人类蜕膜NK细胞特性研究
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摘要
研究背景:
妊娠至今依然是困惑免疫学家的未解之谜。胚胎作为半同种移植物不被母体免疫系统排斥,受多种因素影响,其中子宫内膜局部免疫因素起着重要的调节作用。研究发现在滋养层细胞侵入点有许多免疫细胞围绕其周围,然而,尽管它们有着潜在的细胞毒作用,但在正常妊娠时并没有造成对滋养细胞的杀伤。人们通过对蜕膜内NK细胞的性状研究,发现其明显不同于外周血NK细胞,是一群独特型的淋巴细胞群,因此将蜕膜中NK细胞命名蜕膜NK细胞,简称dNK细胞。dNK细胞从子宫内膜分泌期开始增加并于孕早期达到高峰(约占蜕膜淋巴细胞70%左右),且与绒毛外细胞滋养细胞紧密接触,此后随着妊娠的发展又逐渐下降,到晚孕时占蜕膜淋巴细胞35%左右。dNK细胞在整个妊娠期间的动态变化过程提示其可能在受精卵的种植过程和胎盘生长发育中起重要作用。近年来关于dNK细胞的来源、表型、功能及其与滋养细胞的相互识别关系已成为生殖免疫研究的热点之一。
dNK细胞主要分布于母体与胚胎接触的蜕膜,是母体直接识别胎儿抗原的免疫细胞,它的独特的表型及功能不但能维持母胎界面的免疫耐受,还能分泌一系列细胞因子促进蜕膜血管重建及Th1/ Th2平衡网络的维持。若dNK细胞的数量及功能失调则可能诱发病理妊娠。研究蜕膜组织中NK细胞的功能状态与妊娠的关系,无疑从一个全新的角度诠释妊娠这一生理现象,也为揭示病理性妊娠的发生机制及最终有效防治提供新思路,并为生殖免疫的发展提供了新的理论依据。
目的:
检测蜕膜中NK细胞(dNK细胞)的分布状态,以及其与外周血中NK细胞(pNK细胞)在含量、表型、Th1/Th2型细胞因子表达、杀伤功能方面的变化,探讨蜕膜NK细胞独特的表型、功能及其与滋养细胞的相互识别关系与母胎界面免疫耐受之间的重要联系。
方法:
1)收取正常晚孕胎膜组织(6例),免疫组织化学法检测蜕膜中NK细胞的分布状态。
2)收集晚孕蜕膜组织及同一孕妇外周血(20例),机械研磨法联合密度梯度离心法分离出蜕膜单个核细胞,单纯密度梯度离心法分离出外周血单个核细胞,流式细胞术检测晚孕蜕膜、外周血中NK细胞的含量及表面CD16, CD69, NKG2A和NKG2D的表达变化。
3)收集晚孕胎盘组织8例,RT-PCR技术检测胎盘滋养层中NKG2A的配体HLA-G, HLA-E和NKG2D的配体MICA mRNA的表达情况。
4)流式细胞术检测晚孕蜕膜及外周血中NK细胞内Th1/Th2型细胞因子IFN-γ和IL-4的表达。
5)免疫磁珠分选出蜕膜及外周血中NK细胞,流式细胞术检测其分离纯度,51Cr释放法分别测定不同效靶比NK细胞对其敏感性靶细胞K562的杀伤活性。
结果:
1)蜕膜中的NK细胞有着特殊的分布状态,多数集中在蜕膜与滋养层交界的母胎界面处。
2)相对于pNK细胞,dNK细胞是蜕膜中的主群体淋巴细胞。
3)相对于pNK细胞,dNK细胞表面低表达CD16分子,高表达CD69分子。
4) dNK细胞高表达NKG2受体家族NKG2A和NKG2D,但在滋养层中只检测到NKG2A的配体HLA-G和HLA-E ,而未检测到NKG2D的配体MICA。
5) dNK细胞内Th1/ Th2型细胞因子IFN-γ和IL-4的表达均明显高于pNK细胞。
6)不同效靶比dNK细胞对其敏感性靶细胞K562的杀伤活性明显低于pNK细胞。
结论:
蜕膜NK细胞作为重要的天然淋巴细胞,其含量、表型、Th1/Th2型细胞因子表达以及杀伤功能方面与外周血NK细胞有着明显差异,并且其与滋养细胞之间有着密切联系。蜕膜NK细胞独特的表型及功能在介导母胎界面免疫耐受中发挥了重要的作用。
Backgroud:
In pregnancy, hemiallogeneic fetal cells invade the maternal decidua but remain spared from attack by the maternal immune system, posing a great unsolved paradox of immunology. Although several factors have been proposed to explain or contribute to maternal tolerance, the local immunity of decidua play an important role. Studies have shown that the trophoblast cells are surrounded by many immunological cells when they invade into decidua, however, although these immunological cells have potential cytotoxic action, they do not attack trophoblast cells in normal pregnancy. Through the study of characteristic with decidual NK cells, the subset of CD56brightCD16- NK cells are named as decidual natural killer cells (dNK cells). Human uterine endometrium hosts a significant number of NK cells, the percentage of which change during the menstrual cycle and pregnancy. Decidual NK cells begin to increase from secretory phase, which peaks in early pregnancy when dNK cells comprise about 70% of resident lymphocytes and tightly touch with the invading trophoblasts. With the development of human pregnancy, the percentage of dNK cells then fall off, which account about 35% of resident lymphocytes in term decidua. The changes of the percentage and phenotype of dNK cells during pregnancy propose that they may play important roles in implantation and placenta development. Recently the research of origination, phenotype, function and interaction with trophoblasts about dNK cells has been a hot topic in reproduction immunology.
Decidual NK cells mainly distribute in decidua which links fetal and maternal interface and which can directly recognize fetal antigen. The specific phenotype and function of dNK cells may contribute to keep immunotolerance in fetal-maternal interface, also can they secrete an array of cytokines facilitate decidual blood rebuilding and maintain the balance of Th1/ Th2 cytokines. Study the function and status of dNK cells undoubtedly help us to further comprehend the physiological phenomena of pregnancy and also can provide new ways to research the mechanism of pathological pregnancy, as well as the development in reproduction immunology.
