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G Mor

Publications and source records attributed to G Mor.

At least 19 recordsLinked to original sources
PubMed2000

Apoptosis and apoptosis-related proteins (Fas, Fas ligand, Blc-2, p53) in lymphoid elements of human ovarian tumors.

Different types of lymphocytes have different roles in tumor suppression. Thus, their expression of apoptosis-related proteins (ARP - Fas and Fas ligand, bcl-2, p53) in lymphocytes and their apoptosis were analyzed immunohistochemically in ovarian tumors of different grades. Ovaries without oncologic disorders had few lymphocytes, mainly T cells, and no ARP. Benign cysts presented features of weak immune reaction: small lymphoid infiltration and few lymphocytes. The ARP were present in 13.7% to 23.5% of the lymphocytes, and apoptosis was rare. In borderline tumors, expansion of lymphoid infiltrates and increased density of lymphocytes resulted in a tenfold rise in total lymphocytes, reflecting intensification of the immune response. Most lymphocytes were T cells (92%) predominated by CD8+ cells that were in direct contact with tumor epithelial cells. ARP species were found in 47% to 65% of the lymphocytes, and apoptosis in 2.2%. In carcinomas with ligh lymphoid infiltration, lymphocytes were 2.5 times more abundant, and the apoptotic index as well as the number of CD20+ and CD25+ lymphocytes rose sharply, whereas bcl-2 positive lymphocytes decreased to 8% of their number in borderline tumors. In carcinomas with low lymphoid infiltration, the total lymphocyte count decreased eightfold compared to carcinomas with high lymphoid infiltration, reflecting the deep subcompensation of the lymphoid system. Few p53-positive lymphocytes were found in the carcinomas. In conclusion, we found a positive correlation between apoptosis and the numbers of CD4+ or CD8+ lymphocytes in epithelial ovarian tumors. This correlation could reflect the antitumor activity of T cells. However, the high expression of ARP studied by immune cells at the vicinity of the tumor ARP reveals the lymphoid vulnerability to apoptosis, resulting in devastation of the lymphoid tissue, and consequently in tumor progression.

Adenocarcinoma↗
PubMed1999

Estrogen and microglia: A regulatory system that affects the brain.

Sex hormones are involved in the physiological regulation of several aspects of behavior and neuroendocrine events. It has been accepted that such effects are mediated directly by steroid actions on neurons; however, new studies have shown that the glial cells are also affected by gonadal steroids. The microglia are one specialized brain glial cell type, which is a target for estrogen actions. In fact, we believe that many of the immune and nonimmune regulatory functions of microglia in the brain are influenced directly by estrogen via expression and secretion of cytokines, and growth factors by the microglia. The present review details only a section of the known aspects of microglial function, focusing mainly on nonimmune regulatory actions in the brain and their functional relationship with sex hormones. Moreover, we present evidence for the presence of estrogen receptor-beta (ERbeta) in rat microglial cells.

Animals↗
PubMed1999

Factors associated with the development of neonatal tolerance after the administration of a plasmid DNA vaccine.

A plasmid DNA vaccine encoding the circumsporozoite protein of malaria (pCSP) induces tolerance rather than immunity when administered to newborn mice. We find that this tolerance persists for >1 yr after neonatal pCSP administration and interferes with the induction of protective immunity in animals challenged with live sporozoites. Susceptibility to tolerance induction wanes rapidly with age, disappearing within 1 wk of birth. Higher doses of plasmid are more tolerogenic, and susceptibility to tolerance is not MHC-restricted. CD8+ T cells from tolerant mice suppress the in vitro Ag-specific immune response of cells from adult mice immunized with pCSP. Similarly, CD8+ T cells from tolerant mice transfer nonresponsiveness to naive syngeneic recipients. These findings clarify the cellular basis and factors contributing to the development of DNA vaccine-induced neonatal tolerance.

