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E D Carosella

Publications and source records attributed to E D Carosella.

At least 19 recordsLinked to original sources
PubMed2006

Soluble HLA-G expression and renal graft acceptance.

HLA-G is a potentially interesting molecule associated with immunosuppressive function. We survey here the presence of soluble HLA-G (sHLA-G) in serial serum samples of renal transplants. A total of 330 sera of from 65 patients were tested for sHLA-G with ELISA. IgG/IgM antibodies to HLA, and MICA antibodies were also previously tested. After serial analysis of the 65 patients' 330 sera, 50% of 26 patients in functioning group had consistent sHLA-G expression or became positive, in comparison to 20.5% among 39 patients who rejected their transplants (p=0.013). Thus sHLA-G was associated with functioning transplants. Eighty percent (77 of 96) of the HLA IgG positive sera had no sHLA-G expression, while 81.4% (83 of 102) of the HLA-G(+) sera had no HLA IgG (p=0.005), which showed a negative association between sHLA-G and the presence of HLA IgG antibodies (which was previously been shown to be associated with failure). In this preliminary survey, sHLA-G was found in the serum of about 30% of renal transplant patients. sHLA-G had a negative association with allograft failure from chronic rejection, and a negative relationship with the production of HLA IgG antibodies. The significance of sHLA-G in renal transplants remains to be determined.

Adult↗
PubMed2006

Increase in HLA-G1 proteolytic shedding by tumor cells: a regulatory pathway controlled by NF-kappaB inducers.

HLA-G is expressed by tumors, in which it contributes to the evasion of immunosurveillance. NF-kappaB appears to be a candidate for regulating HLA-G expression, since it is considered to be a hallmark of cancer. We investigated the role of NF-kappaB in modulating HLA-G expression in HLA-G-positive tumor cells, JEG-3 (choriocarcinoma), FON (melanoma), and M8-HLA-G1 (HLAG1-transfected melanoma). The treatment of tumor cells with two NF-kappaB inducers, tumor necrosis factor-alpha and phorbol 12-myristate 13-acetate, decreased HLA-G1 cell surface expression but increased intracytoplasmic HLA-G proteins. Reduction in HLA-G1 cell surface expression is driven by NF-kappaB and involves a proteolytic shedding process dependent on metalloproteinase activity. In contrast, an increase in intracytoplasmic HLA-G proteins involves post-transcriptional mechanisms that are independent of NF-kappaB. These results, and the fact that soluble HLA-G1 reduces the cytotoxicity of the NKL cell line, lead us to propose a novel regulatory pathway for HLA-G expression by tumor cells that may have particular relevance in tumor escape.

Cell Line↗
PubMed2004

[HLA-G in organ transplantation].

The HLA-G molecule plays a crucial role in the protection of the fetus against aggression by the mother's immune system. Recently, it was shown that HLA-G was involved in the protection of the transplanted tissues, via the inhibition of all immune effectors that mediate graft rejection. The inhibitory functions of HLA-G were studied in vitro using allo- and xeno-geneic models, ex vivo on transplanted tissues biopsies, and in an in vivo animal model. In this review, we will summarize recent results which show that HLA-G acts as a regulator of immune function, seems to be directly involved in transplant acceptation, and should be taken into consideration when monitoring transplanted patients' status.

Animals↗
PubMed2004

Pharmacological inhibition of DNA repair enzymes differentially modulates telomerase activity and apoptosis in two human leukaemia cell lines.

PURPOSE: To investigate the effect of wortmannin and 3-aminobenzamide (3-AB) on telomerase activity and apoptosis in two human leukaemia cells. MATERIALS AND METHODS: MOLT-4 (p53-wild type) and KG1a (p53-null) cells were irradiated with gamma-rays (3 Gy at 1.57 Gy min(-1)) and the effects of wortmannin and 3-AB were evaluated. Telomerase activity was measured by polymerase chain reaction and the expression of human telomerase reverse transcriptase, human telomerase RNA and telomerase-associated protein 1 was assessed by reverse transcriptase-polymerase chain reaction. Apoptosis was evaluated by fluorescence microscopy and flow cytometry. RESULTS: A radiation-induced up-regulation of telomerase activity was observed from 4 h post-irradiation in both cell lines. This up-regulation was abrogated by wortmannin and 3-AB. Telomerase activity was maximal 24 h post-irradiation, coinciding with an accumulation of human telomerase reverse transcriptase mRNA. Apoptosis and G2/M arrest were evident from 4 h post-irradiation in MOLT-4 cells. KG1a cells exhibited a G2/M block at 24 h post-irradiation and apoptosis increased between 24 and 48 h post-irradiation. 3-AB abolished G2/M blockage and enhanced radiation-induced apoptosis in both cell lines, while wortmannin increased apoptosis only in MOLT-4 cells. CONCLUSIONS: 3-AB inhibits the radiation-associated telomerase activity increase and enhances apoptosis in MOLT-4 and KG1a cells. Wortmannin, which also inhibits the radiation-associated telomerase activity increase in both cell lines, does not modify radiation-induced apoptosis in KG1a cells. DNA repair enzymes might be selective targets for enhancing radiosensitivity in certain tumour cells.

