References of "Hubert, Pascale"
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See detailRole of hormone cofactors in the human papillomavirus-induced carcinogenesis of the uterine cervix
Delvenne, Philippe ULg; Herman, Ludivine ULg; Kholod, Natalia et al

in Molecular & Cellular Endocrinology (2007), 264(1-2), 1-5

If human papillomavirus (HPV) is necessary for the development of (pre)neoplastic lesions of the uterine cervix, it is not sufficient. Among the cofactors involved in the malignant transformation of cells ... [more ▼]

If human papillomavirus (HPV) is necessary for the development of (pre)neoplastic lesions of the uterine cervix, it is not sufficient. Among the cofactors involved in the malignant transformation of cells infected by HPV, sex hormones may facilitate the cervical carcinogenesis by different mechanisms, including the induction of squamous metaplasia in the transformation zone of the cervix, interactions between steroid hormones and HPV gene expression and alterations of the local immune microenvironment. [less ▲]

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See detailDefensis induce the recruitment of dendritic cells in cervical human papillomavirus-associated (pre)neoplastic lesions formed in vitro and transplanted in vivo
Hubert, Pascale ULg; Herman, Ludivine ULg; Maillard, Catherine ULg et al

in FASEB Journal (2007), 21(11), 2765-75

In addition to their direct antimicrobial activity, defensins might also influence adaptive immunity by attracting immature dendritic cells (DC). As these cells have been shown to be deficient in uterine ... [more ▼]

In addition to their direct antimicrobial activity, defensins might also influence adaptive immunity by attracting immature dendritic cells (DC). As these cells have been shown to be deficient in uterine cervix carcinogenesis, we evaluated the ability of -defensin (HNP-2, human neutrophil defensin 2) and ß-defensin (HßD2, human beta defensin 2) to stimulate their migration in human papillomavirus (HPV)-associated (pre)cancers. We first observed, using RT-PCR and immunohistology, that HßD2 is absent in HPV-transformed keratinocytes and that it is weakly expressed in cervical (pre)neoplastic lesions in comparison with normal keratinocytes. We next demonstrated that defensins exert a chemotactic activity for DC in a Boyden Chamber assay and stimulate their infiltration in an in vitro-formed (pre)neoplastic epithelium (organotypic culture of HPV-transformed keratinocytes). To evaluate the ability of defensins also to recruit DC in vivo, we developed a model of immunodeficient mice grafted with organotypic cultures of HPV+ keratinocytes, which form an epithelium similar to a high-grade neoplastic lesion, with tumoral invasion and neovascularization. Intravenously injected human DC were able to infiltrate grafts of HPV+ keratinocytes after administration of HNP-2 in the transplantation chamber. Taken together, these results suggest that defensins could reverse a frequent immune alteration observed in cancer development. [less ▲]

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See detailDendritic Cells: More Than Just Adaptive Immunity Inducers?
Jacobs, Nathalie ULg; Boniver, Jacques ULg; Hubert, Pascale ULg et al

in Current Immunology Reviews (2007), 2

Dendritic cells (DC) are well known for their capacity to induce immune responses and there is also accumulating evidence of their ability to interact with various cell types of the innate system, such as ... [more ▼]

Dendritic cells (DC) are well known for their capacity to induce immune responses and there is also accumulating evidence of their ability to interact with various cell types of the innate system, such as NK, NKT or TCR gamma-delta cells. These interactions are bi-directional, mediated by soluble or cell surface molecules and have been mainly described in the context of immune responses to infectious agents and tumors. NK, NKT or TCR gamma-delta cells induce the maturation of DC, as shown by the increased expression of CD86, IL12 production and priming of T cell responses. On the other hand, mature DC have the ability to activate NK, NKT or TCR gamma-delta cells for sustained innate immune responses and activated NK cells may kill immature DC. In addition, DC and NK or TCR gamma-delta cells share similar functions such as cytotoxic and antitumor activity, interferon production and antigen presentation capacity. [less ▲]

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See detailPhase I/IIclinical trial of local GM-CSF application in patients with cervical HPV-associated low grade squamous intraepithelial lesions
Hubert, Pascale ULg; Doyen, Jean ULg; Chapelle, X. et al

Conference (2007)

Background: Quantitative and functional alterations of professional antigen-presenting cells (APC) in SIL suggest that these lesions may have a diminished capacity to capture viral antigens. Moreover, GM ... [more ▼]

