Biomedical subjects

Antonis Makrigiannakis

Publications and source records attributed to Antonis Makrigiannakis.

28 records · Page 2Linked to original sources

PubMed2003

Corticotropin-releasing hormone (CRH) and immunotolerance of the fetus.

The hypothalamic neuropeptide corticotropin-releasing hormone (CRH) is produced by several tissues of the female reproductive system, including the endometrial glands and decidualized stroma, as well as the trophoblast, syncytiotrophoblast, and placental decidua. CRH is also secreted at inflammatory sites and possesses potent pro-inflammatory properties influencing both innate and acquired immune processes. Recent experimental findings show that uterine CRH participates in local immune phenomena associated with early pregnancy, such as differentiation of endometrial stroma to decidua and protection of the fetus from the maternal immune system. CRH induces the expression of apoptotic Fas ligand (FasL) on invasive extravillous trophoblast and maternal decidual cells at the fetal-maternal interface. Furthermore, CRH increases the apoptosis of activated T lymphocytes through FasL induction, participating in the processes of both implantation and early pregnancy tolerance.

Animals↗

PubMed2003

Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer.

BACKGROUND: Although tumor-infiltrating T cells have been documented in ovarian carcinoma, a clear association with clinical outcome has not been established. METHODS: We performed immunohistochemical analysis of 186 frozen specimens from advanced-stage ovarian carcinomas to assess the distribution of tumor-infiltrating T cells and conducted outcome analyses. Molecular analyses were performed in some tumors by real-time polymerase chain reaction. RESULTS: CD3+ tumor-infiltrating T cells were detected within tumor-cell islets (intratumoral T cells) in 102 of the 186 tumors (54.8 percent); they were undetectable in 72 tumors (38.7 percent); the remaining 12 tumors (6.5 percent) could not be evaluated. There were significant differences in the distributions of progression-free survival and overall survival according to the presence or absence of intratumoral T cells (P<0.001 for both comparisons). The five-year overall survival rate was 38.0 percent among patients whose tumors contained T cells and 4.5 percent among patients whose tumors contained no T cells in islets. Significant differences in the distributions of progression-free survival and overall survival according to the presence or absence of intratumoral T cells (P<0.001 for both comparisons) were also seen among 74 patients with a complete clinical response after debulking and platinum-based chemotherapy: the five-year overall survival rate was 73.9 percent among patients whose tumors contained T cells and 11.9 percent among patients whose tumors contained no T cells in islets. The presence of intratumoral T cells independently correlated with delayed recurrence or delayed death in multivariate analysis and was associated with increased expression of interferon-gamma, interleukin-2, and lymphocyte-attracting chemokines within the tumor. The absence of intratumoral T cells was associated with increased levels of vascular endothelial growth factor. CONCLUSIONS: The presence of intratumoral T cells correlates with improved clinical outcome in advanced ovarian carcinoma.

Adult↗

PubMed2003

Uterine and embryonic trophoblast CRH promotes implantation and maintenance of early pregnancy.

Epithelial cells of human endometrium and differentiated endometrial stromal cells express the corticotropin-releasing hormone (CRH) gene. CRH is also produced by the human placental cytotrophoblast. Endometrial and placental CRH is under the endocrine control of gonadal steroids as well as under an autocrine/paracrine regulation by prostanoids and interleukins. Human endometrium, myometrium and placenta also express the relevant receptors. Invasive trophoblasts promote apoptosis of activated Fas-expressing human T lymphocytes, an effect potentiated by CRH and inhibited by the CRH type 1 antagonist, antalarmin. Female rats treated with antalarmin during the first 6 days of gestation had a dose-dependent decrease of implantation sites and live embryos, and significantly decreased endometrial FasL expression. Our data suggest important physiological roles of endometrial and placental CRH in the regulation of decidualization, blastocyst implantation, and early maternal tolerance.

Animals↗

PubMed2003

Roles of reproductive corticotropin-releasing hormone.