Animals↗
PubMed1999

FasL (CD95L, Apo1L) is expressed in the normal rat and human brain: evidence for the existence of an immunological brain barrier.

Despite the mechanical blood-brain barrier, activated T-cells can cross brain vessels. Thus, the CNS is routinely surveyed by immune competent cells; yet the healthy brain is not a target of antigen-specific immune reactions. Therefore, mechanisms must exist to prevent brain-antigen-specific T-cells from inducing immune responses. Data indicate that activated T-cells entering the CNS may undergo apoptosis rather than leaving the brain to induce immune responses. Applying RT-PCR, Western-blots, and immunocytochemistry, we have demonstrated expression of the apoptosis-inducing protein Fas ligand on astrocytes and neurons of apparently normal rat and human brains. FasL-positive astrocytes were often situated in close vicinity to cerebral blood vessels in vivo and induced apoptosis of Fas expressing Jurkat cells in vitro. We propose that similar to other immune privileged organs FasL-induced apoptosis of activated T-cells in the brain protects the tissue from self damaging immune attacks by forming an immunological brain barrier.

Animals↗
PubMed1999

The Fas/Fas-ligand system: a mechanism for immune evasion in human breast carcinomas.

Breast tumors are frequently associated with a predominantly lymphocytic infiltrate, which constitutes an immune response against the tumor. In spite of this massive infiltrate, the immune response appears to be inefficient and the tumor is able to evade it. We propose that in breast cancer, tumor escape from immunological surveillance results from the induction of apoptosis of Fas-bearing activated lymphocytes by FasL-bearing breast cancer cells. To test this proposal we studied the expression of FasL by human breast carcinomas and the MCF-7 breast cancer cell line by RT-PCR, immunohistochemistry, and Western Blot. Moreover, we describe the presence of apoptosis and Fas expression in the lymphocytic population surrounding the tumor. Strong membranous and cytoplasmic staining was detected in ductal carcinomas and hyperplastic breast tissue, but it was absent from normal breast tissue. No staining was found in normal glands in the non-tumor quadrants; however, the normal appearing ducts surrounding the carcinoma (tumor quadrant) showed intense immunoreactivity. Apoptosis was found predominantly among the lymphocytic population, as well as in the blood vessels and fibro-fatty tissue close to the tumor. Further characterization of apoptotic cells demonstrated that they were CD3+ cells. Our results suggest the breast tumors may elude immunological surveillance by inducing, via the Fas/FasL system, the apoptosis of activated lymphocytes. Recent data have demonstrated FasL RNA in other tumor types. Upregulation of FasL expression in hyperplastic and normal breast ducts close to the tumor also suggests a possible role in early neoplastic transformation and proliferation.

Apoptosis↗
PubMed1999

Macrophage derived growth factors modulate Fas ligand expression in cultured endometrial stromal cells: a role in endometriosis.

Fas-Fas ligand (FasL) interactions play a significant role in the immune privilege status of certain cell populations, and several cytokines and growth factors can modulate their expression. When a FasL-expressing cell binds a Fas-bearing immune cell, it triggers its death by apoptosis. In this study, we demonstrate that normal human endometrial epithelial but not stromal cells express FasL. Moreover, we showed that macrophage-conditioned media induced FasL expression by endometrial stromal cells in a dose-dependent manner. To elucidate which macrophage product was responsible for the up-regulation of FasL, endometrial stromal cell cultures were treated with the macrophage products platelet-derived growth factor (PDGF), transforming growth factor (TGF)-beta1, and basic fibroblast growth factor (bFGF). The first two (which are known to be elevated in the peritoneal fluid of women with endometriosis) induced a dose-dependent up-regulation of FasL expression, which was specifically inhibited by the antibody. Interestingly, bFGF (which is not elevated in peritoneal fluid of women with endometriosis) did not induce any response. These results suggest that the pro-inflammatory nature of the peritoneal fluid of women with endometriosis induces the FasL expression by regurgitated endometrial cells, and signals Fas-mediated cell death of activated immune cells. This could be a mechanism for endometrial cells to escape immune surveillance, implant and grow.