Objective:
To detect the distribution of dNK cells and compare the percentage, phenotype, Th1/ Th2 cytokine secretion and cytotocxic action between dNK cells and pNK cells, which can help us to further approach the important interaction between immunotolerance in fetal-maternal interface and dNK cells.
Methods:
1) Third-trimester decidua and peripheral blood was obtained during elective caesarean sections (n = 20), the method of IHC was used to detect the distribution of dNK cells.
2) Cell suspensions were prepared by an electromechanical dispersal method and centrifugated using a standard gradient sedimentation technique. The percentage and phenotype of dNK cells and pNK cells were detected by flow cytometric analysis.
3) The method of RT-PCR was used to detect the mRNA expression of HLA-G, HLA-E and MICA , which are ligands of NKG2A and NKG2D respectively.
4) Flow cytometry was used to detect the expression of intracellular Th1/Th2 cytokines IFN-γand IL-4 in dNK cells and pNK cells.
5) dNK cells and pNK cells were separated by MACS from PBMC and DBMC, whose purity was then detected by Flow cytometry. The cytotoxic activity of dNK cells and pNK cells against targets was measured in a standard 4-hr 51Cr-release assay.
Results:
1) The result of IHC showed that the distribution of dNK cells was distinct, many of which distributed at fetal-maternal interface.
2) Comparede with pNK cells, dNK cells are the dominant group of decidual lymphocytes.
3) The expression of CD16 were significantly decreased on dNK cells as compared with those on pNK cells, as we all know, expression of CD16 is one of important signals to measure cytotoxic activity; however, it was unclear that CD69 expression were significantly increased on dNK cells as compared with those on pNK cells, which seemed paradoxical to the theory of immunotolerance in fetal-maternal interface, because that CD69 is the marker of earlier period activation.
4) Decidual natural killer cells had high expression of NKG2A, which ligand HLA-G and HLA-E mRNA were also expressed in trophoblast tissue. Although dNK cells highly expressed NKG2D, there was no MICA mRNA expression.
5) Compared with pNK cells, the expression of intracellular Th1/Th2 cytokines IFN-γand IL-4 were significantly high in dNK cells. IFN-γand IL-4 are the most important cytokines in regulating Th1/Th2 immunological balance, suitable quantity of which play an important role in regulating immunological balance at fetal-maternal interface.
6) Although there is much perforin and granzyme in dNK cells, which propose they have potential cytotoxic action, their cytotoxic activity of dNK cells against targets were significantly decreased than pNK cells, maybe the cytotoxic activity of dNK cells were suppressed by something at fetal-maternal interface .
Conclusions:
Decidual natural killer cells are the important natural lymphocytes, whose percentage, phenotype, Th1/Th2 cytokine secretion and cytotocxic action are obviously different from peripheral NK cells, also they tightly touch with the invading trophoblasts. dNK cells and their secreting cytokines compose the center of decidual immunological regulation through development, regulation, receptor expression, biological effect. From the above results, we conclude that dNK cells play an important role in regulating immunological tolerance at fetal-maternal interface.
妊娠至今依然是困惑免疫学家的未解之谜。胚胎作为半同种移植物不被母体免疫系统排斥,受多种因素影响,其中子宫内膜局部免疫因素起着重要的调节作用。研究发现在滋养层细胞侵入点有许多免疫细胞围绕其周围,然而,尽管它们有着潜在的细胞毒作用,但在正常妊娠时并没有造成对滋养细胞的杀伤。人们通过对蜕膜内NK细胞的性状研究,发现其明显不同于外周血NK细胞,是一群独特型的淋巴细胞群,因此将蜕膜中NK细胞命名蜕膜NK细胞,简称dNK细胞。dNK细胞从子宫内膜分泌期开始增加并于孕早期达到高峰(约占蜕膜淋巴细胞70%左右),且与绒毛外细胞滋养细胞紧密接触,此后随着妊娠的发展又逐渐下降,到晚孕时占蜕膜淋巴细胞35%左右。dNK细胞在整个妊娠期间的动态变化过程提示其可能在受精卵的种植过程和胎盘生长发育中起重要作用。近年来关于dNK细胞的来源、表型、功能及其与滋养细胞的相互识别关系已成为生殖免疫研究的热点之一。
dNK细胞主要分布于母体与胚胎接触的蜕膜,是母体直接识别胎儿抗原的免疫细胞,它的独特的表型及功能不但能维持母胎界面的免疫耐受,还能分泌一系列细胞因子促进蜕膜血管重建及Th1/ Th2平衡网络的维持。若dNK细胞的数量及功能失调则可能诱发病理妊娠。研究蜕膜组织中NK细胞的功能状态与妊娠的关系,无疑从一个全新的角度诠释妊娠这一生理现象,也为揭示病理性妊娠的发生机制及最终有效防治提供新思路,并为生殖免疫的发展提供了新的理论依据。
目的:
检测蜕膜中NK细胞(dNK细胞)的分布状态,以及其与外周血中NK细胞(pNK细胞)在含量、表型、Th1/Th2型细胞因子表达、杀伤功能方面的变化,探讨蜕膜NK细胞独特的表型、功能及其与滋养细胞的相互识别关系与母胎界面免疫耐受之间的重要联系。
方法:
1)收取正常晚孕胎膜组织(6例),免疫组织化学法检测蜕膜中NK细胞的分布状态。
2)收集晚孕蜕膜组织及同一孕妇外周血(20例),机械研磨法联合密度梯度离心法分离出蜕膜单个核细胞,单纯密度梯度离心法分离出外周血单个核细胞,流式细胞术检测晚孕蜕膜、外周血中NK细胞的含量及表面CD16, CD69, NKG2A和NKG2D的表达变化。
3)收集晚孕胎盘组织8例,RT-PCR技术检测胎盘滋养层中NKG2A的配体HLA-G, HLA-E和NKG2D的配体MICA mRNA的表达情况。
4)流式细胞术检测晚孕蜕膜及外周血中NK细胞内Th1/Th2型细胞因子IFN-γ和IL-4的表达。
5)免疫磁珠分选出蜕膜及外周血中NK细胞,流式细胞术检测其分离纯度,51Cr释放法分别测定不同效靶比NK细胞对其敏感性靶细胞K562的杀伤活性。
结果:
1)蜕膜中的NK细胞有着特殊的分布状态,多数集中在蜕膜与滋养层交界的母胎界面处。
2)相对于pNK细胞,dNK细胞是蜕膜中的主群体淋巴细胞。
3)相对于pNK细胞,dNK细胞表面低表达CD16分子,高表达CD69分子。
4) dNK细胞高表达NKG2受体家族NKG2A和NKG2D,但在滋养层中只检测到NKG2A的配体HLA-G和HLA-E ,而未检测到NKG2D的配体MICA。
5) dNK细胞内Th1/ Th2型细胞因子IFN-γ和IL-4的表达均明显高于pNK细胞。
6)不同效靶比dNK细胞对其敏感性靶细胞K562的杀伤活性明显低于pNK细胞。
结论:
蜕膜NK细胞作为重要的天然淋巴细胞,其含量、表型、Th1/Th2型细胞因子表达以及杀伤功能方面与外周血NK细胞有着明显差异,并且其与滋养细胞之间有着密切联系。蜕膜NK细胞独特的表型及功能在介导母胎界面免疫耐受中发挥了重要的作用。
Backgroud:
