Indoleamine 2,3-dioxygenase (IDO) expression in invasive extravillous trophoblast supports role of the enzyme for materno-fetal tolerance

It is still not understood how the fetus escapes from being attacked by the maternal immune system. Recent reports based on mouse and in vitro models have suggested that the enzyme indoleamine 2,3-dioxygenase (IDO) is important for materno-fetal tolerance. IDO activity in the human placenta is known to be high and might lead to inhibition of T-cell proliferation, thus preventing fetal tissue from rejection by the maternal immune system. In an attempt to elucidate the precise location of IDO at the feto-maternal junctional zone, we investigated human placental and decidual tissue of first and third trimester of pregnancy using an immunohistochemical approach. In placental tissues, only syncytiotrophoblast and endothelial cells showed moderate expression of IDO. This pattern was observed regardless of whether first or third trimester tissue was investigated. In early and term decidua, cells with the typical morphology of invasive extravillous trophoblast (EVT) were strongly positive for IDO. Blocking immunohistochemical experiments with cytokeratin and IDO antibodies identified invasive EVT as the location of predominant IDO expression. Since EVT are the fetal cells with the closest contact to the maternal immune system, our results suggest that it is EVT which protects the fetus from rejection by downregulating local maternal T-cell responses.     

Fetomaternale Immunität

The maternal immune system has to fulfill several tasks during pregnancy. On the one hand it has to protect both mother and fetus from infection, and on the other it has to prevent the rejection of the fetus and its extrusion of tissue antigens from both the mother and father. Due to this, maternal immunity changes during pregnancy, particularly the adaptive immune system (T lymphocytes). Active induction of T helper (Th) 2 function occurs at the fetomaternal barrier. Cells in the decidual tissue play an important role in the regulation of this reorientation and support the changes in maternal immunity. These maternal influences induce an effective and functional maturation of the lymphocyte system in the fetus. From the 20th week of pregnancy, the fetal lymphocyte system is fully developed and is able to be confronted with diaplacental transport of antigens. Fetal antigen contact is important for developing immunological tolerance against environmental antigens (e.g., foods) which have to be tolerated immediately after birth. Recently, a number of experimental data have been published. The following article gives a survey of these data.     

Schwangerschaft und maternales Immunsystem

Pregnancy is a successful natural model of immune tolerance. The fetus is not only passively tolerated by the maternal immune system – it is actively supported in its development (immunotrophism), which is in apparent conflict with the primary mechanism of transplantation immunology (recognition of foreign bodies). Its ‘invasive’ growth is made possible by an immunologic situation whose characteristics are being more and more understood. However, disbalance in this fine network can lead to disturbances in implantation and placentation and result in intrauterine growth retardation or spontaneous miscarriage. Understanding immunologic communication at the trophoblastic level can improve understanding of other invasive processes, for example those of malignant degeneration, and open new therapeutic possibilities. We describe three main functions of the immune system that apply in the fetomaternal interphase: (1) trophoblast immune function and the cytokine network, (2) uterine natural killer cells, and (3) the function of the immunosuppressive glycoprotein glycodelin. Current recommendations for immunotherapy in case of recurrent miscarriage are discussed.     

妊娠过程中凋亡级联的作用和调节

细胞凋亡是一种级联事件,在妊娠过程中发挥了重要的作用,主要体现在胎盘形成过程中滋养细胞层分化为合体细胞滋养层,滋养层入侵确保了胎盘锚固于母体血管系统以保证胎儿氧气及营养的供应。滋养层细胞的凋亡限制了子宫壁侵入,维持母体完整性,凋亡产生的多肽是胎儿特异性耐受建立的诱导物。整个级联过程受母体免疫系统的监控,妊娠妇女的免疫应答并没有显著降低,母体免疫系统能够识别胎儿移植物这个外源性抗原并作出应答。母胎界面特定的免疫耐受诱导机制使绒毛外滋养细胞（EVT）限制和容忍相互联系。细胞因子主要由自然杀伤细胞、T细胞分泌,白细胞通过细胞因子发挥其免疫调节作用。凋亡过程受到基因调控、激素及氧化应激等因素的影响。     

Absence of HL-A homology in couples presenting repeated miscarriages. Trials with multidonor transfusions

Maternal tolerance of the fetus involves maternal immuno-regulating mechanisms. The genetic control of this immune response depends on the HL-A system. An extreme HL-A antigenic community between parents might cause a decreased immune response and increased miscarriages. Contrary to some studies from the literature, in our experience, HL-A homology in couples with recurrent miscarriages does not seem significant. This absence of homology may be explained by an extreme polymorphism of HL-A antigens identified and isolated every year. The role of maternal blocking antibodies in maternal tolerance of the fetus is also discussed. The results of a protocol of multi-donor transfusions in 8 patients, is presented and reviewed according to the resulting pregnancies and data from the literature.     