Androstadienes↗
PubMed2004

Expression of HLA-G in inflammatory bowel disease provides a potential way to distinguish between ulcerative colitis and Crohn's disease.

In addition to being involved in nutrient uptake, the epithelial mucosa constitute the first line of defense against microbial pathogens. A direct consequence of this physiological function is a very complex network of immunological interactions that lead to a strong control of the mucosal immune balance. The dysfunction of immunological tolerance is likely to be a cause of inflammatory bowel disease (IBD), ulcerative colitis (UC) and Crohn's disease (CD). HLA-G is a non-classical major histocompatibility complex (HLA) class I molecule, which is highly expressed by human cytotrophoblast cells. These cells play a role in immune tolerance by protecting trophoblasts from being killed by uterine NK cells. Because of the deregulation of immune system activity in IBD, as well as the immunoregulatory role of HLA-G, we have analyzed the expression of HLA-G in intestinal biopsies of patients with UC and CD. Our study shows that the differential expression of HLA-G provides a potential way to distinguish between UC and CD. Although the reason for this differential expression is unclear, it might involve a different mechanism of immune regulation. In addition, we demonstrate that in the lamina propria of the colon of patients with UC, IL-10 is strongly expressed. In conclusion, the presence of HLA-G on the surface of intestinal epithelial cell in patients with UC lends support to the notion that this molecule may serve as a regulator of mucosal immune responses to antigens of undefined origin. Thus, this different pattern of HLA-G expression may help to differentiate between the immunopathogenesis of CD and UC.

Biopsy↗
PubMed2003

Biology and functions of human leukocyte antigen-G in health and sickness.

In 1998, the first International Conference on human leukocyte antigen-G (HLA-G) was held in Paris. At that time, HLA-G was still a new HLA class I molecule, few aspects of its immunological functions were known, and its expression by tumors was just being described. In 1998, tools to properly study HLA-G were lacking, especially monoclonal antibodies, and three conclusions were drawn after the congress: (i) animal models were needed, (ii) the biology of HLA-G isoforms had to be confirmed, and (iii) HLA-G expression by tumors required clarification. Five years later, these three issues have been addressed. HLA-G is now gaining pace and is investigated for its immuno-inhibitory functions in the context of multiple pathologies. Eighty five oral presentations were given this year for more than 200 investigators working on HLA-G by speakers from over 20 countries. The success of the 3rd International Conference on HLA-G reflects the interest and tremendous work of the many research teams which, over the years, contributed to the publication of more than 500 peer-review articles. We summarize the key points that were presented and discussed during this meeting.

Autoimmune Diseases↗
PubMed2003

[HLA-G: immunoregulatory molecule involved in allograft acceptance].

The Human Leucocyte Antigen-G (HLA-G) is a non-classical MHC class I molecule of low polymorphism, restricted tissue distribution and tolerogeneic functions. It is clearly demonstrated that HLA-G contributes to fetal graft tolerance by the maternal immune system. The tolerogeneic properties of HLA-G act via specific inhibitory receptors present on immunocompetents cells: HLA-G inhibits natural killer cells (NK) and CD8+ T cell cytotoxicity, suppresses CD4+ T cell proliferation in response to allogeneic stimulation and promotes T helper 2 (Th2) type responses. The soluble HLA-G protein is spontaneously secreted by allo-sensitized CD4+ T cells during mixed lymphocyte reactions (MLR), and inhibits their proliferative response. Finally, inhibition of dendritic cell maturation has been observed in HLA-G transgenic mice. In human organ transplantation, our group has reported in cardiac and liver-kidney transplanted patients, a positive correlation between the de novo ectopic expression of HLA-G in both patient's serum and graft biopsies, and a lower rate of acute rejection episodes of the grafts. Moreover no chronic graft rejection has been detected in those populations. These results support the involvement of HLA-G in regulatory mechanisms that may occur during human allotransplantation.

