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ABSTRACT: Platinum-resistance is the most crucial problem for treatment of ovarian cancer. There is a clinical need for new treatment strategies which overcome platinum resistance. As survival is strongly influenced by immunological parameters, immunotherapeutic strategies appear promising. Therefore a better understanding of the interaction between ovarian tumour cells and cells of the immune system is a necessary prerequisite. In the present study we aimed to enlighten the interactions between platinum resistant and platinum sensitive ovarian cancer cells and natural-killer (NK)-cells. Modified FATAL assay was used for determining the killing efficiency of NK-cells for the parental A2780 cells and the cis-platinum resistant A2780cis human ovarian cancer cells. Expression of pro- and anti-apoptotic genes as well as ligands involved in NK-cell receptor recognition were analysed by RT-PCR and flow cytometric analysis. The efficiency of NK mediated cell lysis differs between A2780 cells and the cis-platinum-resistant A2780cis cells. A2780cis cells are less accessible for NK-cell mediated killing. Based on this observation we characterized the molecular basis for resistance mechanisms. Besides an increase in anti-apoptotic genes (especially CIAP-1 and -2) that probably render A2780cis cells more resistant against apoptosis an increased amount of soluble MICA/B seems to be responsible for the lower killing rate of platinum-resistant A2780cis cells compared to their parental A2780 cells.
International Journal of Oncology 03/2013; · 2.40 Impact Factor
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ABSTRACT: PURPOSE: Of more than one million global cases of breast cancer diagnosed each year, a high percentage are characterized as triple-negative, lacking the oestrogen, progesterone and Her2/neu receptors. The incidence exceeds the incidence of malignancies like CML by far. Lack of effective therapies, younger age at onset and early metastatic spread have contributed to the poor prognosis and outcomes associated with these malignancies. METHODS: Here, we investigate the ability of the PI3K/AKT inhibitor AEZS 126 to selectively target the triple-negative breast cancer (TNBC) cell proliferation and survival in vitro by MTT-assays and FACS-based analysis. Furthermore, the mechanism of cytotoxicity is analysed by FACS-based assays and Western blots. RESULTS: AEZS 126 showed good anti-tumour activity in in vitro models of TNBC as well as in MCF-7 cells. Main mechanism of cytotoxicity seems to be programmed cell death after an incubation time of 72 h, which could be abrogated by co-incubation with z-VAD-fmk in MCF-7 and MDA-MB468 cells. In HCC1806 cells, addition of necrostatin-1 has only slightly protective effects, but in HCC1937 cells, the addition of necrostatin-1 has the same protective effect as co-incubation with z-VAD-fmk, and this observation argues for cell death caused by apoptosis and necroptosis in this cell line. CONCLUSION: We demonstrated the highly efficient anti-tumour activity of AEZS 126 in in vitro models of TNBC. Due to the good anti-tumour activity and the expected favourable toxicity profile, AEZS 126 in combination with chemotherapy seems to be a promising candidate for clinical testing in TNBC especially in the basal-like subgroup of TNBC.
Journal of Cancer Research and Clinical Oncology 02/2013; · 2.56 Impact Factor
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ABSTRACT: Breast cancer is the most common cancer among women worldwide. Every year, nearly 1.4 million new cases of breast cancer are diagnosed, and about 450.000 women die of the disease. Approximately 15-25% of breast cancer cases exhibit increased quantities of the trans-membrane receptor tyrosine kinase human epidermal growth factor receptor 2 (HER2) on the tumor cell surface. Previous studies showed that blockade of this HER2 proto-oncogene with the antibody trastuzumab substantially improved the overall survival of patients with this aggressive type of breast cancer. Recruitment of natural killer (NK) cells and subsequent induction of antibody-dependent cell-mediated cytotoxicity (ADCC) contributed to this beneficial effect. We hypothesized that antibody binding to HER2-positive breast cancer cells and thus ADCC might be further improved by synergistically applying two different HER2-specific antibodies, trastuzumab and pertuzumab. We found that tumor cell killing via ADCC was increased when the combination of trastuzumab, pertuzumab, and NK cells was applied to HER2-positive breast cancer cells, as compared to the extent of ADCC induced by a single antibody. Furthermore, a subset of CD44(high)CD24(low)HER2(low) cells, which possessed characteristics of cancer stem cells, could be targeted more efficiently by the combination of two HER2-specific antibodies compared to the efficiency of one antibody. These in vitro results demonstrated the immunotherapeutic benefit achieved by the combined application of trastuzumab and pertuzumab. These findings are consistent with the positive results of the clinical studies, CLEOPATRA and NEOSPHERE, conducted with patients that had HER2-positive breast cancer. Compared to a single antibody treatment, the combined application of trastuzumab and pertuzumab showed a stronger ADCC effect and improved the targeting of breast cancer stem cells.
