼠先前用于研究胎盘之外的类似问题。 3）我们将测试细胞毒性T细胞对胎儿的活性是否降低是由于对辅助T细胞功能的特定抑制作用。这些实验将依赖于激活抗原呈递细胞表达的对CD40的单克隆抗体的能力，以代替体内辅助细胞功能。 4）我们将利用甲基 - tryptophan的能力诱导同种异体概念而不是合成性概念的免疫排斥，以分离可能诱导母体免疫耐受性的胎盘组织表达的基因。基因将通过cDNA表示差分析和DNA微芯片阵列分析分离。并将通过其在体内调节肿瘤免疫原性的能力在功能上进行评估。