Cell Differentiation↗
PubMed1999

Monocyte chemotactic protein-1 expression in human corpus luteum.

Invasion of the corpus luteum by macrophages is a characteristic of luteal regression. Monocyte chemotactic protein-1 (MCP-1), a chemokine that recruits macrophages, is expressed in the rat corpus luteum where it increases in amount during luteolysis. In this study we examined the temporal and spatial expression of MCP-1 and changes in macrophage concentration in the human corpus luteum. Corpora lutea (n = 39) were grouped according to menstrual cycle phase and were examined by immunohistochemistry for MCP-1 and macrophages, and by Northern blot for MCP-1 mRNA. We found increasing amounts of macrophages with progressing luteolysis (P < 0.001). Staining for MCP-1 was stronger in the regressing corpora lutea compared with the staining in corpora lutea of early luteal phase (P < 0.05). MCP-1 was more prominent in blood vessel walls surrounding the corpus luteum than in vessels located far from it. The mean MCP-1 mRNA expression in regressing corpora lutea was higher than that observed in corpora lutea of the early and mid-luteal phase (P = 0.003). In conclusion, we found that MCP-1 expression and the number of macrophages increase with regression of the corpus luteum. MCP-1 is mostly expressed in blood vessel walls surrounding the corpus luteum and may play a role in the recruitment of macrophages to the corpus luteum during its regression.

Adult↗
PubMed1999

The potential of aromatase inhibitors in breast cancer prevention.

Substantial evidence supports the concept that estrogens cause breast cancer in animals and in women but the precise mechanism is unknown. The most commonly held theory is that estrogens stimulate proliferation of breast cells and thus statistically increase the chances for genetic mutations which could result in cancer. Another theory is that estrogen metabolism generates oxygen-free radicals and quinones which produce both stable and unstable DNA adducts. Both result in genetic mutations which accumulate and could ultimately cause cancer. A major criticism of the latter hypothesis is that breast tissue contains insufficient concentrations of estrogen for accumulation of genotoxic metabolites. Our hypothesis is that breast tissue estrogen levels, as a result of in situ synthesis, are much higher than previously thought. We and others have shown that estrogen can be made in the breast itself through conversion of androgens to estrogens, a process catalyzed by the enzyme aromatase. The levels of estrogen in the breast increase when aromatase is overexpressed. With sufficient amounts of aromatase in breast tissue, enough estradiol as substrate should be available to allow formation of substantial amounts of genotoxic metabolites. We postulate that aromatase overexpression may in this way cause breast cancer. As evidence supporting this concept, four animal models of aromatase overexpression and either breast cancer or premalignant lesions have been described. We have provided evidence that normal breast tissue can make estrogen and that certain stimulatory compounds can increase aromatase activity in the breast by nearly 10,000-fold. If our concepts are correct, it might be possible to prevent breast cancer by blocking the aromatase enzyme. Drugs are currently available to inhibit aromatase nearly completely without causing significant side-effects. Aromatase inhibitors might be more effective than antiestrogens in preventing breast cancer because of their dual role to block both initiation and promotion of breast cancer. To inhibit the initiation process, these inhibitors would reduce levels of the genotoxic metabolites of estradiol by lowering estradiol concentrations in tissue. At the same time, aromatase inhibitors would inhibit the process of tumor promotion by lowering tissue levels of estradiol and thus blocking cell proliferation. These concepts provide a strong rationale for studies of aromatase inhibitors to prevent breast cancer.

Animals↗
PubMed1999

Aromatase and estrogen receptor immunoreactivity in the coronary arteries of monkeys and human subjects.