American journal of cancer research. 01/2013; 3(2):211-220.
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ABSTRACT: Ovarian cancer is generally thought of as a cancer with poor prognosis. However, prognostic appraisal of the disease is based on tumor stages, surgical features or sensibility towards platinum-based chemotherapy. There are data that also grant immunological parameters such as CD8(+) T-lymphocyte-(CD8 T-cell) infiltration in tumor tissue, a prognostic role. Macrophage migration-inhibitory factor (MIF) has been described as a tumor-derived protein which allows tumor cell immune escape from antitumoral host natural killer (NK) - and CD8 T-cells. This immune escape is functionally based on down-regulation of the receptor natural killer group 2D (NKG2D). We here report that the levels of the MIF protein which is known to be secreted in ascites and serum of patients with ovarian cancer, not only seems to correlate with common prognostic parameters such as tumor stage or platinum sensitivity, but also with CD8 T- and NK-cell infiltration in tumor tissue. We therefore believe that MIF may play a suppressive role in the host antitumor immune response, which may have a negative impact on the course of the disease. The fact that MIF levels in serum of patients at primary diagnosis correlate with platinum sensibility supports the hypothesis that serum MIF levels should be evaluated as a parameter reflecting tumor sensibility towards chemotherapy in early stages of the disease.
Anticancer research 12/2012; 32(12):5233-8. · 1.73 Impact Factor
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ABSTRACT: Abstract Pregnancies that occur after infertility treatment, particularly after assisted reproduction, constitute high-risk pregnancies. Occurrences of conditions such as high blood pressure, preeclampsia, growth retardations and bleeding are higher in comparison with the norm of spontaneously entered pregnancies. The rate of premature births and the frequency of intrauterine deaths are much higher than the average for all pregnancies. Furthermore, pregnancies resulting from in-vitro fertilisation (IVF) have significantly higher rates of requiring induced labour or caesarean section. However, it is to be assumed that these complications and unfortunate developments are not caused by extracorporeal fertilisation itself, but rather are due to the frequency of multiples and to the risk factors of the women involved. These women are, on average, older and there are often more problems with cycle irregularities, uterine anomalies and obesity than in the total collective of all pregnancies. The methods of modern reproductive medicine often bring a higher rate of multiple pregnancies. The clinical problem of multiple pregnancies is, above all, the raised rate of premature births and intrauterine growth retardations that contribute to the significantly higher rate of morbidity and mortality for these children. The slightly higher rate of congenital defects after IVF and intracytoplasmic sperm injection (ICSI) are also attributed more to the risk profile of the parents and less to the techniques themselves. The most important and easy-to-avoid complication is the multiple pregnancy, and it should be our goal to lower this rate even further.
Journal of Perinatal Medicine 08/2012; · 1.70 Impact Factor
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ABSTRACT: The success of artificial reproductive techniques not only depends on the quality of oocytes and spermatozoa but also on the receptivity of the endometrium. The aim of this study was to assess the value of measurement of endometrial volume by three-dimensional (3D) in comparison to 2D-ultrasound in the prediction of implantation in women having transfer of cryopreserved embryos.
One hundred and eight couples were included in this prospective study. All patients underwent the IVF or ICSI program and had transfer of cryopreserved embryos. Sixty-eight transfers were done in a spontaneous cycle and 40 in an artificial cycle. Endometrial thickness, pattern and three-dimensional volume were measured immediately before embryo transfer.
Twenty clinical pregnancies were achieved (PR 18.5 % per transfer), the PR being similar in spontaneous (22.1 %) and artificial (12.5 %, ns) cycles. Three to five days after ovulation (spontaneous cycles) or after the endometrium reached a thickness of at least 8 mm (artificial cycles), a median of three embryos were replaced. In spontaneous cycles, there were no significant differences in endometrial thickness or volume between pregnant (11.9 mm, 2.9 ml) and non-pregnant women (10.7 mm, 3.4 ml). In artificial cycles, the endometrial volume (3.9 vs. 2.5 ml, p < 0.05), but not endometrial thickness (10.7 vs. 10.2 mm, ns) was significantly higher in pregnant than in non-pregnant women.