In pregnancy, hemiallogeneic fetal cells invade the maternal decidua but remain spared from attack by the maternal immune system, posing a great unsolved paradox of immunology. Although several factors have been proposed to explain or contribute to maternal tolerance, the local immunity of decidua play an important role. Studies have shown that the trophoblast cells are surrounded by many immunological cells when they invade into decidua, however, although these immunological cells have potential cytotoxic action, they do not attack trophoblast cells in normal pregnancy. Through the study of characteristic with decidual NK cells, the subset of CD56brightCD16- NK cells are named as decidual natural killer cells (dNK cells). Human uterine endometrium hosts a significant number of NK cells, the percentage of which change during the menstrual cycle and pregnancy. Decidual NK cells begin to increase from secretory phase, which peaks in early pregnancy when dNK cells comprise about 70% of resident lymphocytes and tightly touch with the invading trophoblasts. With the development of human pregnancy, the percentage of dNK cells then fall off, which account about 35% of resident lymphocytes in term decidua. The changes of the percentage and phenotype of dNK cells during pregnancy propose that they may play important roles in implantation and placenta development. Recently the research of origination, phenotype, function and interaction with trophoblasts about dNK cells has been a hot topic in reproduction immunology.
Decidual NK cells mainly distribute in decidua which links fetal and maternal interface and which can directly recognize fetal antigen. The specific phenotype and function of dNK cells may contribute to keep immunotolerance in fetal-maternal interface, also can they secrete an array of cytokines facilitate decidual blood rebuilding and maintain the balance of Th1/ Th2 cytokines. Study the function and status of dNK cells undoubtedly help us to further comprehend the physiological phenomena of pregnancy and also can provide new ways to research the mechanism of pathological pregnancy, as well as the development in reproduction immunology.
Objective:
To detect the distribution of dNK cells and compare the percentage, phenotype, Th1/ Th2 cytokine secretion and cytotocxic action between dNK cells and pNK cells, which can help us to further approach the important interaction between immunotolerance in fetal-maternal interface and dNK cells.
Methods:
1) Third-trimester decidua and peripheral blood was obtained during elective caesarean sections (n = 20), the method of IHC was used to detect the distribution of dNK cells.
2) Cell suspensions were prepared by an electromechanical dispersal method and centrifugated using a standard gradient sedimentation technique. The percentage and phenotype of dNK cells and pNK cells were detected by flow cytometric analysis.
3) The method of RT-PCR was used to detect the mRNA expression of HLA-G, HLA-E and MICA , which are ligands of NKG2A and NKG2D respectively.
4) Flow cytometry was used to detect the expression of intracellular Th1/Th2 cytokines IFN-γand IL-4 in dNK cells and pNK cells.
5) dNK cells and pNK cells were separated by MACS from PBMC and DBMC, whose purity was then detected by Flow cytometry. The cytotoxic activity of dNK cells and pNK cells against targets was measured in a standard 4-hr 51Cr-release assay.
Results:
1) The result of IHC showed that the distribution of dNK cells was distinct, many of which distributed at fetal-maternal interface.
2) Comparede with pNK cells, dNK cells are the dominant group of decidual lymphocytes.
3) The expression of CD16 were significantly decreased on dNK cells as compared with those on pNK cells, as we all know, expression of CD16 is one of important signals to measure cytotoxic activity; however, it was unclear that CD69 expression were significantly increased on dNK cells as compared with those on pNK cells, which seemed paradoxical to the theory of immunotolerance in fetal-maternal interface, because that CD69 is the marker of earlier period activation.
4) Decidual natural killer cells had high expression of NKG2A, which ligand HLA-G and HLA-E mRNA were also expressed in trophoblast tissue. Although dNK cells highly expressed NKG2D, there was no MICA mRNA expression.
5) Compared with pNK cells, the expression of intracellular Th1/Th2 cytokines IFN-γand IL-4 were significantly high in dNK cells. IFN-γand IL-4 are the most important cytokines in regulating Th1/Th2 immunological balance, suitable quantity of which play an important role in regulating immunological balance at fetal-maternal interface.
6) Although there is much perforin and granzyme in dNK cells, which propose they have potential cytotoxic action, their cytotoxic activity of dNK cells against targets were significantly decreased than pNK cells, maybe the cytotoxic activity of dNK cells were suppressed by something at fetal-maternal interface .
Conclusions:
Decidual natural killer cells are the important natural lymphocytes, whose percentage, phenotype, Th1/Th2 cytokine secretion and cytotocxic action are obviously different from peripheral NK cells, also they tightly touch with the invading trophoblasts. dNK cells and their secreting cytokines compose the center of decidual immunological regulation through development, regulation, receptor expression, biological effect. From the above results, we conclude that dNK cells play an important role in regulating immunological tolerance at fetal-maternal interface.