Corticotropin-releasing hormone (CRH), the principal regulator of the hypothalamic-pituitary-adrenal axis, as well as its receptors, have been identified in most female reproductive tissues, including the uterus, placenta, and ovary. Endometrial CRH may participate in decidualization, implantation, and early maternal tolerance; placental CRH may participate in the physiology of pregnancy and the onset of parturition, and ovarian CRH may participate in follicular maturation, ovulation, and luteolysis. The hypercortisolism of the latter half of pregnancy can be explained by increased levels of placental CRH in plasma. This hypercortisolism is followed by a transient suppression of hypothalamic CRH secretion in the postpartum period, which may explain the blues or depression and autoimmune phenomena frequently observed during this period.

Animals↗

PubMed2003

Endometrial pinopodes and uterine receptivity.

The human endometrium is an extremely sensitive target for steroid hormones. During the menstrual cycle, this tissue undergoes dynamic changes which are reflected on the surface morphology of the epithelium, and which can be followed by scanning electron microscopy. The morphological changes peak at the midsecretory phase, with the formation of the so-called pinopodes. Increasing evidence suggests that these pinopodes are accurate markers for endometrial receptivity, and their detection may be of high clinical utility for the preparation of endometrium before embryo transfer.

Biomarkers↗

PubMed2003

Molecules in blastocyst implantation. Role of matrix metalloproteinases, cytokines and growth factors.

Initiation of implantation is due not to passive growth pressure but to an active biochemical process that requires a blastocyst to interact with a carefully prepared endometrium. This versatile and dynamic process requires a variety of different molecules secreted by human trophoblast as well as endometrial cells that play a unique role. Several molecules have been shown to regulate, by an autocrine and paracrine manner, the cross-talk between the implanting blastocyst and the endometrial epithelium. Particularly, the molecular dialogue involves either cell-to-cell or cell-to-extracellular matrix interactions, mediated by matrix metalloproteinases, cytokines and growth factors. The present overview of the literature reports on the most significant molecules involved in the implantation process and describes the mechanisms of interaction and control. Since impaired blastocyst implantation is a significant cause of natural and in vitro fertilization pregnancy failure, a better understanding of the aforementioned molecular dynamics would be useful in improving the chance of viable pregnancy.

Abortion, Habitual↗

PubMed2003

Synchronous expression of pinopodes and alpha v beta 3 and alpha 4 beta 1 integrins in the endometrial surface epithelium of normally menstruating women during the implantation window.

OBJECTIVE: To use histology, scanning electron microscopy (SEM) and immunohistochemistry to examine the expression of pinopodes, and alpha v beta 3 and alpha 4 beta 1 integrins in the same endometrial biopsies. STUDY DESIGN: A prospective observational study. Fifteen consecutive regularly menstruating women with normal hormone profiles were followed for detection of ovulation and then biopsied twice, on postovulatory days luteinizing hormone (LH) +6 and LH +8. Measurements included abundance and development stage of pinopodes and a semiquantitative assessment of intensity of antibody staining for integrins. RESULTS: All biopsies observed under light microscopy showed an in-phase endometrium. Pinopodes were found developing mostly on day LH +6 and were fully developed on day LH +8. The expression of alpha v beta 3 dimer increased significantly from day LH +6 to day LH +8, while alpha 4 beta 1 dimer did not show any significant change during the same period. Fully developed pinopodes and strong intensity of alpha v beta 3 integrin were the most common findings. CONCLUSION: These results indicate a coordinated, synchronous change in morphology and adhesion molecule expression of endometrial epithelial cells on day LH +8 of a normal menstrual cycle.

Adult↗

PubMed2002

Syncytiotrophoblast is a barrier to maternal-fetal transmission of herpes simplex virus.