Background: Quantitative and functional alterations of professional antigen-presenting cells (APC) in SIL suggest that these lesions may have a diminished capacity to capture viral antigens. Moreover, GM-CSF (whose production is decreased in HPV-transformed keratinocytes) is an essential factor for the migration of APC in cervical (pre)neoplastic lesions formed in vitro and transplanted in vivo on mouse. In this study we performed a phase I/II clinical trial in order to determine whether a local application of GM-CSF on cervical low-grade squamous intraepithelial lesions (LSIL) might increase the recruitment of APC into the epithelium and indirectly the viral antigen presentation to the immune system. Methods: Fifteen patients with LSIL (10 GM-CSF and 5 placebo) were enrolled in this study. Patients received 4 GM-CSF applications (or placebo gel) and were followed during 6-7 months. APC infiltration was quantified by immunostaining with anti-CD1a mAb. Cellular immune response was evaluated by using an IFN-gamma intracellular staining on PBMC stimulated in vitro with the E7 HPV16 protein and L1 HPV16 Virus-like particles (VLP). Hybrid capture was performed to semi-quantify the viral DNA in cervical brush specimens. Results: GM-CSF applications were well tolerated in all patients. No difference in the cytological/histological and viral parameters assessed at 2 and 6 months after the last application was observed between the GM-CSF and the placebo group. An increased number of CD1a+ APC was observed in 6/10 patients treated by GM-CSF compared to 1/5 patient in the placebo group. There was an increased immune response against HPV in the GM-CSF group showed by NK and T cells producing IFN-gamma. [less ▲]

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See detailProduction of large numbers of Langerhans' cells with intraepithelial migration ability in vitro
Hubert, Pascale ULg; Bousarghin, Latifa; Greimers, Roland ULg et al

in Experimental Dermatology (2005), 14(6), 469-477

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See detailHuman papillomavirus 16 virus-like particles use heparan sulfates to bind dendritic cells and colocalize with langerin in Langerhans cells.
Bousarghin, Latifa; Hubert, Pascale ULg; Franzen, Elisabeth et al

in Journal of General Virology (The) (2005), 86(Pt 5), 1297-305

Langerhans cells (LC), the immature dendritic cells (DC) that reside in epithelial tissues are among the first immune cells to encounter human papillomavirus (HPV) and are not activated by HPV virus-like ... [more ▼]

Langerhans cells (LC), the immature dendritic cells (DC) that reside in epithelial tissues are among the first immune cells to encounter human papillomavirus (HPV) and are not activated by HPV virus-like particles (VLPs) in contrast to DC. The notion that the differences in response to HPV VLPs between LC and DC are associated with different types of cell binding and intracellular trafficking has been addressed. Inhibition experiments with heparin and sodium chlorate showed that heparan sulfates are necessary for HPV 16 VLPs to bind to DC but not to LC. Electron microscopy analysis demonstrated a colocalization of HPV 16 VLPs and langerin, which is expressed only by LC. This colocalization was observed on the cell surface but also in cytoplasmic vesicles. As anti-langerin antibodies, HPV 16 VLPs were associated with a faster entry kinetics in LC, as reflected by the fact that VLPs were observed near the nuclear membrane of LC within 10 min whereas more than 60 min were needed in DC. However, no difference between LC and DC was observed for the endocytosis pathway. HPV 16 VLPs entered in both DC and LC by a clathrin-dependent-pathway and were then localized in large cytoplasmic vesicles resembling endosomes. [less ▲]

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See detailPhase I/II trial of immunogenicity of a human papillomavirus (HPV) type 16 E7 protein-based vaccine in women with oncogenic HPV-positive cervical intraepithelial neoplasia
Hallez, Sophie; Simon, Philippe; Maudoux, Frédéric et al

in Cancer Immunology, Immunotherapy (2004), 53(7), 642-650

Purpose: Infection with oncogenic human papillomavirus (HPV) and HPV-16 in particular is a leading cause of anogenital neoplasia. High-grade intraepithelial lesions require treatment because of their ... [more ▼]