引文
1. Damber MG, von Schoultz B, Stigbrand T .The immunological paradox of pregnancy. Acta Obstet Gynecol Scand Suppl. 1977;66:39-47. Review.
2. Matsubayashi H, Shida M, Kondo A, Suzuki T, Sugi T, Izumi S, Hosaka T, Makino T.Preconception peripheral natural killer cell activity as a predictor of pregnancy outcome in patients with unexplained infertility.Am J Reprod Immunol. 2005;53(3):126-31.
3. Bulmer JN, Lash GE.Human uterine natural killer cells: a reappraisal.Mol Immunol. 2005 ;42(4):511-21. Review.
4. Moffett-King A. Natural killer cells and pregnancy. Nat Rev Immunol 2002; 2:656-63.
5. Parham. NK cells and trophoblasts: partners in pregnancy. J Exp Med 2004; 200:951-5.
6. Koopman LA, Kopcow HD, Rybalov B,et al.Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J Exp Med,2003 , 198(8):1201-1212
7. Szekeres-Bartho J. Immunological relationship between the mother and the fetus. Int Rev Immunol. 2002 Nov-Dec; 21(6): 471-95
8. Hunt JS, Petroff MG, McIntire RH, HLA-G and immune tolerance in pregnancy. FASEB J. 2005 May; 19(7): 681-93.
9. Gonen-Gross T, Achdout H, Gazit R, et al. Complexes of HLA-G protein on the cell surface are important for leukocyte Ig-like receptor-1 function. J Immunol, 2003 , 171(3):1343-1351
10. Guimond MJ, Wang B, Croy BA. Engraftment of bone marrow from severe combined immunodeficient (SCID) mice reverses the reproductive deficits in natural killer cell-deficient tg epsilon 26 mice. J Exp Med, 1998 , 187(2):217-223
11. Eidukaite A, Siaurys A, Tamosiunas V. Differential expression of KIR/NKAT2and CD94 molecules on decidual and peripheral blood CD56bright and CD56dim natural killer cell subsets. Fertil Steril, 2004, 81 (1): 863-868
12. Koopman LA, Kopcow HD, Rybalov B,Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential.J Exp Med. 2003 Oct 20;198(8):1201-12
13. Hanna J, Wald O, Goldman-Wohl D, et al.CXCL12 expression by invasive trophoblasts induces the specific migration of CD16- human natural killer cells.Blood. 2003,102(5):1569-1577
14. Wu X, Jin LP, Yuan MM, et al.Human first-trimester trophoblast cells recruit CD56brightCD16- NK cells into decidua by way of expressing and secreting of CXCL12/stromal cell-derived factor 1. J Immunol. 2005,175(1):61-68
15. Barber EM, Pollard JWThe uterine NK cell population requires IL-15 but these cells are not required for pregnancy nor the resolution of a Listeria monocytogenes infection. J Immunol. 2003 ;171(1):37-46
16. Wold AS, Arici A. Natural killer cells and reproductive failure. Curr Opin Obstet Gynecol. 2005 Jun;17(3):237-241
17. Ntrivalas EI, Bowser CR, Kwak-Kim J, et al. Expression of killer immunoglobulin-like receptors on peripheral blood NK cell subsets of women with recurrent spontaneous abortions or implantation failures. Am J Reprod Immunol. 2005, 53(5): 215-221
18. Sindram-Trujillo AP, Scherjon SA, van Hulst-van Miert PP, et al. Differential distribution of NK cells in decidua basalis compared with decidua parietalis after uncomplicated human term pregnancy. Hum Immunol, 2003,64(10): 921-929
19. Sindram-Trujillo AP, Scherjon SA, van Hulst-van Miert PP, et al. Comparison of decidual leukocytes following spontaneous vaginal delivery and elective cesarean section in uncomplicated human term pregnancy. J Reprod Immunol, 2004,62(1-2): 125-137
20. Bin Ling, Fengqiu Yao, Ying Zhou, et.al. Cell-mediated immunity imbalance in patients with intrahepatic cholestasis of pregnancy. Cellular & Molecular Immunology. 2007.4(1):71-75
21. Elami-Suzin M, Mankuta D.Natural killer cells in pregnancy and recurrent pregnancy loss: endocrine and immunologic perspectives.Endocr Rev. 2005 ;26(1):44-62. Review.
22. Croy BA, Di Santo JP, Greenwood JD, Chantakru S, Ashkar AA.Transplantation into genetically alymphoid mice as an approach to dissect the roles of uterine natural killer cells during pregnancy--a review.Placenta. 2000 Mar-Apr;21 Suppl A:S77-80. Review.
23. Okada H, Nakajima T, Sanezumi M, Ikuta A, Yasuda K, Kanzaki H.Progesterone enhances interleukin-15 production in human endometrial stromal cells in vitro.J Clin Endocrinol Metab. 2000;85(12):4765-70.
24. Henderson TA, Saunders PT, Moffett-King A, Groome NP, Critchley HO.Steroid receptor expression in uterine natural killer cells.J Clin Endocrinol Metab. 2003 ;88(1):440-9.
25. Quenby S, Farquharson R.Uterine natural killer cells, implantation failure and recurrent miscarriage.Reprod Biomed Online. 2006 ;13(1):24-8. Review.
26. Matsubara K, Nagamatsu T, Fujii T, Kozuma S, Taketani Y.Lymphokine-activated killer cells induced from decidual lymphocytes reduce the angiogenic activity of trophoblasts by enhancing the release of soluble fms-like tyrosine kinase-1 from trophoblasts: an implication for the pathophysiology of preeclampsia.J Reprod Immunol. 2005 ;68(1-2):27-37.
27. von Rango U, Classen-Linke I, Kertschanska S, Kemp B, Beier HM.Effects of trophoblast invasion on the distribution of leukocytes in uterine and tubal implantation sites.Fertil Steril. 2001;76(1):116-24.