OBJECTIVE: The objective of this study was to determine whether estrogen could be formed locally in the coronary arteries. DESIGN: Coronary arteries were examined from monkeys (Macaca fascicularis, one male and one female) and human subjects (one premenopausal woman, one postmenopausal woman, and one man) by immunocytochemistry, using purified antisera against human placental estrogen synthetase (aromatase) and ER alpha. The arteries were graded for the amount of atherosclerosis. RESULTS: There was clear immunopositivity for both aromatase and estrogen receptors in all arteries studied. Although all endothelial cells (CD31 positive) stained for both antigens, the staining in macrophages, fibroblasts, and smooth muscle cells was irregular. CONCLUSION: The present results provide the first evidence for the local formation of estrogen in the coronary arteries. In addition to complementing the evidence of a cardioprotective effect of estrogen on the coronary circulation, our results highlight the potential importance of local regulation of estrogen formation and the role of available precursor androgens in maintaining the cardiovascular system.

Animals↗
PubMed1999

Apoptosis and apoptosis-related proteins in the epithelium of human ovarian tumors: immunohistochemical and morphometric studies.

BACKGROUND: The origin of malignant ovarian tumors is the subject of considerable controversy, which may be resolved by elucidation of molecular mechanisms of tumorigenesis. Therefore we have undertaken the study of apoptosis in these tumors. METHODS: Apoptosis and the expression of its related proteins, Fas, Fas ligand (FasL), bcl-2 and p53, in epithelial cells of human ovarian tumors of different histological grades, were determined immunohistochemically and morphometrically. RESULTS: Apoptosis-related proteins were absent from ovarian epithelia of patients afflicted with non-cancerous diseases. In ovarian tumors, the distribution of individual proteins varied, and depended on the grade and type of tumor. Fas and FasL were highly expressed in all tumors, while epithelial cells expressing bcl-2 were abundant in benign tumors, but their numbers significantly dwindled with the progression of malignancy. Cells expressing p53 were found in borderline tumors, and their numbers increased with malignancy, inverse of bcl-2 expression. Apoptotic tumor cells were scarce in borderline tumors and abundant in carcinomas. Grouping apoptosis was found in approximately 60% of the carcinomas. CONCLUSIONS: The initial development of ovarian tumors is accompanied by high epithelial expression of Fas, FasL and bcl-2 proteins, while apoptosis and p53 proteins are detected only at later stages of tumorigenesis.

Apoptosis↗
PubMed1998

Plasmid DNA: a new era in vaccinology.

DNA vaccination is a novel approach for inducing an immune response. Purified plasmid DNA containing an antigen's coding sequences and the necessary regulatory elements to express them is introduced into the tissue via intramuscular injection or particle bombardment. Once the DNA reaches the tissue, the antigen is expressed in enough quantity to induce a potent and specific immune response and to confer protection against further infections. The effectiveness of DNA vaccines against viruses, parasites, and cancer cells has been demonstrated in numerous animal models. This new approach comes as an aid for the prevention of infectious diseases for which the conventional vaccines have failed. Research on DNA vaccines is providing new insights into some of the basic immunological mechanisms of vaccination such as antigen presentation, the role of effector cells, and immunoregulatory factors. In addition, DNA vaccines may enable us to manipulate the immune system in situations where the response to agents is inappropriate or ineffective. The study of the potential deleterious effects of DNA vaccines is furthering our knowledge regarding the relationship between bacterial DNA and the immune system, as well as its potential application for the study of neonatal tolerance and autoimmunity.

Humans↗
PubMed1998

A monoclonal antibody to oestradiol potentiates the stimulation of the specific activity of the brain type creatine kinase by oestrogen in vivo and in vitro.