Natural Killer Cells and Dendritic Cells at the Human Feto-maternal Interface: an Effective Cooperation?

Human endometrium and in particular decidua, harbours a considerable population of immunocompetent cells. The most prominent of these are uterine natural killer (uNK) cells, which differ considerably from their peripheral blood counterparts in terms of both gene expression and function. Recently, the existence of DC-SIGN positive immature dendritic cells (DCs) in human decidua has been demonstrated. Evidence exists that immature DCs are required for the initiation and maintenance of peripheral tolerance, whereas mature DCs, which are only found in minimal amounts in human decidua, are associated with a Th1 polarization of T cells. Although the study of uNK-DC cross-talk is only beginning, it may in the future provide important insights into how acceptance of the fetus by the maternal immune system is mediated.     

Fetal stem-cell transplantation

Fetal stem-cell transplantation is an attractive approach to the treatment of a variety of hematological, metabolic and immunological diseases before birth. The possibility of delivering a large number of cells in an early stage of life, and of taking advantage of normal fetal stem-cell migration and development, is promising. During fetal life, the capacity to mount an immune response to allogeneic cells is impaired compared with adult life. This provides an opportunity to induce tolerance to alloantigens without the need for myeloablation, although there are possible immune barriers to foreign cells in the fetus.     

CD4＋T细胞在原因不明复发性流产中的研究进展

正常妊娠有赖于母体对胚胎半同种抗原的免疫耐受,一旦免疫耐受失衡,将导致免疫排斥、免疫攻击从而导致自然流产,原因不明复发性流产被认为与母胎免疫耐受失衡有关.CD4＋T在同种异体急性排斥反应中发挥重要作用,根据所分泌的细胞因子不同,CD4＋T 细胞分为Th1、Th2、调节性T细胞（Treg）及新近发现的Th17细胞.早期研究发现母体外周血、母胎界面CD4＋T细胞增高与复发性流产密切相关.随免疫耐受机制研究的不断深入,母胎免疫耐受的研究历经Th1/Th2平衡到Treg的免疫负调控作用,再到Th17/Treg平衡.综述CD4＋T细胞在原因不明复发性流产中的研究进展.     

Fetal gene therapy

Fetal gene therapy has the potential to treat inherited genetic diseases in utero before significant organ damage has occurred. Rapidly expanding stem cell populations may be targeted and the introduction of transgenes to the fetus during development of the immune system could result in immune tolerance and facilitate repeat treatment postnatally. Genetic diseases such as cystic fibrosis, which are life-threatening and for which there are no currently acceptable treatments available, are suggested targets for this therapy.

Ultrasound may be a safe method of delivering a therapeutic gene into the fetus, although most studies have used more invasive techniques, even in large animal models. Viral vectors currently offer the most potential. Adenovirus-based vectors are stable, independent of host cell replication, efficient at tissue infection and have been used as a 'pathfinder' to test routes of administration. Unfortunately, they are also highly immunogenic and other systems based on retrovirus or adeno-associated virus may offer advantages because of their lower immunogenicity and potential for permanent transgene expression.

Our group is developing the fetal sheep model for the investigation of ultrasound-guided gene therapy in utero. This model is suitable since the sheep fetus is tolerant to manipulations, has a consistent gestation period and shows many similarities with human pregnancy. We have demonstrated significant transfection of the fetal liver and adrenal cortex after ultrasound-guided percutaneous injection of the umbilical vein with adenoviral vectors in the late gestation sheep. We are investigating and here discuss alternative routes of administration to target the fetus in early gestation via ultrasound-guided minimally invasive techniques.     

Trophoblast deportation: just a waste disposal system or antigen sharing?

Trophoblast deportation, the removal of trophoblastic debris from the placenta via the maternal blood, was first described over 100 years ago. Deported trophoblastic debris ranges in size from nano-meter scale subcellular particles to large multinucleated syncytial knots. Whether trophoblast deportation has any biological significance remains unclear. However, the (semi) allogeneic fetus must induce maternal tolerance to paternally inherited placental antigens. We propose that the clearance of deported trophoblasts may be a mechanism by which the maternal immune system is maintained in a state of tolerance towards paternal antigens. Using an in vitro model, we have shown that when syncytial knots are shed by an apoptosis-like programmed cell death process, then phagocytosed by macrophages, the macrophages produce a tolerogenic response. However, necrotic syncytial knots, when phagocytosed, appear to be immunostimulatory. We have also shown that endothelial cells are likely to be involved in the clearance of syncytial knots from the pulmonary vessels. Phagocytosis of apoptotic syncytial knots by endothelial cells is silent while phagocytosis of necrotic syncytial knots leads to endothelial cell activation characterised by increased endothelial cell-surface adhesion molecule expression and secretion of IL-6 and TGFβ1. All of these molecules may interact with the maternal immune system to exacerbate any adverse maternal response. We propose that in normal pregnancy clearance of apoptotic syncytial knots is important to maintain maternal immune tolerance to the fetus and that in abnormal pregnancies, especially preeclampsia, clearance of necrotic syncytial knots may contribute to the pathogenesis of that condition.     