28. Ogasawara K, Hamerman JA, Ehrlich LR, Bour-Jordan H, Santamaria P,Bluestone JA, Lanier LL.NKG2D blockade prevents autoimmune diabetes in NOD mice.Immunity. 2004 ;20(6):757-67.
29. Dosiou C, Giudice LC.Natural killer cells in pregnancy and recurrent pregnancy loss: endocrine and immunologic perspectives.Endocr Rev. 2005;26(1):44-62. Review.
30. Eriksson M, Meadows SK, Wira CR, Sentman CL. Unique phenotype of human uterine NK cells and their regulation by endogenous TGF-beta.J Leukoc Biol. 2004 ;76(3):667-75.
31. Coulam CB.Understanding the immunobiology of pregnancy and applying it to treatment of recurrent pregnancy loss.Early Pregnancy. 2000 ;4(1):19-29. Review.
32. Yokoyama WM, Kim S, French AR.The dynamic life of natural killer cells.Annu Rev Immunol. 2004;22:405-29. Review.
33. Croy BA, Esadeg S, Chantakru S, van den Heuvel M, Paffaro VA, He H, Black GP, Ashkar AA, Kiso Y, Zhang J.Update on pathways regulating the activation of uterine Natural Killer cells, their interactions with decidual spiral arteries and homing of their precursors to the uterus.J Reprod Immunol. 2003 ;59(2):175-91. Review.
34. Sindram-Trujillo AP, Scherjon SA, van Hulst-van Miert PP, et al. Comparison of decidual leukocytes following spontaneous vaginal delivery and elective cesarean sectioninuncomplicatedhumantermpregnancy.ReprodImmunol,2004,62(1-2):125-137.
35. Hill JA,Melling GC,ohnson PM, et al. Immunohistochemical studies of human uteroplacental tissues from first trimester spontaneous abortion . AM J Obstet Gynecol,1995, 173(1) : 90-95.
36. Cooper M A,Fehniger T A ,Caligiuri M A. The biology of human natural killer cell subsets. Trends Immunol ,2001 ;22(11) :633-640.
37. Nakayama T,Kasprowicz DJ,Yamashita M,et al.The generation of mature ,singlepositive thymocyte in vivo is dysregulated by CD69 blockade oroverexpression. J Immunol ,2002 ,168(1) :87-94.
38. Lanier LL, Buck DW, Rhodes L, Ding A, Evans E, Barney C, Phillips JH.Interleukin 2 activation of natural killer cells rapidly induces the expression and phosphorylation of the Leu-23 activation antigen.J Exp Med. 1988;167(5):1572-85.
39. Chao KH, Wu MY, Chen CD, Yang JH, Yang YS and Ho HN .Theexpression of killer cell inhibitory receptor on natural killer cells and activationstatus of CD4t and CD8t T cell in the decidua of normal andabnormal early pregnancy. Hum Immunol .1999;60,791–797.
40. Ho HN, Chao KH, Chen CK, Yang YS and Huang SC .Activation statusof T, NK cells in the endometrium through menstrual cycle and normaland abnormal early pregnancy. Hum Immunol. 1996;49,130–136.
41. Griffim F M,Fujita T O. The functional studies of high immunity blood liquid. Vet Sci ,1984,48(4) :519-526.
42. Garrido F, Ruiz-Cabello F, Cabrera T, et al . Implications for immunosurveillance of altered HLA class I phenotypes in human tumours.Immunol Today. 1997,18(2):89-95. Review.
43. Borrego F, Kabat J, Kim DK, et al.Structure and function of major histocompatibility complex (MHC) class I specific receptors expressed on human natural killer (NK) cells.Mol Immunol. 2002,38(9):637-660
44. Friese MA , Platten M, Lutz SZ , et al . MICA/NKG2D-mediated immunogene therapy of experimental gliomas. Cancer Res , 2003 , 63 ( 24) :8996-9006.
45. Doubrovina ES , Doubrovin MM, Vider E , et al . Evasion from NK cell immunity by MHC class I chain-related molecules expressing colon adenocarcinoma. J Immunol , 2003 ,171(12) :6891-6899.
46. Wegmann TG, Lin H, Guilbert L, Mosmann TR.Bidirectional cytokineinteractions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today. 1993,14(7):353-356
47. Chan WL, Pejnovic N, Lee CA,et al.Human IL-18 receptor and ST2L are stable and selective markers for the respective type 1 and type 2 circulating lymphocytes.J Immunol. 2001 ,167(3):1238-1244
48. Borzychowski AM, Croy BA, Chan WL,et al.Changes in systemic type 1 and type 2 immunity in normal pregnancy and pre-eclampsia may be mediated by natural killer cells.Eur J Immunol. 2005 ,35(10):3054-3063
49. Dong ZJ, Wei HM, Sun R, Tian ZG, Gao B.Isolation of murine hepatic lymphocytes using mechanical dissection for phenotypic and functional analysis of NK1.1+ cells.World J Gastroenterol. 2004 ;10(13):1928-33.
50. Lobo SC, Huang ST, Germeyer A, Dosiou C, Vo KC, Tulac S, Nayak NR, Giudice LC.The immune environment in human endometrium during the window of implantation.Am J Reprod Immunol. 2004 ;52(4):244-51.
1 Hanna J, Goldman-Wohl D, Hamani Y, et al . Decidual NK cells regulate key developmental processes at the human fetal-maternal interface[J]. Nat Med, 2006, 12(9):1065-1074.
2 Sargent IL, Borzychowski AM, Redman CW. NK cells and human pregnancy - an inflammatory view[J].Trends Immunol, 2006, 27(9):399-404.
3 Moffett-King A.Natural killer cells and pregnancy[J]. Nat Rev Immunol, 2002, 2(9):656-663.
4 Eidukaite A,Siaurys A,Tamosiunas V. Differential expression of KIR/NKAT2and CD94 molecules on decidulal and peripheral blood CD56brigh and CD56dim natural killer cell subsets[J].Fertil Steril, 2004, 81 suppl 1:863-868.
5 Chantakru S, Miller C, Roach L, et al. Contributions from self-renewal and trafficking to the uterine NK cell population of early pregnancy[J]. J Immunol, 2002, 168(1):22-28.