We described previously the in vivo immunoneutralization effects of a high affinity anti-oestradiol antibody clone 15 in blocking ovulation and synaptic remodeling in cycling female rats. In the present study we report the enhancing effects of this antibody. Treatment of ovariectomized female rats or female derived skeletal cell cultures in vitro with anti-E2 15 plus oestrogen (E2) potentiated the specific activity of the brain type creatine kinase (CK) response to E2 in the rat tissues or skeletal cells. The enhancing CK response of anti E2 15 plus E2 was time- and dose-dependent in the uterus, thymus, epiphysis and diaphysis of ovariectomized female rats. In the pituitary, on the other hand, anti-E2 15 blocked the stimulatory CK response to E2. Two other high affinity anti-E2 antibodies, clones 8D9 and 11B6, had no effect in augmenting the response of CK to E2 in rat tissues. Moreover, the enhancing CK response in rat tissues was specific to anti-E2 15 plus E2 since the intact anti-E2 in the presence of other oestrogen mimetics, such as oestriol or stilbestrol or tamoxifen did not potentiate the CK response in rat tissues. In this model system the Fab' monomer of anti-E2 15 abolished the CK response to E2 in rat tissues and not to anti-E2 15 plus E2 whereas tamoxifen completely blocked the CK response to anti E2 plus E2. Anti E2 15 may therefore serve as a specific carrier in delivering E2 to oestrogen sensitive rat tissues or cells containing functional oestrogen receptors and thereby increasing the magnitude of E2 effects in vivo and in vitro.

Animals↗
PubMed1998

Macrophages, estrogen and the microenvironment of breast cancer.

Estrogen is a major mitogenic stimulus to established breast cancer. Estrogen sources include ovarian, extraglandular sites and breast tissue. Which source primarily maintains benign and breast cancer tissue estrogen concentrations remains unclear. While macrophages may comprise up to 50% of the mass of breast carcinomas, previous studies neglected to study them as possible sources of estrogen. We present evidence that breast macrophages constitute an in situ source of estradiol and that the amount produced is sufficient to mediate cellular proliferation. We utilized immunohistochemistry and RT-PCR to study cell-specific aromatase expression in (i) 29 breast biopsies, (ii) human monocytes/macrophages and (iii) a myeloid cell line (THP-1) capable of differentiating into macrophages. Use of a breast cancer cell line (MCF-7) provided biologic confirmation of the role of aromatization in cell proliferation. We demonstrated considerable amounts of immunoreactive-aromatase (irARO) in breast tissue macrophages and a positive correlation between the proportion of irARO present in macrophages and lesion severity. Using in vitro techniques, we demonstrated that monocytes and THP-1 cells require differentiation into macrophages to produce aromatase in amounts approaching placental levels. The amount of estrogen produced by THP-1 cells stimulated MCF-7 cells to proliferate, an effect blocked by aromatase inhibitors. Estrogen production by macrophages in breast tissue appears sufficient to stimulate the proliferation of adjacent epithelial cells and to autoregulate cytokine production. These findings represent a new dimension of cellular regulation in breast tissue with major biologic implications, amenable to pharmacological manipulation.

Antineoplastic Agents↗
PubMed1998

Fas-fas ligand system-induced apoptosis in human placenta and gestational trophoblastic disease.

PROBLEM: The low frequency of maternal immune responses to paternally inherited fetal antigens raises the following question: What regulates the immunobiology of pregnancy? Data suggest that this state is the result of peripheral immune-tolerance, an active process of immune-regulation in which activated T cells undergo apoptosis. We studied Fas ligand (FasL) expression and apoptosis in normal and pathologic placentas to find out whether the Fas-FasL-induced apoptosis takes place during implantation. METHOD OF STUDY: FasL expression in paraffin sections was detected using specific antibodies and confirmed with reverse transcriptase-polymerase chain reaction of total RNA from frozen placentas. Apoptosis was detected using the terminal deoxy (d)-UTP nick end-labeling assay. RESULTS: FasL was found in the normal placenta and in gestational trophoblastic disease. Apoptotic leukocytes were localized to the maternal-fetal interface corresponding in localization with the distribution of FasL. CONCLUSIONS: We propose that FasL expression in the placenta is a mechanism responsible for the development of maternal immune tolerance specific for paternal alloantigens and operates in pathologic states characterized by trophoblastic invasion/proliferation.