Purpose: Infection with oncogenic human papillomavirus (HPV) and HPV-16 in particular is a leading cause of anogenital neoplasia. High-grade intraepithelial lesions require treatment because of their potential to progress to invasive cancer. Numerous preclinical studies have demonstrated the therapeutic potential of E7-directed vaccination strategies in mice tumour models. In the present study, we tested the immunogenicity of a fusion protein (PD-E7) comprising a mutated HPV-16 E7 linked to the first 108 amino acids of Haemophilus influenzae protein D, formulated in the GlaxoSmithKline Biologicals adjuvant AS02B, in patients bearing oncogenic HPV-positive cervical intraepithelial neoplasia (CIN). Methods: Seven patients, five with a CIN3 and two with a CIN1, received three intramuscular injections of adjuvanted PD-E7 at 2-week intervals. Three additional CIN1 patients received a placebo. CIN3 patients underwent conization 8 weeks postvaccination. Cytokine flow cytometry and ELISA were used to monitor antigen-specific cellular and antibody responses from blood taken before and after vaccine or placebo injection. Results: Some patients had preexisting systemic IFN-gamma CD4(+) (1/10) and CD8(+) (5/10) responses to PD-E7. Vaccination, not placebo injection, elicited systemic specific immune responses in the majority of the patients. Five vaccinated patients (71%) showed significantly increased IFN-gamma CD8(+) cell responses upon PD-E7 stimulation. Two responding patients generated long-term T-cell immunity toward the vaccine antigen and E7 as well as a weak H. influenzae protein D (PD)-directed CD4(+) response. All the vaccinated patients, but not the placebo, made significant E7- and PD-specific IgG. Conclusions: The encouraging results obtained from this study performed on a limited number of subjects justify further analysis of the efficacy of the PD-E7/AS02B vaccine in CIN patients. [less ▲]

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See detailDelivery of granulocyte-macrophage colony-stimulating factor in bioadhesive hydrogel stimulates migration of dendritic cells in models human papillomavirus-associated (pre)neoplastic epithelial lesions
Hubert, Pascale ULg; Evrard, Brigitte ULg; Maillard, Catherine ULg et al

in Antimicrobial Agents and Chemotherapy (2004), 48(11), 4342-4348

Because of the central role of dendritic cells and/or Langerhans cells(DC/LC) in the induction of cellular immune responses, pharmacological agents that modulate the recruitment of these cells might have ... [more ▼]

Because of the central role of dendritic cells and/or Langerhans cells(DC/LC) in the induction of cellular immune responses, pharmacological agents that modulate the recruitment of these cells might have a clinical interest. The present study was designed to evaluate the capacity of several pharmaceutical formulations to topically deliver granulocyte-macrophage colony-stimulating factor (GM-CSF) on human papillomavirus (HPV)-associated genital (pre)neoplastic lesions. The formulations were evaluated for their bioactivity and for their potential to recruit DC in organotypic cultures of HPV-transformed keratinocytes. We found that a bioadhesive polycarbophil gel (Noveon) at pH 5.5 is able to maintain the bioactivity of GM-CSF at 4 or 37°C for at least 7 days, whereas a decreased activity of GM-CSF was observed when the molecule is included in other polymer gels. GM-CSF incorporated in the polycarbophil gel was also a potent factor in enhancing the colonization of DC into organotypic cultures of HPV-transformed keratinocytes since the infiltration of DC in the in vitro-formed (pre)neoplastic epithelium was very low under basal conditions and dramatically increased in the presence of GM-CSF gel. We next demonstrated that GM-CSF incorporated in polycarbophil gel induces the recruitment of human DC in a human (pre)neoplastic epithelium grafted into NOD/SCID mice. The efficacy of GM-CSF in this formulation was equivalent to that observed with liquid GM-CSF. These results suggest that GM-CSF incorporated in polycarbophil gel could play an important role in the recruitment of DC/LC in mucosal surfaces and be useful as a new immunotherapeutic approach for genital HPV-associated (pre)neoplastic lesions. [less ▲]

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See detailEpithelial metaplasia: an inadequate environment for antitumour immunity?
Delvenne, Philippe ULg; Hubert, Pascale ULg; Jacobs, Nathalie ULg

in Trends in Immunology (2004), 25(4), 169-73

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See detailDevelopment of a hydrogel containing GM-CSF to improve the dendritic cells colonisation of HPV+ epithelium
Evrard, Brigitte ULg; Hubert, Pascale ULg; Delvenne, Philippe ULg et al

in Proceedings of Eur conference on drug delivery and pharmaceutical technology (2004)

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See detailModèles expérimentaux in vitro des HPV
Delvenne, Philippe ULg; Hubert, Pascale ULg; Havard, Laurence et al

in Aubin, F.; Pretet, J. F.; Mougin, C. (Eds.) Papillomavirus Humains (2003)

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See detailDistinct T cell subsets and cytokine production in cultures derived from transformation zone and squamous intraepithelial lesion biopsies of the uterine cervix.
Jacobs, Nathalie ULg; Renard, Isabelle; Al-Saleh, Walid et al

in American Journal of Reproductive Immunology (2003), 49(1), 6-13

PROBLEM: The characterization of lymphocytes issued from squamous intraepithelial lesions (SIL) and from the transformation zone (TZ), where the majority of SIL occur, is important to understand the role ... [more ▼]

