[Immunologic and tumor biology aspects of placentation in humans]. / Immunologische und tumorbiologische Aspekte zur Plazentation beim Menschen.

In this survey, findings relating to the control of infiltration by the cytotrophoblast during human placentation are reviewed, with particular reference to immunology and tumour biology. Possible effects on pregnancy and parturition due to failure of the regulatory processes involved in placentation are discussed.

A subset of CD56+ large granular lymphocytes in first-trimester human decidua are proliferating cells.

OBJECTIVE: To determine whether the unusually high number of CD56+ large granular lymphocytes (LGL) in the decidua of early human pregnancy arises from selective migration or in situ proliferation. DESIGN: Controlled clinical study. SETTING: Academic research environment. PATIENT(S): Thirty healthy women undergoing therapeutic abortion of an intact pregnancy at 5-11 weeks' gestation. INTERVENTION(S): Decidua was obtained by suction curettage; tissue and isolated cells were subjected to immunohistochemical and flow cytometric investigation. MAIN OUTCOME MEASURE(S): Proliferation rate of LGL. RESULT(S): The proportion of CD56+ cells positive for the proliferation-associated Ki-67 antigen was found to be 7%-23.5% by three different methods of investigation. These findings are consistent with those of flow cytometric analysis of the nuclear phase, which revealed 6%-22% of the LGL nuclei to be in the phases S+G2+M. CONCLUSION(S): The various methods of investigation revealed marked proliferative activity in the LGL of early pregnancy decidua. This finding suggests that in situ proliferation may be responsible for the high density of these cells in the decidua.

[Placentation in the human: a transplantation or tumor model?]. / Die Plazentation beim Menschen: Ein Transplantations-oder Tumormodell?

In human placentation, anchoring villi develop to attach the placenta to the wall of the uterus. This attachment is brought about by extensive infiltration of the maternal tissue by cytotrophoblast cells of fetal origin. As trophoblast cells do not express classical histocompatibility antigens (HLA antigens), increasing doubt has been cast upon the "transplantation" model of pregnancy. However, more recently discovered, previously unknown HLA antigens on the invasive cytotrophoblast cells could lead to maternal immune responses similar to those observed following organ transplantation. Nevertheless, the biological behaviour of the invasive cytotrophoblast cells suggests more parallels with the processes of invasion and metastasis seen in malignant tumours, although there is regulation of the timing and extent of cytotrophoblast invasion of the uterus in normal pregnancy. In this survey, findings relating to the control of infiltration by the cytotrophoblast are reviewed, with particular reference to immunology and tumour biology. Possible effects on pregnancy and parturition due to failure of the regulatory processes involved in placentation are discussed.

Interleukin-12- and interleukin-2-stimulated release of interferon-gamma by uterine CD56++ large granular lymphocytes is amplified by decidual macrophages.

Numerous studies have suggested that interferon-gamma (IFN-gamma) exhibits an inhibitory effect on conceptus development during pregnancy, and recent investigations have shown that decidual CD56++, CD16- large granular lymphocytes (LGL) contain mRNA for IFN-gamma. We have investigated the influence of exogenous interleukin-12 (IL-12) and interleukin-2 (IL-2) on IFN-gamma secretion by cultivated LGL and macrophages isolated from first trimester human decidua. The effect of decidual macrophages on IFN-gamma secretion by LGL was also assessed using co-incubation experiments. Neither IL-12 nor IL-2 stimulated the secretion of IFN-gamma by decidual macrophages. IL-12 alone, but not IL-2 alone, stimulated the release of IFN-gamma by LGL. However, IL-2 acted synergistically with IL-12 to enhance the release of IFN-gamma by LGL. Unstimulated and IL-12- and IL-2-stimulated LGL incubated with macrophages exhibited a marked increase in secretion of IFN-gamma compared to those in monoculture. This effect was also seen when the LGL and macrophages were separated by a semi-permeable membrane. The results suggest that interactions between decidual LGL and macrophages, possibly mediated by soluble factors, could play a role in regulating IFN-gamma secretion at the materno-fetal interface and thus contribute to the control of invasion by the trophoblast.