Apoptosis↗
PubMed1998

Estrogen-receptor expression and function in thymocytes in relation to gender and age.

The expression of estrogen receptor (ER) in thymocytes was studied in young, middle-aged, and old (2, 12, and 24 months, respectively) female and male C57BL/6J mice. Western immunoblots prepared from the thymocytes of females of all age groups showed the presence of a 67-kD protein band, which has been associated with the apparent MW of denatured ER. Flow cytometry analysis of cells stained with a monoclonal anti-ER antibody (clone 13H2) disclosed ER expression in both females and males of all age groups. In vivo treatment with estradiol (E2) led to an increase in the specific activity of thymic creatine kinase (CK) in the female mice, whereas the male thymocytes responded with an increase in CK activity only on treatment with dihydrotestosterone (DHT). The data show no differences in ER expression between male and females, but the receptor appears not to be functional in males. Interestingly, when estradiol was applied to co-cultures of lymphoid-depleted fetal thymus (FT) explants and bone-marrow cells, or thymocytes, from young and old females, it resulted in increased cellularity of cultures containing cells of the young, and not those of the old. The proportion of CD4/CD8 phenotypes of the developing cells in these cultures was not affected by E2 treatment. These observations provide a new insight into ER expression and function in T-cell development in relation to gender and age.

Age Factors↗
PubMed1998

Raloxifene induces neurite outgrowth in estrogen receptor positive PC12 cells.

OBJECTIVE: It is well established that gonadal steroids have direct in vivo and in vitro effects on neurons. To further study these effects, we used rat PC 12 cells to examine the effects of estrogen receptor (ER) ligands on neuronal morphology. DESIGN: PC 12 cells constitutively express ER beta, but only strongly express ER alpha after long-term priming with nerve growth factor (NGF). We therefore primed PC12 cells with NGF for 14 days before testing them for estradiol (10(-9)M)- and/or raloxifene (10(-7) M)-induced neurite growth. Neurite growth was assessed by quantitative light microscopy. As control, ER status of the PC12 cells was assessed by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: In this study, both estradiol and raloxifene induced the outgrowth of neurites in NGF-treated PC 12 cells (p < 0.05). The combination of estradiol- and raloxifene-induced neurite growth was statistically greater than the effects of either agent alone. RT-PCR confirms that NGF-treated PC 12 cells express both ERalpha and ERbeta. CONCLUSIONS: This report is the first on the neurotrophic effect of raloxifene. At 10(-7) M, raloxifene's effect equaled that of estradiol; moreover, raloxifene did not block the neurite growth of simultaneously estradiol-treated PC 12 cells, despite its functional antiestrogenic effects in vivo. We conclude that raloxifene is estrogen agonistic in this animal model and therefore studies are warranted to delineate the relationship between steroidal estrogen and raloxifene.

Animals↗
PubMed1997

Do DNA vaccines induce autoimmune disease?

This report examines whether plasmid DNA vaccines induce the production of anti-DNA or anti-muscle cell autoantibodies. A three-fold increase in the number of B cells secreting immunoglobulin G (IgG) anti-DNA autoantibodies was detected in BALB/c mice immunized and boosted with any of three DNA plasmids (p < 0.004). This correlated with a transient increase in serum anti-DNA autoantibody titers but was not associated with the development of glomerulonephritis or autoimmune disease. None of the DNA vaccines examined stimulated the production of anti-muscle cell autoantibodies or the development of myositis. The effect of DNA vaccines on the development of nascent autoimmunity in lupus-prone (NZB x NZW)F1 mice was also examined. Repeated vaccination did not alter the onset or course of disease in these animals. These findings suggest that DNA vaccines neither initiate nor accelerate the development of systemic autoimmunity.

Animals↗