免疫機構から見た流産の病態解明とその対策 [in Japanese] Role of NK Cells in Women with Recurrent Pregnancy Loss and Implantation Failure [in Japanese]
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Natural Killer (NK) cells play important roles in reproductive immunology. In order to attain a successful pregnancy, an appropriate regulation of maternal immune system is mandatory. While the dysfunction of uterine and circulating peripheral blood NK cells has been shown to associate with reproductive failure such as recurrent pregnancy loss (RPL), or implantation failure. The function of NK cells is regulated by several factors such as an expression of inhibitory and activating receptors on their surface, the number and ratio of NK cell population and their cytokine production. The present study was aimed to clarify the pathophysiological roles of NK cells during normal pregnancy and pregnancy failure. The main population of uterine NK cell is CD16^-/CD56^<bright> cytokine producing cells and that of peripheral blood NK cell is CD16^+/CD56^<dim> cytotoxic NK cell. We reported that the percentages of CD16^+/CD56^<dim> NK cells in peripheral blood and the endometrium were significantly higher while that of CD16^-/CD56^<btight> NK cells was markedly lower in reproductive failures in IVF-ET cycle compared to successful group. As the NK cell surface markers, NK cells express several types of inhibitory and activating receptors on their surface and the functions of NK cells are regulated by the balance between activating and inhibitory receptors. One of NK cell receptors is natural cytotoxicity receptor (NCR), which includes NKp30, NKp44 and NKp46. NCR regulates NK cell cytotoxicity and cytokine production. We found that CD56^+/NKp46^+ cells were notably decreased in women with RPL as compared to those of controls in both peripheral blood and the endometrium. However, proportion of CD56^<bright>/IFN-γ^+/TNF-α^+ cells and the TNF-α/GM-CSF expressing CD56^<bright> cell ratio were significantly higher in women with RPL and implantation failure as compared with that of normal controls, suggesting that cytokine production may be more importantly involved in these reproductive failures. While, proportions of CD56^<bright>/TNF-α^+ cells and CD56^<bright>/IFN-γ^+ cells were significantly lower in women with RPL compared to controls in endometrial NK cells. In addition, RPL and implantation failures have lack of, or negative correlation between NCRs and intracellular cytokines expression. This suggests that excessive pro-inflammatory cytokine expression in NK cells in RPL and implantation failures may be exerted through the NCRs. It has been a matter of concern whether the peripheral blood NK cell levels reflect changes in decidual NK cell levels. If so, we can estimate NK cell activities in the uterine endometrium by measuring peripheral blood NK cell activities. On the other hand, others reported that examination of peripheral blood NK cells would not tell us what is happening in the uterus. In this study, we found the correlation between NKp46^+ NK cells of peripheral blood and the endometrium at the midsecretory phase, suggesting that evaluation of peripheral blood NKp46^+ NK cells can be clinically useful for estimating uterine NKp46^+ NK cell activities. During pregnancy, pregnant women who had a history of PRL had significantly decreased percentages of CD56^<bright>/NKp46^+ cells. Women with a history of RPL may carry a dysfunction in cytokines production by NK cells, even though their pregnancies are ongoing. CD56^+/NKp46^+ cells in pregnant women were negatively correlated with CD56^<bright>/IFN-γ^-/TNF-α^+ cells and positively correlated with CD56^<bright>/IFN-γ^+/TNF-α^- cells. TNF-α is known to play vasculogenesis, while IFN-γ vascular remodelling. Therefor, it is suggested that both increased IFN-γ production and decreased TNF-α production are responsible for pregnancy failure in these women. The lower expression of NKp46^+ NK cells is also observed in women with preeclampsia, and we suppose that pregnancy failure and preeclampsia are immunologically on the same line of their pathogenesis. It is of quite interest to investigate whether implantation failure or PRL can be remedied by correcting NK cells abnormalities. For this purpose, we treated women with implantation failure and RPL by immune modulatory drugs (Dananzol and intravenous immunoglobulin). Briefly, Danazol was administered for women with implantation failure before IVF-ET for 12 weeks. Endometrial NK cell subpopulation and clinical outcomes were evaluated before and after treatment. Intravenous immunoglobulin was administered for women with RPL and higher NK cell cytotoxicity and/or abnormal NK cell subpopulation immediately after their positive pregnancy test. After treatment with Danazol, endometrial CD16^-/CD56^<bright> cells were significantly decreased and CD16^-/CD56^<bright> cells were significantly increased. And, the pregnancy rate, implantation rate and abortion rate were significantly improved using Danazol. After treatment with intravenous immunoglobulin, NK cell cytotoxicity was significantly decreased. The ongoing pregnancy rate is 100% except chromosomal abnormal miscarriage. The different profile of NCRs expression in peripheral blood and endometrial NK cells may suggest presence of abnormal regulation of NK cell in women with reproductive failures. Women with a history of RPL carry immunological abnormalities of NCRs on peripheral blood NK cells during pregnancy. The lower expression of NKp46^+ NK cells in women with RPL may account for the higher production of NK1 cytokine that is known as NK1 shift. Modification of NK cell abnormality using Danazol and intravenous immunoglobulin can be one of the options for the treatment of RPL and implantation failure. In conclusion, women with reproductive failure have an increased NK cell cytotoxicity and cytokine production, probably due to abnormal expressions of NK cell surface antigens. Correction of these abnormalities by immune modulatory drugs is effective to treat reproductive failures.
日本産科婦人科學會雜誌 63(12), 2167-2184, 2011-12-01