Immune Sensitization to the 60 kD Heat Shock Protein and Pregnancy Outcome.

Heat shock proteins are highly conserved proteins present in organisms ranging from bacteria to man. They are both dominant microbial immunogens and among the first proteins produced during mammalian embryo development. Since bacterial and human heat shock proteins share a high degree of amino acid sequence homology, it has been suggested that sensitization to bacterial heat shock proteins during an infection may result in autoimmunity to human heat shock proteins. Infertile couples seeking in vitro fertilization (IVF) may have been previously sensitized to bacterial heat shock proteins as a consequence of an asymptomatic upper genital tract infection. Due to daily clinical monitoring and precisely timed fertilization these patients are an ideal study group to investigate the effect of prior sensitization to heat shock proteins on preimplantation embryo development and implantation failure. Immune sensitization at the level of the cervix to the 60 kD heat shock protein (hsp60) has been associated with implantation failure in some IVF patients. Similarly, the highest prevalence of circulating hsp60 antibodies among IVF patients was found in the sera of women whose embryos failed to develop in vitro. To more directly assess whether humoral immunity to hsp60 influenced in vitro embryo development, a mouse embryo culture model was established. Monoclonal antibody to mammalian hsp60 markedly impaired mouse embryo development in vitro. These data suggest that immune sensitization to human hsp60, possibly developed as a consequence of infection, may adversely affect pregnancy outcome in some patients.

An accurate method for sonographic estimation of the weight of very preterm fetuses.

This study was undertaken to test the accuracy of formulas we recently developed for the sonographic estimation of the weight of very preterm fetuses. The formulas were used to determine estimated weights from prenatal sonographic data for 62 premature infants born at 23-29 weeks of gestation, weight < or = 1,400 g. The mean absolute deviation of the actual birth weight from the estimated weight was 75.8 +/- (SD) 68.5 g, the mean percent deviation +0.60% and the absolute mean percent deviation 8.1 +/- (SD) 5.6%; 90.3% of the birth weights lay within 15% of the estimated weight. The model described represents an accurate method for prenatal estimation of the weight of very preterm fetuses.

Recurrent first trimester spontaneous abortion associated with antiphospholipid antibodies: a pilot study of treatment with intravenous immunoglobulin.

BACKGROUND: Antiphospholipid antibodies, unassociated with an underlying connective tissue disease, have repeatedly been detected in women suffering from recurrent spontaneous abortions. Several therapeutic regimens have been advocated for pregnant women with recurrent fetal loss and antiphospholipid antibodies. However, most of these approaches were empirical, using several drugs simultaneously, and most reports describe single cases or limited series. PATIENTS AND INTERVENTIONS: In a pilot study, thirty-eight women with a history of three or more consecutive first trimester spontaneous abortions and antiphospholipid antibodies were treated with intravenous immunoglobulin. As soon as pregnancy had been confirmed, intravenous immunoglobulin was administered at a dose of 300 mg/kg bodyweight, and infusions were repeated at three-weekly intervals until the 16th-17th week of pregnancy. RESULTS: Pregnancy proceeded beyond the first trimester in 34 of the patients (89.4%), and 31 patients (81.4%) gave birth to healthy infants at 37 to 42 weeks' gestation. CONCLUSIONS: Although the results are promising, randomized placebo-controlled trials are necessary to exclude the influence of other factors (e.g. intense obstetric supervision and psychological factors) on pregnancy outcome and confirm the effectiveness of intravenous immunoglobulin in patients with recurrent spontaneous abortions and antiphospholipid antibodies.

Immunohistochemical localization of tissue inhibitor of metalloproteinases-2 (TIMP-2) in first trimester human placental decidua.