Tissue microcircumstances for leukocytic infiltration into the testis and epididymis in mice

Spermatozoa do not appear in the seminiferous epithelium until puberty, when immune tolerance has already been established. Therefore, they contain various autoimmunogenic materials which are recognized as foreign by the self immune system. However, the testis and epididymis are known as immunologically privileged organs. In particular, the blood-testis barrier (BTB) formed by Sertoli cells and the blood-epididymal barrier formed by epididymal epithelial cells protect autoimmunogeneic spermatozoa from attack by the self immune system. The immune privileged circumstances in the testis and epididymis have been demonstrated by many studies to involve a local transplantation system. We review here the immune privileged status of these organs from the viewpoint of induction of inflammatory cell responses in mice. The testicular interstitium in mice is resistant to vasculitis, lymphangitis, spermatic granuloma and polymorphonuclear cell infiltration: however, the epididymal interstitium is vulnerable to them. Therefore, the testicular tissue outside BTB is also protected from inflammatory cell infiltration, although many resident macrophages are normally present in the testis. In sharp contrast, subcutaneous injection of viable syngeneic testicular germ cells (TGC) alone induces autoimmune orchitis with no involvement of the epididymitis in mice. In the testes of TGC-immunized animals, severe lymphocytic infiltration with aspermatogenesis was seen in spite of no use of adjuvants. Unexpectedly, injections of viable epididymal spermatozoa (ES) did not evoke any autoimmune inflammation in the epididymides. Therefore, the testis rather than the epididymis may easily become an unprivileged organ as to autoimmunity under some special conditions.     

Gamma-delta T cells in midgestation human placental villi

One question that remains is how the immune system at the maternal-fetal interface supports tolerance of the fetus while at the same time protecting it from infection. A potential answer is that local innate immunity is augmented while adaptive immunity is downregulated. In this study, we focus on T cells of the gamma-delta lineage, thought to be important in certain innate responses. Using tissue from normal pregnancies, we documented the presence of gamma-delta T cells and their counterpart, alpha-beta T cells, in midgestation human placental villi. The variable presence of these two T cell lineages in this anatomic site may suggest differential regulation, and herein we describe potential mechanisms for this phenomenon.     

Evolution of mammalian pregnancy in the presence of the maternal immune system

Eutherian mammals have inherited a typical vertebrate immune system, which protects the body against infectious organisms by detecting and destroying foreign biological material. However, with the evolution of longer gestation periods, this protective mechanism became a potential threat to the 'semi-foreign' fetus and so eutherians have developed systems to prevent immune rejection of their developing fetuses. In many species, this is achieved by reducing placental expression of major histocompatibility complex (MHC) genes, the products of which are responsible for most transplantation rejection reactions. Unexpectedly, however, major histocompatibility complex expression is often re-established in the most invasive trophoblast cells. It is not known why transplantation antigen expression in the fetal cells most exposed to the maternal immune system is advantageous. It is possible that such expression aids the process of invasion or exerts an immunoprotective effect on the fetus. It may prove possible to identify the essential steps that all eutherian fetuses take to ensure their survival in the face of potential maternal immune attack by studying the common features of the placental immunology of different species.     

Placental angiotensin II receptor AT1R in normotensive patients and its correlation between infant birth weight

OBJECTIVE: To evaluate angiotensin II type 1 receptor (AT1R) in the third trimester placenta from normotensive women and the correlation between placental AT1R immunoreactivity and infant birth weight. PATIENTS AND METHODS: The study was carried out on 18 healthy normotensive patients with singleton uncomplicated pregnancies. Immunohistochemistry was used to examine the localization of AT1R in the human placenta. RESULTS: Immunohistochemistry using a monoclonal antibody showed that angiotensin II (Ang II) receptor subtype 1 is localized in the decidual cells, syncytiotrophoblast, cytotrophoblast, Hofbauer cells and vascular endothelium. In our study group of patients, we found a significant negative correlation between histological staining in placental tissue and infant birth weight. CONCLUSION: It seems that the appropriate placental AT1R expression and its normal vascular and endocrine activity plays a very important role in oxygenation and nutrition of the fetus and this ensures proper fetal development and growth.     