In artificial cycles, a low endometrial volume is associated with a poor likelihood of implantation. Endometrial volume measured by 3D-ultrasound is an objective parameter to predict endometrial receptivity.
Archives of Gynecology 04/2012; 286(2):517-23. · 0.91 Impact Factor
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Jörg B Engel,
Theresa Martens,
Jens C Hahne,
Sebastian F M Häusler,
Mathias Krockenberger,
Sabine Segerer,
Antonia Djakovic,
Susanne Meyer, Johannes Dietl,
Jörg Wischhusen,
Arnd Honig
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ABSTRACT: Lobaplatin as a single agent and in combination with tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is investigated in in-vitro models of p53-negative triple-negative breast cancers (TNBCs) and compared with a model of oestrogen receptor-positive p53-positive breast cancer. In addition, the induction of programmed cell death by lobaplatin is further explored. By using cell viability assays and western blotting, the cytotoxic effects of lobaplatin alone and in combination with TRAIL are compared with cisplatin in HCC 1806, HCC 1937, and MCF 7 cells. The multicaspase inhibitor z-VAD-fmk and necrostatin, an inhibitor of necroptosis, are used to demonstrate the mechanism of cell death caused by lobaplatin. Lobaplatin displayed antitumour activity in all three cell lines, which increased time dependently. Cotreatment of lobaplatin and TRAIL induced an increase in cytotoxicity by 30-50% in the different cell lines. The pan-caspase inhibitor z-VAD-fmk as well as necrostatin could weaken but not abolish the cytotoxic effect of lobaplatin and cisplatin. Lobaplatin showed substantial cytotoxic effects in two in-vitro models of p53-mutated TNBC. Cotreatment with TRAIL and platinum agents resulted in increased antitumour activity in the TNBC cell lines investigated. Cell death subsequent to treatment with cisplatin and lobaplatin occurred because of apoptosis. However, caspase-independent mechanisms of programmed cell death were also involved. It was also demonstrated that platinum compounds could induce necroptosis, although to a minor extent.
Anti-cancer drugs 04/2012; 23(4):426-36. · 2.23 Impact Factor
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ABSTRACT: The female reproductive tract represents a great challenge to the residing immune cells: Concomitantly, those immune-competent cells have to provide tolerogenic mechanisms favoring the development of a successful pregnancy while permitting protection against harmful pathogens. The predominant cell population facing this "double edged" regulatory capacity within the reproductive tract is that of dendritic cells (DC). There is evidence that DC represent a highly adaptive cell type, which can either be transformed in an immune-stimulatory phenotype after exposure to inflammatory or infectious signals, or in an immune inhibitory phenotype preventing T cell activation when located in an adequate antiinflammatory microenvironment. Thus, this review highlights this two-faced character of DC focusing on their morphology and function within the human reproductive tract and especially during pregnancy.
Current pharmaceutical biotechnology 02/2012; 13(8):1378-84. · 3.40 Impact Factor
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ABSTRACT: A case of a papillary squamotransitional cell carcinoma (PSTCC) of the vagina with a follow-up of 3 years is presented here. The characteristics of this case support a squamous rather than urothelial origin of this rare entity. Unlike its counterparts in the cervix uteri, the clinical behavior of vaginal PSTCC is more favorable than squamous cell carcinoma. Histological and clinical features are compared to those of previously described cases of vaginal and cervical PSTCC.