BACKGROUND: Matrix metalloproteinases have been shown to play an important role both in the invasive growth of malignant tumors and in human placentation. However, unlike tumor cell invasion, cytotrophoblast invasion is strictly controlled in its extent. Tissue inhibitors of metalloproteinases (TIMP) may play an important role in the modulation of cytotrophoblast growth into maternal tissue. STUDY DESIGN: We have undertaken an immunohistochemical study of the distribution of TIMP-2 in the decidua of first trimester human pregnancy. RESULTS: Moderate to strong staining for TIMP-2 was found in decidual stromal cells and the walls of blood vessels in all cases. No unequivocal staining of decidual leukocytes was seen. CONCLUSION: These findings suggest that TIMP-2 secretion in first trimester human decidua is confined to certain cell populations. Decidual stromal cells are probably an important source of TIMP and may contribute to the regulation of human cytotrophoblast invasion in vivo.

The distribution of tissue inhibitor of metalloproteinases-2 (TIMP-2) in the human placenta.

Matrix metalloproteinases (MMPs) secreted by human cytotrophoblasts are crucial for the invasion of the placental bed by these cells. The invasive growth of the trophoblast is similar to that of malignant tumours in many respects, but, unlike the latter, it is strictly controlled. Tissue inhibitors of metalloproteinases (TIMPs) have been postulated to play a role in the control of trophoblast invasion. In this immunohistochemical study, the distribution of TIMP-2 in the human placenta was investigated. In first trimester placenta, the cytotrophoblasts in columns exhibited strong cytoplasmic staining for TIMP-2. Villous cytotrophoblasts exhibited staining of moderate intensity with accentuation at the cell membrane, especially at the interfaces with the syncytiotrophoblast and the villous stroma. Staining of the cytoplasm and apical border of the syncytiotrophoblast was weak and focal. In term placenta, the few cytotrophoblasts present exhibited a staining pattern similar to that of the cytotrophoblasts in first trimester placenta, and there was marked linear staining of the syncytiotrophoblast at the interface with the stroma. Because it is the first trimester cytotrophoblast columns that invade the placental bed, the results demonstrate that the strongest immunoreactivity for TIMP-2 in the trophoblast is found in cells that are known to produce MMPs and exhibit an invasive growth pattern. These findings indicate that TIMP-2 may be involved in autoregulation of the invasive growth of the trophoblast.

[Diagnosis and therapy of fetal alloimmune thrombocytopenia]. / Diagnostik und Therapie der fetalen Alloimmunthrombozytopenie.

In fetal alloimmune thrombocytopenia, maternal IgG antibodies directed against platelets pass into the fetal circulation and lead to the destruction of fetal platelets. Fetal thrombocytopenia is usually first noted postnatally, but the maternal alloantibodies may lead to severe fetal haemorrhage in utero in the second or, more commonly, third trimester. Platelet-specific antibodies appear to play the major role in the pathogenesis of fetal alloimmune thrombocytopenia. Antenatal serological diagnosis is complicated by the fact that no platelet-specific alloantibodies are detectable in untreated maternal serum in about 20% of cases. Even when antibodies are detected, repeated estimation of the titre in the mother gives no indication of the severity of the fetal thrombocytopenia. Therefore, when the diagnosis of fetal alloimmune thrombocytopenia is suspected, it should be confirmed and subsequently monitored by cordocentesis. The intrauterine transfusion of compatible platelets and the administration of high dose IgG infusions to the mother and/or fetus are currently being used as approaches to treatment. Despite advances in the antenatal diagnosis and therapy of fetal alloimmune thrombocytopenia, the clinical effects on the fetus remain unpredictable.

Comparative analysis of the immunophenotypes of decidual and peripheral blood large granular lymphocytes and T cells during early human pregnancy.