6 Hanna J, Wald O, Goldman-Wohl D, et al.CXCL12 expression by invasive trophoblasts induces the specific migration of CD16- human natural killer cells[J].Blood, 2003, 102(5):1569-1577.
7 Hu Y, Dutz JP, MacCalman CD, Yong P, Tan R, von Dadelszen P. Decidual NK cells alter in vitro first trimester extravillous cytotrophoblast migration: a role for IFN-gamma[J].J Immunol,2006, 177(12):8522-8530.
8 Moscoso J, Serrano-Vela JI, Pacheco R, Arnaiz-Villena A.HLA-G, -E and -F: allelism,function and evolution[J].Transpl Immunol,2006,17(1):61-64.
9 Trowsdale J.Genetic and functional relationships between MHC and NK receptor genes[J].Immunity, 2001,15(3):363-374.
10 Croy BA, He H, Esadeg S, et al.Uterine natural killer cells: insights into their cellular and molecular biology from mouse modelling [J].Reproduction, 2003,126(2):149-160.
11 Hiby SE, Walker JJ, O'shaughnessy KM, et al.Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success[J].J Exp Med,2004 ,200(8):957-965.
12 Borrego F, Kabat J, Kim DK, et al.Structure and function of major histocompatibility complex (MHC) class I specific receptors expressed on human natural killer (NK) cells[J].Mol Immunol,2002,38(9):637-660.
13 Wegmann TG, Lin H, Guilbert L, Mosmann TR.Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon[J]? Immunol Today, 1993,14 (7):353-356.
14 Chan WL, Pejnovic N, Lee CA,et al.Human IL-18 receptor and ST2L are stable and selective markers for the respective type 1 and type 2 circulating lymphocytes[J].J Immunol, 2001 ,167(3):1238-1244.
15 Borzychowski AM, Croy BA, Chan WL,et al.Changes in systemic type 1 and type 2 immunity in normal pregnancy and pre-eclampsia may be mediated by natural killer cells[J]. Eur J Immunol, 2005,35(10):3054-3063.
16 Sacks GP, Redman CW, Sargent IL.Monocytes are primed to produce the Th1 type cytokine IL-12 in normal human pregnancy: an intracellular flow cytometric analysis of peripheral blood mononuclear cells[J].Clin Exp Immunol,2003,131(3):490-497.
17 Sacks GP, Seyani L, Lavery S, et al,Maternal C-reactive protein levels are raised at 4 weeks gestation[J].Hum Reprod,2004,19(4):1025-3100.
18 Hahn S, Huppertz B, Holzgreve W.Fetal cells and cell free fetal nucleic acids in maternal blood: new tools to study abnormal placentation[J]? Placenta,2005,26(7):515-526.
19 Moffett A, Hiby SE. How Does the maternal immune system contribute to the development of pre-eclampsia[J]?Placenta, 2007, 28 Suppl A:S51-56.
20 Gupta AK, Rusterholz C, Huppertz B,et al.A comparative study of the effect of three different syncytiotrophoblast micro-particles preparations on endothelial cells[J].Placenta,2005 ,26(1):59-66.
2. Matsubayashi H, Shida M, Kondo A, Suzuki T, Sugi T, Izumi S, Hosaka T, Makino T.Preconception peripheral natural killer cell activity as a predictor of pregnancy outcome in patients with unexplained infertility.Am J Reprod Immunol. 2005;53(3):126-31.
3. Bulmer JN, Lash GE.Human uterine natural killer cells: a reappraisal.Mol Immunol. 2005 ;42(4):511-21. Review.
4. Moffett-King A. Natural killer cells and pregnancy. Nat Rev Immunol 2002; 2:656-63.
5. Parham. NK cells and trophoblasts: partners in pregnancy. J Exp Med 2004; 200:951-5.
6. Koopman LA, Kopcow HD, Rybalov B,et al.Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential. J Exp Med,2003 , 198(8):1201-1212
7. Szekeres-Bartho J. Immunological relationship between the mother and the fetus. Int Rev Immunol. 2002 Nov-Dec; 21(6): 471-95
8. Hunt JS, Petroff MG, McIntire RH, HLA-G and immune tolerance in pregnancy. FASEB J. 2005 May; 19(7): 681-93.
9. Gonen-Gross T, Achdout H, Gazit R, et al. Complexes of HLA-G protein on the cell surface are important for leukocyte Ig-like receptor-1 function. J Immunol, 2003 , 171(3):1343-1351
10. Guimond MJ, Wang B, Croy BA. Engraftment of bone marrow from severe combined immunodeficient (SCID) mice reverses the reproductive deficits in natural killer cell-deficient tg epsilon 26 mice. J Exp Med, 1998 , 187(2):217-223
11. Eidukaite A, Siaurys A, Tamosiunas V. Differential expression of KIR/NKAT2and CD94 molecules on decidual and peripheral blood CD56bright and CD56dim natural killer cell subsets. Fertil Steril, 2004, 81 (1): 863-868
12. Koopman LA, Kopcow HD, Rybalov B,Human decidual natural killer cells are a unique NK cell subset with immunomodulatory potential.J Exp Med. 2003 Oct 20;198(8):1201-12
13. Hanna J, Wald O, Goldman-Wohl D, et al.CXCL12 expression by invasive trophoblasts induces the specific migration of CD16- human natural killer cells.Blood. 2003,102(5):1569-1577
14. Wu X, Jin LP, Yuan MM, et al.Human first-trimester trophoblast cells recruit CD56brightCD16- NK cells into decidua by way of expressing and secreting of CXCL12/stromal cell-derived factor 1. J Immunol. 2005,175(1):61-68
15. Barber EM, Pollard JWThe uterine NK cell population requires IL-15 but these cells are not required for pregnancy nor the resolution of a Listeria monocytogenes infection. J Immunol. 2003 ;171(1):37-46
16. Wold AS, Arici A. Natural killer cells and reproductive failure. Curr Opin Obstet Gynecol. 2005 Jun;17(3):237-241
17. Ntrivalas EI, Bowser CR, Kwak-Kim J, et al. Expression of killer immunoglobulin-like receptors on peripheral blood NK cell subsets of women with recurrent spontaneous abortions or implantation failures. Am J Reprod Immunol. 2005, 53(5): 215-221
18. Sindram-Trujillo AP, Scherjon SA, van Hulst-van Miert PP, et al. Differential distribution of NK cells in decidua basalis compared with decidua parietalis after uncomplicated human term pregnancy. Hum Immunol, 2003,64(10): 921-929
19. Sindram-Trujillo AP, Scherjon SA, van Hulst-van Miert PP, et al. Comparison of decidual leukocytes following spontaneous vaginal delivery and elective cesarean section in uncomplicated human term pregnancy. J Reprod Immunol, 2004,62(1-2): 125-137
20. Bin Ling, Fengqiu Yao, Ying Zhou, et.al. Cell-mediated immunity imbalance in patients with intrahepatic cholestasis of pregnancy. Cellular & Molecular Immunology. 2007.4(1):71-75
21. Elami-Suzin M, Mankuta D.Natural killer cells in pregnancy and recurrent pregnancy loss: endocrine and immunologic perspectives.Endocr Rev. 2005 ;26(1):44-62. Review.