Herpes simplex virus (HSV)-1 has been discovered in placental tissue from spontaneous miscarriages, but reports of transplacental transmission and fetal infection are extremely rare. Previously, we demonstrated that the villous syncytiotrophoblast, which forms a continuous layer between the maternal and fetal circulation, is resistant to HSV entry. Here, we tested our hypothesis that the villous syncytiotrophoblast prevents transplacental transmission of HSV secondary to decreased expression of HSV entry mediators (HveA, HveB, and HveC). In addition, we investigated the ability of HSV to infect extravillous trophoblast cells, which mediate placental attachment to the uterine wall, and the expression of HSV receptors in these cells. We performed fluorescence-activated cell sorting (FACS) analyses and immunostaining to demonstrate that HveA, HveB, and HveC were not expressed in third-trimester villous trophoblast cells. Consequently, villous explants obtained from third-trimester placentas were resistant to infection by a recombinant HSV-1 vector, HSV-1 KOS, but approximately 20% of mesenchymal cells within the villous core were infected when villous explants were pretreated with trypsin to disrupt the villous trophoblast layer. Conversely, FACS analysis and immunostaining demonstrated that extravillous trophoblast cells expressed HveA, HveB, and HveC, and these cells were efficiently infected by HSV vectors. Infection of extravillous trophoblast cells by HSV-1 was not reduced when the cells were pretreated with an antibody against HveA but was partially reduced when the cells were pretreated with antibodies directed against HveB and HveC. Thus, the decreased expression of herpesvirus entry mediators in villous syncytiotrophoblast prevents placental villous infection, thereby limiting maternal-fetal transmission of HSV.

Cell Separation↗

PubMed2002

Involvement of human PECAM-1 in angiogenesis and in vitro endothelial cell migration.

Platelet endothelial cell adhesion molecule (PECAM)-1 has been implicated in angiogenesis, but a number of issues remain unsettled, including the independent involvement of human PECAM-1 (huPECAM-1) in tumor angiogenesis and the mechanisms of its participation in vessel formation. We report for tumors grown in human skin transplanted on severe combined immunodeficiency mice that antibodies against huPECAM-1 (without simultaneous treatment with anti-VE-cadherin antibody) decreased the density of human, but not murine, vessels associated with the tumors. Anti-huPECAM-1 antibody also inhibited tube formation by human umbilical vein endothelial cells (HUVEC) and the migration of HUVEC through Matrigel-coated filters or during the repair of wounded cell monolayers. The involvement of huPECAM-1 in these processes was confirmed by the finding that expression of huPECAM-1 in cellular transfectants induced tube formation and enhanced cell motility. These data provide evidence of a role for PECAM-1 in human tumor angiogenesis (independent of VE-cadherin) and suggest that during angiogenesis PECAM-1 participates in adhesive and/or signaling phenomena required for the motility of endothelial cells and/or their subsequent organization into vascular tubes.

Animals↗

PubMedDate not supplied

Stress neuropeptides in the human endometrium: paracrine effects on cell differentiation and apoptosis.

Human endometrium exhibits characteristics of a neuroendocrine-like stress organ in addition to its classical role as the main target of ovarian steroid hormones. Indeed, the epithelial cells of human endometrium express the stress-associated neuropeptide genes corticotropin-releasing hormone (CRH), proopiomelanocortin, proenkephalin and prodynorphin. Furthermore, endometrium stroma cells also express CRH when they differentiate into decidual cells. Multiple lines of evidence suggest that the stress-associated neuropeptides of human endometrium are under the endocrine control of gonadal steroids as well as under an autocrine/paracrine regulation by prostanoids and interleukins. Endometrial stress-associated neuropeptides appear to exert their biological effect locally, i.e. within the uterus since human endometrium and myometrium also express the relevant receptors. More specifically, recent data suggest that endometrial CRH participates in the regulation of intrauterine inflammatory processes taking place in early pregnancy including stroma decidualization, blastocyst implantation and early maternal tolerance. Similarly, endometrial opioids participate in the regulation of uterine tissue remodeling via their effect on endometrial cell apoptosis. Thus, endometrial stress neuropeptides act as paracrine regulators of uterine cell differentiation and tissue remodeling as well as modulators of local immune responses.

Journal Article↗