Journal of Obstetrics and Gynaecology Research 09/2011; 37(12):1851-5. · 0.94 Impact Factor
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Sebastian F M Häusler,
Itsaso Montalbán del Barrio,
Jenny Strohschein,
P Anoop Chandran,
Jörg B Engel,
Arnd Hönig,
Monika Ossadnik,
Evi Horn,
Birgitt Fischer,
Mathias Krockenberger,
Stefan Heuer,
Ahmed Adel Seida,
Markus Junker,
Hermann Kneitz,
Doris Kloor,
Karl-Norbert Klotz, Johannes Dietl,
Jörg Wischhusen
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ABSTRACT: The ectonucleotidases CD39 and CD73 degrade immune stimulatory ATP to adenosine that inhibits T and NK cell responses via the A(2A) adenosine receptor (ADORA2A). This mechanism is used by regulatory T cells (T(reg)) that are associated with increased mortality in OvCA. Immunohistochemical staining of human OvCA tissue specimens revealed further aberrant expression of CD39 in 29/36 OvCA samples, whereas only 1/9 benign ovaries showed weak stromal CD39 expression. CD73 could be detected on 31/34 OvCA samples. While 8/9 benign ovaries also showed CD73 immunoreactivity, expression levels were lower than in tumour specimens. Infiltration by CD4(+) and CD8(+) T cells was enhanced in tumour specimens and significantly correlated with CD39 and CD73 levels on stromal, but not on tumour cells. In vitro, human OvCA cell lines SK-OV-3 and OaW42 as well as 11/15 ascites-derived primary OvCA cell cultures expressed both functional CD39 and CD73 leading to more efficient depletion of extracellular ATP and enhanced generation of adenosine as compared to activated T(reg). Functional assays using siRNAs against CD39 and CD73 or pharmacological inhibitors of CD39, CD73 and ADORA2A revealed that tumour-derived adenosine inhibits the proliferation of allogeneic human CD4(+) T cells in co-culture with OvCA cells as well as cytotoxic T cell priming and NK cell cytotoxicity against SK-OV3 or OAW42 cells. Thus, both the ectonucleotidases CD39 and CD73 and ADORA2A appear as possible targets for novel treatments in OvCA, which may not only affect the function of T(reg) but also relieve intrinsic immunosuppressive properties of tumour and stromal cells.
Cancer Immunology and Immunotherapy 06/2011; 60(10):1405-18. · 3.70 Impact Factor
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Johannes Dietl
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ABSTRACT: Endometrial cancer has in the meantime become the most frequent malignant tumor of the female genital tract. With a 5-year survival rate of 82% for all stages and more than 90% for the most common stage I, it is a carcinoma with an excellent prognosis. Against this background and in light of the results of recent studies, the value of extensive surgical staging including pelvic and para-aortic lymphadenectomy beyond the standard therapy of hysterectomy with bilateral adnexectomy must be questioned.
International Journal of Gynecological Cancer 04/2011; 21(3):507-10. · 1.65 Impact Factor
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ABSTRACT: We analyzed the anti-tumor effect and the mechanism of action of perifosine, an orally active alkylphospholipid AKT inhibitor using in vitro models of human ovarian cancer.
Ovarian cancer cells OAW42, PA-1, SKOV3, and A2780 as well as platinum resistant A2780cis cells were incubated with increasing concentrations of perifosine, with and without multi-caspase inhibitor zVAD-FMK. The effect of a combined treatment with cisplatin and perifosine was investigated in OAW42, SKOV3, A2780 and A2780cis cells. Cytotoxic effects of perifosine were analyzed using crystal violet staining, FACS analysis of DNA content as well as Annexin V/propidium iodide-double staining. The effect of perifosine on AKT phosphorylation was determined by Western blotting.
Perifosine displayed anti-tumor activity in all five cell lines, which increased time-dependently. While IC(50) values at 24 h were >40 μM, IC(50) values after 72 h decreased to 10 μM in OAW42 and 25 μM in PA-1 and 30 μm in SKOV3 cells. In platinum resistant A2780cis cells perifosine showed good antiproliferative activity (IC(50) = 3 μm). At adequate doses, perifosine increased cytotoxic effects of cisplatin in OAW42, A2780 and A2780cis cell. Anti-tumor activity of perifosine was not confined to a specific phase of the cell cycle and could not be decreased by the pan-caspase inhibitor zVAD-FMK. AnnexinV/propidium iodide-double staining after treatment with perifosine was not indicative of classical apoptosis. AKT phosphorylation was dose-dependently inhibited by perifosine.
Perifosine showed substantial cytotoxic effects in various in vitro models of ovarian cancer. Since anti-tumor effects were not confined to platinum-sensitive cells perifosine seems to be a good candidate for clinical studies in patients especially with platinum resistant ovarian cancer.