22. Croy BA, Di Santo JP, Greenwood JD, Chantakru S, Ashkar AA.Transplantation into genetically alymphoid mice as an approach to dissect the roles of uterine natural killer cells during pregnancy--a review.Placenta. 2000 Mar-Apr;21 Suppl A:S77-80. Review.
23. Okada H, Nakajima T, Sanezumi M, Ikuta A, Yasuda K, Kanzaki H.Progesterone enhances interleukin-15 production in human endometrial stromal cells in vitro.J Clin Endocrinol Metab. 2000;85(12):4765-70.
24. Henderson TA, Saunders PT, Moffett-King A, Groome NP, Critchley HO.Steroid receptor expression in uterine natural killer cells.J Clin Endocrinol Metab. 2003 ;88(1):440-9.
25. Quenby S, Farquharson R.Uterine natural killer cells, implantation failure and recurrent miscarriage.Reprod Biomed Online. 2006 ;13(1):24-8. Review.
26. Matsubara K, Nagamatsu T, Fujii T, Kozuma S, Taketani Y.Lymphokine-activated killer cells induced from decidual lymphocytes reduce the angiogenic activity of trophoblasts by enhancing the release of soluble fms-like tyrosine kinase-1 from trophoblasts: an implication for the pathophysiology of preeclampsia.J Reprod Immunol. 2005 ;68(1-2):27-37.
27. von Rango U, Classen-Linke I, Kertschanska S, Kemp B, Beier HM.Effects of trophoblast invasion on the distribution of leukocytes in uterine and tubal implantation sites.Fertil Steril. 2001;76(1):116-24.
28. Ogasawara K, Hamerman JA, Ehrlich LR, Bour-Jordan H, Santamaria P,Bluestone JA, Lanier LL.NKG2D blockade prevents autoimmune diabetes in NOD mice.Immunity. 2004 ;20(6):757-67.
29. Dosiou C, Giudice LC.Natural killer cells in pregnancy and recurrent pregnancy loss: endocrine and immunologic perspectives.Endocr Rev. 2005;26(1):44-62. Review.
30. Eriksson M, Meadows SK, Wira CR, Sentman CL. Unique phenotype of human uterine NK cells and their regulation by endogenous TGF-beta.J Leukoc Biol. 2004 ;76(3):667-75.
31. Coulam CB.Understanding the immunobiology of pregnancy and applying it to treatment of recurrent pregnancy loss.Early Pregnancy. 2000 ;4(1):19-29. Review.
32. Yokoyama WM, Kim S, French AR.The dynamic life of natural killer cells.Annu Rev Immunol. 2004;22:405-29. Review.
33. Croy BA, Esadeg S, Chantakru S, van den Heuvel M, Paffaro VA, He H, Black GP, Ashkar AA, Kiso Y, Zhang J.Update on pathways regulating the activation of uterine Natural Killer cells, their interactions with decidual spiral arteries and homing of their precursors to the uterus.J Reprod Immunol. 2003 ;59(2):175-91. Review.
34. Sindram-Trujillo AP, Scherjon SA, van Hulst-van Miert PP, et al. Comparison of decidual leukocytes following spontaneous vaginal delivery and elective cesarean sectioninuncomplicatedhumantermpregnancy.ReprodImmunol,2004,62(1-2):125-137.
35. Hill JA,Melling GC,ohnson PM, et al. Immunohistochemical studies of human uteroplacental tissues from first trimester spontaneous abortion . AM J Obstet Gynecol,1995, 173(1) : 90-95.
36. Cooper M A,Fehniger T A ,Caligiuri M A. The biology of human natural killer cell subsets. Trends Immunol ,2001 ;22(11) :633-640.
37. Nakayama T,Kasprowicz DJ,Yamashita M,et al.The generation of mature ,singlepositive thymocyte in vivo is dysregulated by CD69 blockade oroverexpression. J Immunol ,2002 ,168(1) :87-94.
38. Lanier LL, Buck DW, Rhodes L, Ding A, Evans E, Barney C, Phillips JH.Interleukin 2 activation of natural killer cells rapidly induces the expression and phosphorylation of the Leu-23 activation antigen.J Exp Med. 1988;167(5):1572-85.
39. Chao KH, Wu MY, Chen CD, Yang JH, Yang YS and Ho HN .Theexpression of killer cell inhibitory receptor on natural killer cells and activationstatus of CD4t and CD8t T cell in the decidua of normal andabnormal early pregnancy. Hum Immunol .1999;60,791–797.
40. Ho HN, Chao KH, Chen CK, Yang YS and Huang SC .Activation statusof T, NK cells in the endometrium through menstrual cycle and normaland abnormal early pregnancy. Hum Immunol. 1996;49,130–136.
41. Griffim F M,Fujita T O. The functional studies of high immunity blood liquid. Vet Sci ,1984,48(4) :519-526.
42. Garrido F, Ruiz-Cabello F, Cabrera T, et al . Implications for immunosurveillance of altered HLA class I phenotypes in human tumours.Immunol Today. 1997,18(2):89-95. Review.