Cytokines↗
PubMed2002

HLA-G protein processing and transport to the cell surface.

Data are presented on the intracellular trafficking of HLA-G protein, taking the unique features of this non-classical molecule into consideration: the existence of seven isoforms resulting from alternative splicing (HLA-G1 to G7), and reduced tail length compared with HLA class I antigens. Biochemical studies and analysis of viral strategies for escaping the host immune system led to the demonstration that (i) both the membrane-bound (HLA-G1) and the soluble (HLA-G5) forms of the molecule require peptide association for cell surface expression, using TAP-dependent or TAP-independent pathways; (ii) peptide loading onto the HLA-G protein plays a critical role in controlling the quality of the molecule reaching the cell surface; (iii) surface expression of truncated HLA-G molecules is possible, and (iv) HLA-G expression may be restricted to soluble HLA-G5. These data reveal that HLA-G presents specific cell trafficking pathways and strongly support the contention that the primary function of HLA-G is as of an inhibitor ligand for immune-competent cells.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2002

Radiation-induced up-regulation of telomerase in KG1a cells is influenced by dose-rate and radiation quality.

PURPOSE: To examine the influence of dose, dose-rate and radiation quality on telomerase activity (TA) in the KG1a hematopoietic cell line. MATERIALS AND METHODS: KG1a cells were irradiated with gamma-rays (0.5-5 Gy) at 0.025 Gy/min, 0.30 Gy/min and 1.57 Gy/min and with a neutron/gamma-ray field (5 Gy). Cell viability was determined by trypan blue exclusion. Apoptosis and cell cycle distribution were evaluated by flow cytometry. Proliferative capacity was studied by MTS assay and TA by PCR. Following 3Gy gamma-irradiation, the expression of hTERT, hTR and TP1 genes was evaluated by RT-PCR. RESULTS: Dose- and dose-rate-dependent telomerase activation with an increase in hTERT mRNA and a drop in hTP1 mRNA were observed after irradiation. Down-regulation of telomerase activity occurred in a dose-dependent manner. Although non-significant changes in short-term survival were observed after irradiation, late apoptosis became evident after G2/M arrest. Early repression of TA preceded telomerase activation in samples irradiated with a neutron/gamma-ray field, in which short-term survival was affected. CONCLUSIONS: Radiation-induced telomerase activation depends on dose-rate. High-LET and low-LET irradiations induce similar changes in TA that differ mainly in their kinetics and their magnitude. Changes in TA are not related to cell-cycle redistribution nor to the induction of cell death; they are the consequence of specific regulatory responses to ionizing radiation. Mechanisms including both transcriptional and post-translational control may be involved in this regulation.

Apoptosis↗
PubMed2001

Soluble HLA-G protein secreted by allo-specific CD4+ T cells suppresses the allo-proliferative response: a CD4+ T cell regulatory mechanism.

We recently reported that the nonclassical HLA class I molecule HLA-G was expressed in the endomyocardial biopsies and sera of 16% of heart transplant patients studied. The aim of the present report is to identify cells that may be responsible for HLA-G protein expression during the allogeneic reaction. Carrying out mixed lymphocyte cultures in which the responder cell population was depleted either in CD4(+) or CD8(+) T cells, we found that soluble HLA-G5 protein but not the membrane-bound HLA-G isoform was secreted by allo-specific CD4(+) T cells from the responder population, which suppressed the allogeneic proliferative T cell response. This inhibition may be reversed by adding the anti-HLA-G 87G antibody to a mixed lymphocyte culture. That may indicate a previously uncharacterized regulatory mechanism of CD4(+) T cell proliferative response.

Apoptosis↗
PubMed2001

Tumor-specific up-regulation of the nonclassical class I HLA-G antigen expression in renal carcinoma.

HLA-G is a nonclassical class I antigen mainly expressed at the maternofetal interface during pregnancy where it is thought to down-modulate maternal immune response against the semiallogeneic fetus. Recent studies indicate that ectopic up-regulation of HLA-G expression on melanoma cells may also favor their escape from antitumor immune response. HLA-G expression was here investigated on paraffin-embedded tumor and adjacent normal renal tissues of 18 renal cell carcinoma (RCC) patients. We provide evidence that HLA-G antigen is differentially expressed in carcinoma and normal renal cells and that up-regulation of this antigen in the tumor cells is more frequent than alterations of other MHC class I or class II antigens. We also demonstrated that HLA-G cell surface expression and secretion is maintained in a tumor cell line (DM) established from an HLA-G-positive RCC lesion. Furthermore, we show that type I (alpha and beta) and, in particular, type II (gamma) IFN treatment enhances steady-state mRNA levels and cell surface expression of HLA-G in the DM cell line. As several studies suggest that HLA-G displays various functional features that allow down-modulation of immune response in vitro, we propose that selective in vivo expression of HLA-G may participate in the impairment of antitumor immunity in RCC.