Archives of Gynecology 03/2011; 283(3):603-10. · 0.91 Impact Factor
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Nature Reviews Cancer 03/2011; 11(3):227; author reply 227. · 29.54 Impact Factor
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ABSTRACT: During the process of fertilization, human spermatozoa are confronted with phagocytic cells of the female reproductive tract. Part of this host mucosal barrier are immature dendritic cells (DCs), which play an important role in the defense of invading microbial pathogens. In the present study, we investigated the potential interaction of spermatozoa with DCs and raised the question of whether seminal plasma impacts the interaction of DCs with spermatozoa or pathogenic microbes.
Flow cytometry and microscopy detected a strong association between spermatozoa and human monocyte-derived DCs, which was partly mediated by the DC-specific adhesion receptor, DC-specific intercellular adhesion molecule 3-grabbing non-integrin (DC-SIGN). Coincubation assays also showed that capture of spermatozoa by DCs was blocked in the presence of increasing concentrations of seminal plasma. This inhibitory effect of seminal plasma was accompanied by altered DC maturation, revealed by flow cytometry analysis of maturation-specific DC surface markers. Phalloidin-staining of the DC cytoskeleton further visualized an impact of seminal plasma on DC morphology. To elucidate the molecular nature of the inhibitory activity of seminal plasma on sperm-DC -association, binding assays were performed in the presence of individual seminal plasma components. This approach identified specific prostaglandins-in particular, PGE₁, 19-OH-PGE₁ and PGE₂, which are present in seminal plasma at high concentrations-as likely inhibitory factors. In contrast to glass beads, the yeast Candida albicans, a common commensal organism and frequent pathogen of the genital tract, was also found to be protected from capture by DCs in the presence of seminal plasma or the specific prostaglandins.
The immunomodulatory power of seminal plasma may help spermatozoa to circumvent the attack of DCs of the female reproductive tract, thereby supporting successful fertilization. At the same time, however, such protective effects of seminal plasma may also modulate DC action during host-pathogen interactions.
Human Reproduction 02/2011; 26(5):987-99. · 4.47 Impact Factor
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ABSTRACT: Increasing evidence supports GnRH agonists to be an effective treatment to preserve ovarian function during chemotherapy, but the initial flare-up of FSH during the first week after GnRH agonist application still limits its use. The combination of GnRH agonists with GnRH antagonists might solve this problem to some extent as the addition of GnRH antagonists at least significantly reduces the FSH flare-up.
Fertility and sterility 01/2011; 95(1):452-4. · 3.97 Impact Factor
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ABSTRACT: To illustrate pitfalls in the diagnosis of endometriosis and cervical cancer.
Case report.
University hospital, department of obstetrics and gynecology.
A 45-year-old woman with menorrhagia, pelvic mass, right-sided hydronephrosis, and unexplained weight loss.
Cervical biopsies were suggestive of cervical endometriosis. Laparoscopy confirmed endometriosis. Associated pleural effusion, without cytologic signs of malignancy, was interpreted as caused by thoracic endometriosis. The patient had a transabdominal hysterectomy and unilateral salpingo-oophorectomy. Histopathologic examination confirmed endometriosis and revealed a residual tubo-ovarian abscess. After surgery, the patient developed spontaneous seropneumothorax. Pleural biopsies revealed a well-differentiated epithelial malignant pleural mesothelioma. The patient underwent hypofractionated radiation of drain sites. She is now observed in our outpatient clinic.
Steps to the correct diagnosis.
The patient had an association of cervical and pelvic endometriosis, residual tubo-ovarian abscess, and malignant pleural mesothelioma.
Usually, the simplest diagnosis explaining a complex of symptoms and clinical and diagnostic findings is the one most likely to be correct. This is an application of Occam's razor to medicine. Our case illustrates that occasionally the simplest and therefore most probable diagnosis can be wrong, and on these occasions one should consider a "third man."
Fertility and sterility 12/2010; 95(5):1787.e5-7. · 3.97 Impact Factor
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12/2010; 107(50):902; author reply 902. · 2.92 Impact Factor
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ABSTRACT: Matrix metalloproteinases (MMPs) are involved in the degradation of protein components of the extracellular matrix and thus play an important role in tumor invasion and metastasis. Their expression is related to the progression of gynecological cancers (e.g. endometrial, cervical or ovarian carcinoma). In this study we investigated the expression pattern of the 23 MMPs, currently known in humans, in different gynecological cancer cell lines.