PROBLEM: The functional role of the leukocytes in the decidual is not clear. They may regulate the maternal immune response to the fetal allograft. However, the factors controlling maternal and fetal communication have not yet been identified. METHOD: A comparative analysis of the phenotypes of decidual and peripheral blood large granular lymphocytes (LGLs) and T lymphocytes in early human pregnancy was performed on decidual tissue and blood samples obtained from ten patients at therapeutic abortion. RESULTS: Whereas most of the decidual LGLs were found to have a CD56bright++ phenotype, most of the peripheral blood NK cells (90%) showed the classical CD56dim+ phenotype, and only a small proportion were CD56bright+ cells. Another striking difference was found in the expression of very late antigen 1 (VLA-1, CD49a): Almost all the decidual CD56bright++ LGLs, but virtually none of the peripheral blood CD56+ NK cells expressed this antigen. Further differences were found in the expression of CD16, CD44, CD45RA, CD54, and CD57. There were also differences in phenotype between T cells derived from decidual tissue and those derived from peripheral blood. Approximately 31% of the CD3+ decidual T cells expressed VLA-1, but this antigen was virtually absent on peripheral blood T cells. A further difference was seen in the expression of HLA-DR. This activation antigen was found on 32 +/- 13% of the decidual T cells but only 8 +/- 5% of the peripheral blood T cells. Additionally, the proportion of cells expressing CD38 was higher among decidual than peripheral blood T cells. CONCLUSION: The findings suggest that both decidual LGLs and a subset of decidual T cells are activated and possibly play a role in the control of trophoblast growth and placental development.

Expression of the p53 tumour suppressor gene in human placenta: an immunohistochemical study.

Since human trophoblast undergoes extensive proliferation and exhibits invasive growth comparable to that of a malignant tumour, human placenta at various different stages of gestation was investigated immunohistochemically with the monoclonal antibody Ab-6 for expression of the p53 tumour suppressor gene. p53 protein was detected in the nuclei of a few trophoblastic cells, almost all belonging to the cytotrophoblast and only very few to the syncytiotrophoblast, in nearly all specimens investigated (first trimester 10/10, second trimester 5/5, third trimester 4/5). First trimester trophoblast exhibited increased expression of p53 protein in the juxtastromal areas of cytotrophoblast cell islands and columns, that is, in areas where high proliferative activity and increased expression of the epidermal growth factor receptor have been described in the literature. Staining was also occasionally seen in trophoblast invading the myometrium. It is most likely that immunohistochemically detectable expression of p53 protein in the trophoblast is due not to mutation of the gene, as in malignant tumours, but rather to up-regulation of the p53 tumour suppressor gene, which could be a mechanism for controlling trophoblast proliferation.

A new formula for prenatal ultrasonographic weight estimation in extremely preterm fetuses.

A new formula for the prenatal estimation of the weight of extremely preterm fetuses was derived using ultrasound measurements and birth weights of 73 premature infants delivered before 30 completed weeks of pregnancy and weighing between 400 and 1,680 g at birth. The actual birth weight lay within +/- 15% of the estimated weight calculated with this formula in 92% of the cases. Preliminary testing of the reliability of the formula was performed on a further test group of 19 nonselected cases. The formula developed in this study offers a reliable and simple method of prenatal estimation of fetal weight between 23 and 30 weeks of gestation.

[Functional significance of CD56 large granular lymphocytes in the decidua in early pregnancy in the human]. / Zur funktionellen Bedeutung der CD56++ Large Granular Lymphocytes (LGL) in der Dezidua der Frühschwangerschaft beim Menschen.

OBJECTIVE: The study was undertaken to characterize the large granular lymphocytes (LGL) found in large numbers in the decidua of early pregnancy, in order to investigate their functional significance in placentation. METHODS: The LGL were investigated by immunohistochemical, flow cytometric and molecular biological techniques. RESULTS AND CONCLUSIONS: The LGL resemble a small subpopulation of Natural Killer cells (NK-cells) in the peripheral blood, express activation antigens and produce cytokines that may have a regulatory/modulatory influence on trophoblast growth.

A new insufflation needle with a special optical system for use in laparoscopic procedures.

A new insufflation needle with a special optical system consisting of a transparent, conical tip, to which an endoscope can be attached, allows perforation of the abdominal wall under direct vision. A video camera can be attached to the instrument, so that its progress through the abdominal wall can be observed on a monitor. The danger of damage to vessels and intra-abdominal organs associated with blind insertion of the insufflation needle is thus avoided. There is also no risk of insufflation of the properitoneal space because the exact position of the needle tip is known. Use of this new instrument could further improve the safety of laparoscopic procedures.