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Biomedical subjects

Philippe Delvenne

Publications and source records attributed to Philippe Delvenne.

15 recordsLinked to original sources
PubMed2005

E-cadherin-dependent adhesion of dendritic and Langerhans cells to keratinocytes is defective in cervical human papillomavirus-associated (pre)neoplastic lesions.

Although human papillomavirus (HPV) DNA is detected in the majority of squamous intraepithelial lesions (SILs) and squamous cell carcinomas (SCCs) of the uterine cervix, the persistence and progression of cervical lesions suggest that viral antigens are not adequately presented to the immune system. This hypothesis is reinforced by the observation that most SILs show quantitative and functional alterations of Langerhans cells (LCs). The aim of this study was to determine whether modulation of E-cadherin-mediated homophilic and heterotypic interactions between keratinocytes and LCs is involved in these abnormalities of LCs in (pre)neoplastic cervical epithelium. Cell membrane expression of E-cadherin and the density of CD1a+ LCs were low in the epithelium of SILs and SCC biopsy specimens, compared with normal exocervical epithelium. Dendritic cells (DCs) and LCs generated in vitro were randomly distributed throughout the full thickness of organotypic cultures of E-cadherin- HPV-transformed cells. In contrast, these cells rapidly adhered to the keratinocyte cell layers when HPV-transformed cells transfected with E-cadherin were used. These data suggest that the E-cadherin-mediated contact between keratinocytes and LCs is potentially important for initiating or maintaining the immune response during chronic HPV infection.

Antigens, CD1↗
PubMed2005

Human papillomavirus 16 virus-like particles use heparan sulfates to bind dendritic cells and colocalize with langerin in Langerhans cells.

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.

Antigens, CD↗
PubMed2005

Production of large numbers of Langerhans' cells with intraepithelial migration ability in vitro.

Langerhans' cells (LCs) are a subset of immature dendritic cells (DCs) and play a key role in the initiation and regulation of immune responses. Functional studies of these cells have been hampered by difficulties in generating a large number of LCs in vitro. We describe a new method to efficiently generate immature DCs exhibiting morphological, immunohistochemical, and ultrastructural features of LCs (CD1a+, Birbeck Granules+, CD207+, E-cadherin+, cutaneous lymphocyte-associated antigen+, and CCR6+) from a limited number of CD34+ cord blood progenitors. This method is based on a two-step procedure consisting of an amplification phase followed by a terminal differentiation induction. The amplification step is initiated with a combination of hematopoietic growth factors (thrombopoietin/stem cell factor/fetal liver tyrosine kinase-3 ligand), cytokines (granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-alpha, and interleukin-4), and 5 ng/ml of transforming growth factor (TGF)-beta1. The differentiation is induced by increasing the concentration of TGF-beta1 to 12.5 ng/ml. These culture conditions were efficient for generating a large number of immature LCs (8.74 x 10(6) +/- 3.2) from 15 x 10(4) CD34+ progenitor cells. In addition, these LCs were shown to be able to infiltrate an in vitro reconstructed epithelium. Because LCs play an important role in the mucosal immunity, this technique could be useful to study their interactions with epithelial pathogenic agents and to perform pharmacological, toxicological, and clinical research.

Antigens, CD↗
PubMed2004

Phase 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.

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.

Adult↗
PubMed2004

Pathbase: a database of mutant mouse pathology.

Pathbase is a database that stores images of the abnormal histology associated with spontaneous and induced mutations of both embryonic and adult mice including those produced by transgenesis, targeted mutagenesis and chemical mutagenesis. Images of normal mouse histology and strain-dependent background lesions are also available. The database and the images are publicly accessible (http://www.pathbase.net) and linked by anatomical site, gene and other identifiers to relevant databases; there are also facilities for public comment and record annotation. The database is structured around a novel ontology of mouse disorders (MPATH) and provides high-resolution downloadable images of normal and diseased tissues that are searchable through orthogonal ontologies for pathology, developmental stage, anatomy and gene attributes (GO terms), together with controlled vocabularies for type of genetic manipulation or mutation, genotype and free text annotation for mouse strain and additional attributes. The database is actively curated and data records assessed by pathologists in the Pathbase Consortium before publication. The database interface is designed to have optimal browser and platform compatibility and to interact directly with other web-based mouse genetic resources.

Animals↗
PubMed2004

Pathbase: a new reference resource and database for laboratory mouse pathology.