In total, cell lines from three endometrium carcinomas (Ishikawa, HEC-1-A, AN3 CA), three cervical carcinomas (HeLa, Caski, SiHa), three chorioncarcinomas (JEG, JAR, BeWo), two ovarian cancers (BG-1, OAW-42) and one teratocarcinoma (PA-1) were examined. The expression of MMPs was analyzed by RT-PCR, Western blot and gelatin zymography.
We demonstrated that the cell lines examined can constitutively express a wide variety of MMPs on mRNA and protein level. While MMP-2, -11, -14 and -24 were widely expressed, no expression was seen for MMP-12, -16, -20, -25, -26, -27 in any of the cell lines. A broad range of 16 MMPs could be found in the PA1 cells and thus this cell line could be used as a positive control for general MMP experiments. While the three cervical cancer cell lines expressed 10-14 different MMPs, the median expression in endometrial and choriocarcinoma cells was 7 different enzymes. The two investigated ovarian cancer cell lines showed a distinctive difference in the number of expressed MMPs (2 vs. 10).
Ishikawa, Caski, OAW-42 and BeWo cell lines could be the best choice for all future experiments on MMP regulation and their role in endometrial, cervical, ovarian or choriocarcinoma development, whereas the teratocarcinoma cell line PA1 could be used as a positive control for general MMP experiments.
BMC Cancer 10/2010; 10:553. · 3.01 Impact Factor
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ABSTRACT: Extracellular adenosine exerts powerful paracrine effects on immune cells. Thus, adenosine signaling has to be strictly regulated. This is achieved by its rapid internalization or enzymatic degradation. Consequently, free adenosine is extremely difficult to measure in cell culture systems and may escape from detection by time-consuming endpoint measurements like high-performance liquid chromatography (HPLC). Therefore, we have now developed a highly sensitive assay which enables the quantification of biologically relevant extracellular adenosine via the activation of an ectopically expressed Adenosine 2a-receptor (ADORA2A) in HEK-293 reporter cells. Binding of the short-lived nucleoside to this receptor induces a cAMP-dependent signal which can be detected via a cAMP-responsive luciferase construct. Tests with exogenously added adenosine confirmed that the resulting luminescence signals correlate with the respective adenosine levels and thus allow quantitative measurements in a range from 20 nM to 80 μM free extracellular adenosine. Inhibition of adenosine uptake by dipyridamole further increased the sensitivity of the assay. We further validated our approach by quantifying the adenosine levels that are generated by regulatory T cells via ectonucleotidase-mediated cleavage of ATP. As expected, values returned to baseline when ADORA2A was inhibited. This confirmed that this new cell-based reporter assay constitutes a biologically relevant, technically easy, versatile, scalable and cost-effective approach that allows the non-radioactive quantification of adenosine as a signaling intermediate.
Journal of immunological methods 09/2010; 361(1-2):51-6. · 2.35 Impact Factor
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ABSTRACT: Inflammatory cells play a crucial role in human parturition. Different populations of leucocytes invade the reproductive tract. Numerous studies have described the decidual immune cell population in pregnant and non-pregnant endometrium. However, little is known about the presence of immune cells in human myometrium.
we herein analysed a spectrum of immune cells in human myometrium comparing tissue samples from non-pregnant (n = 8) and pregnant (n = 10) uteri. Applying immunohistochemistry with a panel of antibodies specific for T cells, monocytes, natural killer cells, B cells and antigen-presenting cells (CD4, CD8, CD14, CD15, CD16, CD19, CD56, CD68, CD83, HLA-DR, DC-Sign, mast cell tryptase), we characterized the immune cell population of human myometrium.
a significantly higher number of CD14, CD15, CD16, DC-SIGN as well as CD4-positive cells were found in myometrium of pregnant compared to non-pregnant uteri, while mast cells were significantly reduced in pregnant myometrium.
all markers found increased in pregnant myometrium indicate monocyte/macrophage lineage cells and thus suggest a possible involvement of these cells in healthy pregnancy maintenance. Monocytes/macrophages might produce a microenvironment that permits a controlled invasion of trophoblast cells into the myometrium while preventing a rejection of the semiallogenic conceptus and providing an important barrier against invading pathogenes.
American Journal Of Reproductive Immunology 09/2010; 64(3):188-96. · 2.17 Impact Factor