43. Borrego F, Kabat J, Kim DK, et al.Structure and function of major histocompatibility complex (MHC) class I specific receptors expressed on human natural killer (NK) cells.Mol Immunol. 2002,38(9):637-660
44. Friese MA , Platten M, Lutz SZ , et al . MICA/NKG2D-mediated immunogene therapy of experimental gliomas. Cancer Res , 2003 , 63 ( 24) :8996-9006.
45. Doubrovina ES , Doubrovin MM, Vider E , et al . Evasion from NK cell immunity by MHC class I chain-related molecules expressing colon adenocarcinoma. J Immunol , 2003 ,171(12) :6891-6899.
46. Wegmann TG, Lin H, Guilbert L, Mosmann TR.Bidirectional cytokineinteractions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today. 1993,14(7):353-356
47. Chan WL, Pejnovic N, Lee CA,et al.Human IL-18 receptor and ST2L are stable and selective markers for the respective type 1 and type 2 circulating lymphocytes.J Immunol. 2001 ,167(3):1238-1244
48. Borzychowski AM, Croy BA, Chan WL,et al.Changes in systemic type 1 and type 2 immunity in normal pregnancy and pre-eclampsia may be mediated by natural killer cells.Eur J Immunol. 2005 ,35(10):3054-3063
49. Dong ZJ, Wei HM, Sun R, Tian ZG, Gao B.Isolation of murine hepatic lymphocytes using mechanical dissection for phenotypic and functional analysis of NK1.1+ cells.World J Gastroenterol. 2004 ;10(13):1928-33.
50. Lobo SC, Huang ST, Germeyer A, Dosiou C, Vo KC, Tulac S, Nayak NR, Giudice LC.The immune environment in human endometrium during the window of implantation.Am J Reprod Immunol. 2004 ;52(4):244-51.
1 Hanna J, Goldman-Wohl D, Hamani Y, et al . Decidual NK cells regulate key developmental processes at the human fetal-maternal interface[J]. Nat Med, 2006, 12(9):1065-1074.
2 Sargent IL, Borzychowski AM, Redman CW. NK cells and human pregnancy - an inflammatory view[J].Trends Immunol, 2006, 27(9):399-404.
3 Moffett-King A.Natural killer cells and pregnancy[J]. Nat Rev Immunol, 2002, 2(9):656-663.
4 Eidukaite A,Siaurys A,Tamosiunas V. Differential expression of KIR/NKAT2and CD94 molecules on decidulal and peripheral blood CD56brigh and CD56dim natural killer cell subsets[J].Fertil Steril, 2004, 81 suppl 1:863-868.
5 Chantakru S, Miller C, Roach L, et al. Contributions from self-renewal and trafficking to the uterine NK cell population of early pregnancy[J]. J Immunol, 2002, 168(1):22-28.
6 Hanna J, Wald O, Goldman-Wohl D, et al.CXCL12 expression by invasive trophoblasts induces the specific migration of CD16- human natural killer cells[J].Blood, 2003, 102(5):1569-1577.
7 Hu Y, Dutz JP, MacCalman CD, Yong P, Tan R, von Dadelszen P. Decidual NK cells alter in vitro first trimester extravillous cytotrophoblast migration: a role for IFN-gamma[J].J Immunol,2006, 177(12):8522-8530.
8 Moscoso J, Serrano-Vela JI, Pacheco R, Arnaiz-Villena A.HLA-G, -E and -F: allelism,function and evolution[J].Transpl Immunol,2006,17(1):61-64.
9 Trowsdale J.Genetic and functional relationships between MHC and NK receptor genes[J].Immunity, 2001,15(3):363-374.
10 Croy BA, He H, Esadeg S, et al.Uterine natural killer cells: insights into their cellular and molecular biology from mouse modelling [J].Reproduction, 2003,126(2):149-160.
11 Hiby SE, Walker JJ, O'shaughnessy KM, et al.Combinations of maternal KIR and fetal HLA-C genes influence the risk of preeclampsia and reproductive success[J].J Exp Med,2004 ,200(8):957-965.
12 Borrego F, Kabat J, Kim DK, et al.Structure and function of major histocompatibility complex (MHC) class I specific receptors expressed on human natural killer (NK) cells[J].Mol Immunol,2002,38(9):637-660.
13 Wegmann TG, Lin H, Guilbert L, Mosmann TR.Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon[J]? Immunol Today, 1993,14 (7):353-356.
14 Chan WL, Pejnovic N, Lee CA,et al.Human IL-18 receptor and ST2L are stable and selective markers for the respective type 1 and type 2 circulating lymphocytes[J].J Immunol, 2001 ,167(3):1238-1244.
15 Borzychowski AM, Croy BA, Chan WL,et al.Changes in systemic type 1 and type 2 immunity in normal pregnancy and pre-eclampsia may be mediated by natural killer cells[J]. Eur J Immunol, 2005,35(10):3054-3063.
16 Sacks GP, Redman CW, Sargent IL.Monocytes are primed to produce the Th1 type cytokine IL-12 in normal human pregnancy: an intracellular flow cytometric analysis of peripheral blood mononuclear cells[J].Clin Exp Immunol,2003,131(3):490-497.
17 Sacks GP, Seyani L, Lavery S, et al,Maternal C-reactive protein levels are raised at 4 weeks gestation[J].Hum Reprod,2004,19(4):1025-3100.
18 Hahn S, Huppertz B, Holzgreve W.Fetal cells and cell free fetal nucleic acids in maternal blood: new tools to study abnormal placentation[J]? Placenta,2005,26(7):515-526.
19 Moffett A, Hiby SE. How Does the maternal immune system contribute to the development of pre-eclampsia[J]?Placenta, 2007, 28 Suppl A:S51-56.
20 Gupta AK, Rusterholz C, Huppertz B,et al.A comparative study of the effect of three different syncytiotrophoblast micro-particles preparations on endothelial cells[J].Placenta,2005 ,26(1):59-66.