Pathbase (http://www.pathbase.net) is a web accessible database of histopathological images of laboratory mice, developed as a resource for the coding and archiving of data derived from the analysis of mutant or genetically engineered mice and their background strains. The metadata for the images, which allows retrieval and interoperability with other databases, is derived from a series of orthogonal ontologies and controlled vocabularies. One of these controlled vocabularies, MPATH, was developed by the Pathbase Consortium as a formal description of the content of mouse histopathological images. The database currently has over 1000 images on-line with 2000 more under curation and presents a paradigm for the development of future databases dedicated to aspects of experimental biology.

Animals↗
PubMed2004

Delivery of granulocyte-macrophage colony-stimulating factor in bioadhesive hydrogel stimulates migration of dendritic cells in models of human papillomavirus-associated (pre)neoplastic epithelial lesions.

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 degrees 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.

Acrylic Resins↗
PubMed2004

Mycosis fungoides progression and chronic solvent exposure.

The effect of repeated exposure to specific chemicals on the initiation or progression of mycosis fungoides (MF) remains unsettled. A patient with low-grade patch stage MF progressively developed MF plaques restricted to his arms, and a tumour on his right thigh. These areas were subject to repeated exposure to solvents. His thigh was indeed in close contact with his trousers pocket where he used to store a wiping rag drenched into white spirit and cellulosic thinner. Immunophenotyping these lesions revealed a dense LCA+, CD2+, CD3+, CD4+, CD5+, CD7+, CD45+, CD45RO+ T-cell infiltrate admixed with many factor XIIIa+ dendrocytes. T-cell receptor rearrangement analysis identified a monoclonal T-cell infiltrate. An internal work-up remained negative. Stopping further solvent exposure failed to improve his condition. Oral corticotherapy combined with low-dose interferon-alpha2a halted disease progression. This observation suggests that long-term solvent exposure may trigger MF and hasten its progression from the patch stage to the plaque and tumour stages.

Adrenal Cortex Hormones↗
PubMed2003

TIMP-2 and PAI-1 mRNA levels are lower in aneurysmal as compared to athero-occlusive abdominal aortas.

OBJECTIVE: Significant alterations of the vascular wall occurs in abdominal aortic aneurysm (AAA) and atherosclerotic occlusive disease (AOD) that ultimately may lead to either vascular rupture or obstruction. These modifications have been ascribed to one or a group of proteases, their inhibitors or to the matrix macromolecules involved in the repair process without considering the extent of the observed variations. METHODS: The mRNA steady-state level of a large spectrum of proteolytic enzymes (matrix metalloproteinases: MMP-1, -2, -3, -8, -9, -11, -12, -13, -14; urokinase plasminogen activator: u-PA), their physiological inhibitors (tissue inhibitors of MMPs: TIMP-1, -2, -3; plasminogen activator inhibitor: PAI-1) and that of structural matrix proteins (collagens type I and III, decorin, elastin, fibrillins 1 and 2) was determined by RT-PCR made quantitative by using a synthetic RNA as internal standard in each reaction mixture. The profile of expression was evaluated in AAA (n=7) and AOD (n=5) and compared to non-diseased abdominal (CAA, n=7) and thoracic aorta (CTA, n=5). RESULTS: The MMPs -8, -9, -12 and -13 mostly associated with inflammatory cells were not or barely detected in CAA and CTA while they were largely and similarly expressed in AAA and AOD. Expression of protease inhibitors or structural proteins were only slightly increased in both pathological conditions with the exception of elastin which was reduced. The main significant difference between AAA and AOD was a lower expression of TIMP-2 and PAI-1 in the aneurysmal lesions. CONCLUSIONS: The remodeling of the aortic wall in AAA and AOD involves gene activation of a large and similar spectrum of proteolytic enzymes while the expression of two physiological inhibitors, TIMP-2 and PAI-1, is significantly lower in AAA compared to AOD. The repair process in the aneurysmal disease seems similar to that of the occlusive disease.

Aged↗
PubMed2003

High intraepithelial expression of estrogen and progesterone receptors in the transformation zone of the uterine cervix.

OBJECTIVE: Because sex hormones may be involved in tumor initiation and progression, we analyzed the presence of hormone receptors in the transformation zone of the uterine cervix where the majority of human papillomavirus infections and associated (pre)neoplastic lesions develop. STUDY DESIGN: By using 23 total hysterectomy samples from young women who underwent surgery for noncervical benign uterine disease, we analyzed, by immunohistologic techniques, the in situ expression of estrogen (E(2)-R) and progesterone (P(4)-R) receptors in the transformation zone and ectocervix of the same women. RESULTS: The expression of estrogen receptors and progesterone receptors is significantly higher in the transformation zone compared with the ectocervix. Immunohistochemical localization indicated that hormone receptor-positive cells are mainly observed in (para)basal and intermediate cell layers in both the transformation zone and ectocervical epithelium. When transformation zone samples were segregated into epithelial tissues with a predominantly mature (7/23 samples) or immature (16/23 samples) squamous metaplasia, only biopsy specimens with immature squamous metaplasia showed a significantly higher density of hormone receptor-positive cells compared with ectocervical epithelium (P<.01). CONCLUSION: Our results suggest that the cervical transformation zone may be at increased risk of the development of cancer because of a high sensitivity to sex hormone regulation.

