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NK and NKT cells, Th1/Th2 cytokines in immune reproductive failure

免疫生殖失败中的 NK 和 NKT 细胞、Th1/Th2 细胞因子

基本信息

批准号：
14370521
负责人：
YAMADA Hideto
金额：
$ 7.1万
依托单位：
HOKKAIDO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14370521/
关键词：
Infertility Recurrent Miscarriage NK cell NKT cell Th1 cytokine Th2 cytokine

项目摘要

The aim of this study was to investigate pathophysiological roles of NK and NKT cells, Th1/Th2 cytokines in immune reproductive failure. We found that high NK cell activities in the circulation of women with recurrent miscarriage (RM) were associated with subsequent miscarriage with normal fetal chromosome. Decreases in KIR2DL1 (CD158a) expression on NK cells and in T cell population, Th2/Tc2-sift were found in the circulation of RM women. Frequencies of CD3+cells, CD4+IFN-g+cells, CD4+TNF-a+cells were decreased in the endometria of RM women. In a prospective study, we found decreases in CD158a, CD94, and CD244 expression on NK cells and increases in perform expression in the deciduas of sporadic cases of miscarriage with normal fetal chromosome.Gene polymorphisms such as GST M1 null (OR2.2), CYP17 A2 allele (OR2.4), IL-6 G allele (OR0.46) were found to be associated RM risk, suggesting that RM is a polygenetic disease. We found that daily caffeine intake was associated with RM risk only in women who carried CYP1A2^* 1F homozygous A allele (100-299 mg/day OR 1.9,≧300mg/day OR 5.2), and suggested that RM is a life-style related disease.We used poly(I:C)-induced fetal resorption prone mating of CBA/J×DBA/2J mice. Injections of intact type human Ig and mouse Ig significantly reduced fetal resorption rates from 55% to 8.5% and 0%, respectively. But this anti-miscarriage effect was not detected by injections of Fab fragments of human Ig. We performed a variety of adoptive transfer experiments in which spleen cells from Ig-injected donors were transferred to poly(I:C)-injected pregnant recipients. Adoptive transfer of spleen cells with enrichment of macrophages retained the anti-miscarriage effect. However, this anti-miscarriage effect completely disappeared, if macrophages were depleted from transferred spleen cells. It was for the first time demonstrated that Ig-stimulated macrophages carried the anti-miscarriage effects in which Fc portions of Ig playd a critical role.

本研究旨在探讨NK和NKT细胞、Th1/Th2细胞因子在免疫生殖衰竭中的病理生理作用。我们发现，高NK细胞活性的循环妇女复发性流产（RM）与随后流产与正常胎儿染色体有关。NK细胞和T细胞群中的KIR2DL1 （CD158a）表达降低，在RM妇女的循环中发现Th2/Tc2-sift。RM妇女子宫内膜中CD3+细胞、CD4+IFN-g+细胞、CD4+TNF-a+细胞的频率降低。在一项前瞻性研究中，我们发现NK细胞上CD158a、CD94和CD244的表达减少，而在染色体正常的散发性流产患者的蜕膜中CD158a、CD94和CD244的表达增加。GST M1空（OR2.2）、CYP17 A2等位基因（OR2.4）、il - 6g等位基因（OR0.46）等基因多态性与RM风险相关，提示RM是一种多遗传疾病。我们发现，只有携带CYP1A2^* 1F纯合A等位基因的女性每日咖啡因摄入量与RM风险相关（100-299 mg/天OR 1.9，≧300mg/天OR 5.2），并提示RM是一种与生活方式相关的疾病。我们采用poly（I:C）诱导的CBA/J×DBA/2J小鼠的胎儿吸收倾向交配。注射完整型人Ig和小鼠Ig可显著降低胎儿吸收率，分别从55%降至8.5%和0%。但注射人Ig的Fab片段没有检测到这种抗流产作用。我们进行了多种过继移植实验，将注射igg的供者的脾细胞转移到注射poly（I:C）的妊娠受体。巨噬细胞富集的过继脾细胞保留抗流产作用。然而，如果巨噬细胞从转移的脾细胞中消失，这种抗流产作用完全消失。这是第一次证明Ig刺激的巨噬细胞具有抗流产作用，其中Ig的Fc部分发挥了关键作用。