Effects of ionizing radiation on the embryo and fetus

The developing embryo and fetus are extremely sensitive to ionizing radiation. The main effects of radiation on he human embryo and fetus are: growth retardation, prenatal or neonatal death, congenital malformations and mental retardation. The incidence of these radiation effects at different stages of gestation, the relations with absorbed doses and threshold doses are discussed. Epidemiological data that reveal high susceptibility to carcinogenic effects of radiation during in utero life are presented. A dose of 0.1 Gy (10 rad) to the embryo and fetus is recommended as a threshold dose, above which a therapeutic abortion should be considered. Diagnostic radiation exposures will reach this level in a very rare cases. The threshold dose, which is an indication for pregnancy termination must be flexible, in a large tolerance, depending on other possible risks of the pregnancy as well as the personality of the future parents.     

Specific mucosal immunity in the female reproductive tract: general introduction (part 1)

Immune mediated defense against pathogenic microorganisms and maintenance of immune tolerance to allogeneic antigens of sperm and fetus are main function of female reproductive tract mucosal immune system. Basic mechanisms of mucosal immune system and the unique features of female reproductive tract immune system are reviewed in this article.     

Diminished expression of placental isoferritin p43 component in first trimester abnormal pregnancies

Human placental isoferritin (PLF) is a sub-type of human ferritin mainly composed of a 43 kD protein, which has an immunosuppressive activity and may be involved in the downregulation of the maternal immune system during pregnancy. The aim of this study was to evaluate the distribution of p43 in the placental tissue of abnormal first trimester pregnancies. Samples of villous and decidual tissues were collected between 7 and 12 weeks' gestation from 28 missed abortions and eight complete moles. Samples of placental tissue from 20 normal pregnancies of similar gestational age were used as controls. The localization of p43 was determined by immunohistochemical techniques using CM-H9 monoclonal antibody. Compared to controls, specific p43 immunoreactivity was low in the villous syncytiotrophoblast of missed abortions and absent from all villous cellular types in complete moles. These findings correlate well with the low level of maternal serum PLF found previously in early pregnancy failures and molar gestation. This suggests that PLF may be involved in the pathogenesis of early pregnancy disorders related to an abnormal placentation.     

Correlation between oral sex and a low incidence of preeclampsia: a role for soluble HLA in seminal fluid?

The involvement of immune mechanisms in the aetiology of preeclampsia is often suggested. Normal pregnancy is thought to be associated with a state of tolerance to the foreign antigens of the fetus, whereas in preeclamptic women this immunological tolerance might be hampered. The present study shows that oral sex and swallowing sperm is correlated with a diminished occurrence of preeclampsia which fits in the existing idea that a paternal factor is involved in the occurrence of preeclampsia. Because pregnancy has many similarities with transplantation, we hypothesize that induction of allogeneic tolerance to the paternal HLA molecules of the fetus may be crucial. Recent data suggest that exposure, and especially oral exposure to soluble HLA (sHLA) or HLA derived peptides can lead to transplantation tolerance. Similarly, sHLA antigens, that are present in the seminal plasma, might cause tolerance in the mother to paternal antigens. In order to test whether this indeed may be the case, we investigated whether sHLA antigens are present in seminal plasma. Using a specific ELISA we detected sHLA class I molecules in seminal plasma. The level varied between individuals and was related to the level in plasma. Further studies showed that these sHLA class I molecules included classical HLA class I alleles, such as sHLA-A2, -B7, -B51, -B35 and sHLA-A9. Preliminary data show lower levels of sHLA in seminal plasma in the preeclampsia group, although not significantly different from the control group. An extension of the present study is necessary to verify this hypothesis.     

Innate immune cell recruitment in the fetus and neonate

Recruitment of innate immune cells from the vasculature into infected tissue is a key event in primary host defense against invading pathogens. This highly regulated process requires a functional interplay of specialized adhesion molecules and involves a series of steps leading from rolling of leukocytes along the endothelium to firm adhesion and finally transmigration. In the developing fetus, innate immune functions are ontogenetically regulated and show increasing maturation throughout gestation. Developmental differences in the innate immune response leave the neonate and especially the premature newborn at high risk of severe infections. Understanding the ontogeny of immune functions in the fetus and newborn is therefore essential for the prevention and treatment of neonatal infections. In this review, an overview will be given of the developmental aspects of innate immune cell recruitment including a discussion of controversial findings and open questions.     

Immunological mother-fetus relationship]

The immunology of propagation and growth is a field of medicine which has been developing in the last 3--4 years. On the basis of the literature data on clinical and experimental works from this field the author tries to explain the essence of the immunological mother-fetus relationship. The non-rejection of the fetus as a foreign transplant is made possible by the suppression of the mother's immunologic capacity (cellular and humoral) on the one hand, and the existence of protective mechanisms of the fetus on the other. Dealing in more detail with elements resulting in the reduced immunological reactivity and the increased tolerance of mother towards fetus, the author concludes that this increased tolerance, along with the existence of the intact placental barrier, is the basic factor which allows the survival of the fetus as an allotransplant.