Adult↗
PubMed2003

Distinct T cell subsets and cytokine production in cultures derived from transformation zone and squamous intraepithelial lesion biopsies of the uterine cervix.

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.

Biopsy↗
PubMed2002

Influence of the mucosal epithelium microenvironment on Langerhans cells: implications for the development of squamous intraepithelial lesions of the cervix.

We have addressed the notion that the initiation and progression of human papillomavirus associated cancer of the uterine cervix are associated with alterations of Langerhans cells (LC) within the mucosal squamous epithelium. Since the transformation zone (TZ) of the cervix is the site where the majority of squamous intraepithelial lesions (SIL) are initiated, in contrast to the exocervix, we decided to investigate the influence of the local microenvironment within the TZ on the function and density of LC. We show that the TZ is associated with a significant reduction in the density of immature LC (CD1a/LAG) compared to the exocervix. In contrast, the development of SILs is attributed with a relative increased density of immature LC, compared to the TZ. Furthermore, we show that this variability in LC density is correlated with a differential expression of TNFalpha and MIP3alpha within the micro-environment of the TZ and SILs. Both TZ and SIL epithelium-derived LC, in the presence of allogeneic PBMC, induced lower levels of proliferation and IL2 production and higher levels of the immunosuppressive cytokine IL10 in comparison to the exocervix. Nevertheless, the epithelium-derived LC in SILs exhibits a reduction in their functional activity, relative to the TZ. Together our studies suggest that the immunosurveillance within the epithelium of the TZ may be intrinsically perturbed due to the altered expression of chemokines/cytokines and the concomitant diminished density of LC. Furthermore, following HPV infection and the development of SILs, the function of LC may be further incapacitated by viral associated mechanisms.

Antigen Presentation↗
PubMed2002

Anti-CD3/anti-epidermal growth factor receptor-bispecific antibody retargeting of lymphocytes against human neoplastic keratinocytes in an autologous organotypic culture model.

Local cellular immune defects have been described in several tumors including human papillomavirus (HPV)-associated cervical cancer. This observation suggests the potential therapeutic benefit of immune manipulations that restore cellular immunity. Here, we evaluated the ability of bispecific monoclonal antibodies (bimAbs) to redirect T cells against keratinocytes transformed in vitro by HPV in an autologous three-dimensional culture model (organotypic cultures). The epidermal growth factor receptor (EGFR) was chosen as target for an anti-CD3/anti-EGFR bimAb because it is overexpressed in many malignant epithelial lesions and only weakly expressed in the basal layers of normal squamous epithelium. Interestingly, in organotypic cultures, the pattern of expression of EGFR was similar to that observed in vivo. The ability of T cells retargeted by CD3/EGFR bimAb to lyse HPV-transformed cell lines was confirmed in monolayer cultures. In autologous organotypic cultures, an increase in apoptotic HPV(+) keratinocytes and a significant decrease in the thickness of HPV(+) organotypic cultures were observed when activated lymphocytes and bimAbs were added to the cultures, whereas organotypic cultures of normal keratinocytes were not significantly affected. These data were similar to those obtained in the allogeneic model. These results suggest the potential usefulness of CD3-EGFR bimAb-retargeted lymphocytes in immunotherapeutic protocols for malignant epithelial lesions.

Antibodies, Monoclonal↗
PubMed2002

[Epstein-Barr virus in Hodgkin's disease: the example of central Tunisia].

The purpose of this study was to evaluate the prevalence of Epstein-Barr virus in Hodgkin disease in Tunisia through a series of 77 cases. Association with Epstein-Barr virus was demonstrated by Epstein-Barr encoded early RNA transcripts (EBER) in situ hybridization in 70% of cases and by latent membrane protein 1 (LMP1) immunohistochemistry in 58.4% of cases. EBER positive cases were more frequent in extreme age classes (<15 and>54 years) there was no correlation with sex, histologic sub-type and clinical stage. Our findings show a high prevalence for EBV infection in Tunisian Hodgkin's disease particularly among extreme ages.

Adolescent↗