Adult↗
PubMed2001

HLA-G2, -G3, and -G4 isoforms expressed as nonmature cell surface glycoproteins inhibit NK and antigen-specific CTL cytolysis.

HLA-G is a nonclassical MHC class I molecule that plays a major role in maternal-fetal tolerance. Four membrane-bound (HLA-G1 to -G4) and two soluble (HLA-G5, and -G6) proteins are generated by alternative splicing. Only HLA-G1 has been extensively studied in terms of both expression and function. We provide evidence here that HLA-G2, -G3, and -G4 truncated isoforms reach the cell surface of transfected cells, as endoglycosidase H-sensitive glycoproteins, after a 2-h chase period. Moreover, cytotoxicity experiments show that these transfected cells are protected from the lytic activity of both innate (NK cells) and acquired (CTL) effectors. These findings highlight the immunomodulatory role that HLA-G2, -G3, and -G4 proteins will assume during physiologic or pathologic processes in which HLA-G1 expression is altered.

Adult↗
PubMed2001

Altered HLA-G transcription in pre-eclampsia is associated with allele specific inheritance: possible role of the HLA-G gene in susceptibility to the disease.

Pre-eclampsia is a disorder of human pregnancy occurring in 5-10% of all births, and represents the leading cause of infant morbidity and mortality and maternal death. In pre-eclampsia, invasion of fetal trophoblasts into maternal arteries during early pregnancy is shallow or absent. Here we examined the hypothesis that HLA-G, a non-classical class I HLA expressed in cytotrophoblasts, may act as a key gene in pre-eclampsia. We analysed HLA-G at the level of transcription and genotyped a silent CAC-CAT polymorphism in exon 3 and a 14-bp insertion/deletion in the 3' untranslated region. A deficit in levels of the HLA-G3 transcript was observed in mild pre-eclampsia compared to normal placentas. The distribution of HLA-G polymorphisms was different between normal and pre-eclampsia samples. A correlation between the alteration in transcription of the HLA-G gene and certain HLA-G genotypes was also observed. Thus we provide the first evidence for a possible role of HLA-G in genetic susceptibility to, and pathogenesis of pre-eclampsia.

Alleles↗
PubMed2001

HLA-G and NK receptor are expressed in psoriatic skin: a possible pathway for regulating infiltrating T cells?

Recent data have suggested that in psoriasis, the T-infiltrating cells could be submitted to regulatory pathways, possibly through natural killer receptors. HLA-G binds to different natural killer receptors and is able to inhibit T-cell functions. Because this molecule is induced by interferon-gamma, a major cytokine in psoriasis, we asked whether HLA-G and its receptor might be expressed in this disease. Specific RNAs for HLA-G1 and HLA-G5 were consistently found in lesional skin specimens, soluble HLA-G5 transcripts being found only in psoriasis. HLA-G protein was found in all psoriatic sections, but never in normal skin controls. Double labeling demonstrated that HLA-G-positive cells were CD68(+), CD11c(+) macrophages. The NKR ILT2 was also present in psoriatic skin, the T CD4(+)-infiltrating cells expressing indeed ILT2. The demonstration of HLA-G and ILT2 expression in psoriatic skin suggests that this pathway may act as an inhibitory feed back aimed to down-regulate the deleterious effects of T-cell infiltrate in this disease.

Alternative Splicing↗
PubMed2001

HLA-G: a shield against inflammatory aggression.

Recent developments in the field of HLA-G research have revealed that, besides its involvement during pregnancy, HLA-G is expressed in peripheral tissues during pathological processes, such as viral infections, malignancies and organ transplantation. Here, we discuss recent findings regarding the influence of HLA-G on the T helper (Th) cytokine balance (favoring Th2-type responses), and the expression of HLA-G during chronic, cutaneous inflammatory diseases, such as psoriasis and atopic dermatitis. We propose a novel role for HLA-G as a tissue-protective molecule in inflammatory responses.

Cytokines↗