PROBLEM: The characterization of lymphocytes issued from squamous intraepithelial lesions (SIL) and from the transformation zone (TZ), where the majority of SIL occur, is important to understand the role of immunity in SIL development. METHOD OF STUDY: We compared lymphocyte populations of the TZ and SIL with those of normal exocervix, using a technique allowing for the isolation of lymphocytes, either from the epithelium or from the underlying stroma of small biopsies. RESULTS: The majority of cells derived from the epithelium of all biopsies were CD8+ T cells. Some SIL-derived cultures were characterized by an increased proportion of activated TCRgammadelta+. The production of the immunosuppressive cytokine IL10 was significantly higher in lymphocyte cultures from the normal TZ in comparison with the exocervix. A decreased percentage of effector T cells was observed in cultures derived from the stroma of normal TZ (TCRgammadelta+) or SIL (CD8+) in comparison with the exocervix. CONCLUSIONS: Our results suggest that a low proportion of effector T cells and IL10 production could contribute to the predisposition of the TZ to the development of SIL and to the progression of SIL to cervical cancer. [less ▲]

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See detailInfluence of the mucosal epithelium microenvironment on Langerhans cells: implications for the development of squamous intraepithelial lesions of the cervix
Giannini, Sandra ULg; Hubert, Pascale ULg; Doyen, Jean ULg et al

in International Journal of Cancer = Journal International du Cancer (2002), 97(5), 654-659

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See detailDendritic cells induce the death of human papillomavirus-transformed keratinocytes
Hubert, Pascale ULg; Giannini, Sandra ULg; Vanderplasschen, Alain ULg et al

in FASEB Journal (2001), 15(13), 2521-2523

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See detailThe organotypic culture of HPV-transformed keratinocytes: an effective in vitro model for the development of new immunotherapeutic approaches for mucosal (pre)neoplastic lesions.
Delvenne, Philippe ULg; Hubert, Pascale ULg; Jacobs, Nathalie ULg et al

in Vaccine (2001), 19(17-19), 2557-64

The purpose of this study is to develop a reliable in vitro human model to test new immunotherapeutic approaches for squamous cell carcinoma that develop on mucosal surfaces. The organotypic (raft ... [more ▼]

The purpose of this study is to develop a reliable in vitro human model to test new immunotherapeutic approaches for squamous cell carcinoma that develop on mucosal surfaces. The organotypic (raft) culture permits cells to proliferate and differentiate at an air-liquid interface on a dermal equivalent support. Normal keratinocytes stratify and fully differentiate in a manner similar to the normal squamous epithelial tissues, while human papillomavirus-immortalized and established squamous carcinoma cell lines exhibit dysplastic morphologies similar to (pre)neoplastic lesions seen in vivo. We have demonstrated the ability of these organotypic cultures to be manipulated by altering the epithelial stratification with cytokines (interferon-gamma and tumor necrosis factor-alpha) and by integrating activated lymphocytes or dendritic cells into the in vitro formed epithelial sheet. This model may provide a useful tool to investigate the factors contributing to the presence and function of immunocompetent cells within a neoplastic epithelium that develops on a mucosal surface. [less ▲]

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See detailIL10 production in cultures of lymphocytes derived from biopsies of normal exocervix, transformation zone and squamous intraepithelial lesion
Jacobs, Nathalie ULg; Renard, Isabelle; Pisvin, Sonia ULg et al

in Monsonego, J. (Ed.) 4th International Multidisciplinary Congress - Eurogin 2000 (2000)

The immune system appears to play a role in the development of squamous intraepithelial lesions (SIL) and their progression to cancer. We have developed a technique to isolate and cultivate lymphocytes ... [more ▼]

The immune system appears to play a role in the development of squamous intraepithelial lesions (SIL) and their progression to cancer. We have developed a technique to isolate and cultivate lymphocytes either from the epithelium or from the underlying stroma of small biopsies from the normal exocervix, the transformation zone (TZ) and SIL. The majority of cells derived from the epithelium of all biopsies were CD8+ T cells. No major difference was observed for the lymphocyte phenotype. Among all cytokines tested by ELISA (IL10, IL4 and IFNγ), only IL10 was significantly higher in the TZ in comparison with the exocervix. In cultures derived from the stroma, a decreased percentage in T cells was observed in the TZ and SIL in comparison with the exocervix. This decrease in T cells concerned CD8+ (SIL) and TCRγδ+ T cells (TZ and SIL). We did not observe any difference in IL10 or IL4 production, although patients with SIL produced more IFNγ. The higher levels of IL10 production by lymphocytes derived from the epithelium of the TZ might contribute to the predisposition of this region to cervical carcinogenesis. [less ▲]

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