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Jacques Boniver

Publications and source records attributed to Jacques Boniver.

At least 19 recordsLinked to original sources
PubMed2006

Teaching communication and stress management skills to junior physicians dealing with cancer patients: a Belgian Interuniversity Curriculum.

BACKGROUND: Ineffective physicians' communication skills have detrimental consequences for patients and their relatives, such as insufficient detection of psychological disturbances, dissatisfaction with care, poor compliance, and increased risks of litigation for malpractice. These ineffective communication skills also contribute to everyday stress, lack of job satisfaction, and burnout among physicians. Literature shows that communication skills training programs may significantly improve physicians' key communication skills, contributing to improvements in patients' satisfaction with care and physicians' professional satisfaction. This paper describes a Belgian Interuniversity Curriculum (BIC) theoretical roots, principles, and techniques developed for junior physicians specializing in various disciplines dealing with cancer patients. CURRICULUM DESCRIPTION: The 40-h training focuses on two domains: stress management skills and communication skills with cancer patients and their relatives. The teaching method is learner-centered and includes a cognitive, behavioral, and affective approach. The cognitive approach aims to improve physicians' knowledge and skills on the two domains cited. The behavioral approach offers learners the opportunity to practice these appropriate skills through practical exercises and role plays. The affective approach allows participants to express attitudes and feelings that communicating about difficult issues evoke. Such an intensive course seems to be necessary to facilitate the transfer of learned skills in clinical practice. CONCLUSIONS: The BIC is the first attempt to bring together a stress management training course and a communication training course that could lead not only to communication skills improvements but also to burnout prevention.

Adaptation, Psychological↗
PubMed2006

Use of histone deacetylase 8 (HDAC8), a new marker of smooth muscle differentiation, in the classification of mesenchymal tumors of the uterus.

UNLABELLED: Uterine smooth muscle tumors (SMTs) are usually recognized on the basis of their routine morphologic features; however, their distinction from endometrial stromal tumors (ESTs), the second most common mesenchymal tumor of the uterus, is sometimes problematic. Histone deacetylases (HDACs) were originally identified as nuclear enzymes regulating histone acetylation. We have recently shown that in normal human tissues, HDAC8 is exclusively expressed in the cytoplasm of cells showing smooth muscle differentiation. In this study, we examined HDAC8 expression in SMTs and ESTs of the uterus to determine whether HDAC8 may be a useful diagnostic tool in the classification of problematic uterine mesenchymal tumors. HDAC8 immunohistochemical staining was performed in 15 leiomyomas (LMs), 9 highly cellular leiomyomas (HCLs), 8 epithelioid SMTs, 13 leiomyosarcomas (LMSs), and 17 ESTs, including 3 with sex-cord differentiation and 5 with smooth muscle differentiation. All tumors were also stained for other smooth muscle markers (desmin, h-caldesmon, smooth muscle actin [SMA], smooth muscle myosin heavy chain) and for CD10. All LMs had moderate to strong expression of all smooth muscle markers. HDAC8 was detected in 8 of 9 HCLs and in all epithelioid SMTs (8 of 8); however, it was weak in 4 epithelioid SMTs. In contrast, desmin, h-caldesmon and smooth muscle myosin were positive in only 2 of 8, 1 of 8 and 4 of 8 epithelioid SMTs, respectively. All smooth muscle markers had similar frequency of staining in LMSs; however, HDAC8 showed overall moderate intensity compared with other smooth muscle markers, which showed stronger staining. HDAC8, h-caldesmon, and smooth muscle myosin did not stain conventional areas of ESTs or ESTs with sex-cord differentiation, whereas SMA and desmin were positive in those areas in 4 of 12 and 3 of 12 ESTs, respectively. Areas of smooth muscle differentiation in ESTs were positive for HDAC8 in all cases, but they were less constantly positive for the other smooth muscle markers. CD10 was expressed in most ESTs (14 of 17), but it was also positive in 15 of 45 SMTs. IN CONCLUSION: 1) HDAC8 seems to be a specific marker of SM differentiation because conventional ESTs and ESTs with sex-cord differentiation are negative for HDAC8, whereas areas of smooth muscle differentiation in these tumors are consistently positive; 2) HDAC8 gives similar results to those obtained with desmin, h-caldesmon, and smooth muscle myosin in both LMs and LMSs, although the staining for HDAC8 in LMSs tends to be less intense; 3) HDAC8 may be a more sensitive marker than desmin and h-caldesmon in epithelioid SMTs. Thus, HDAC8 detection may be useful in helping the differential diagnosis of uterine mesenchymal tumors.

Biomarkers, Tumor↗
PubMed2005

Prostaglandin E2 induces the expression of functional inhibitory CD94/NKG2A receptors in human CD8+ T lymphocytes by a cAMP-dependent protein kinase A type I pathway.

The CD94/NKG2A heterodimer is a natural killer receptor (NKR), which inhibits cell-mediated cytotoxicity upon interaction with MHC class I gene products. It is expressed by NK cells and by a small fraction of activated T cells, predominantly of CD8+ phenotype. Abnormal upregulation of the CD94/NKG2A inhibitory NKR on cytotoxic T cells (CTLs) could be responsible for a failure of immunosurveillance in cancer or HIV infection. In an attempt to identify the mechanisms leading to inhibitory NKR upregulation on T cells, we analyzed the expression of the CD94/NKG2A heterodimer on human CTLs activated with anti-CD3 mAb in the presence of PGE2 or with 8-CPT-cAMP, an analogue of cyclic AMP. As previously described, anti-CD3 mAb-mediated activation induced the expression of CD94/NKG2A on a small fraction of CD8+ T cells. Interestingly, when low concentrations of PGE2 or 8-CPT-cAMP were present during the culture, the proportion of CD8+ T cells expressing CD94/NKG2A was two- to five-fold higher. This upregulation was partially prevented by PKA inhibitors, such as KT5720 and Rp-8-Br-cAMP (type I selective). We also report that cAMP induces upregulation of NKG2A at the mRNA level. We further demonstrated that cross-linking of CD94 on CD8+ T cells expressing the CD94/NKG2A heterodimer inhibits their cytotoxic activity in a bispecific antibody redirected lysis assay. Our findings clearly demonstrate that the PGE2/cAMP/PKA type I axis is involved in the expression of CD94/NKG2A receptor on human CD8+ T lymphocytes.

Antigens, CD↗
PubMed2005

Germinal center dendritic cells express more ICAM-1 than extrafollicular dendritic cells and ICAM-1/LFA-1 interactions are involved in the capacity of dendritic cells to induce PBMCs proliferation.

Germinal center dendritic cells (GCDCs) have been identified as CD11c(+) CD4(+) CD3(-) cells located in GCs with the ability of inducing marked proliferation of allogenic T cells. Using immunofluorescence techniques, we have observed that this CD11c(+) CD4(+) CD3(-) immunophenotype identified GCDCs but also a subset of extrafollicular DCs. By flow cytometry, we were able to discriminate the GCDCs (CD11c(high) CD4(high) lin(-)) from the other tonsil DCs. By immunofluorescence and flow cytometry, we found that dendritic cells of germinal centers express more intracellular adhesion molecule-1 (ICAM-1) (CD54) than extrafollicular dendritic cells. Proliferation of peripheral blood mononuclear cells (PBMCs) induced by coculture with purified CD11c(+) CD4(+) CD3(-) DCs was reduced by addition of blocking anti-CD54 antibodies. In summary, distinct levels of ICAM-1 expression allow the distinction between GCDCs and extrafollicular DCs, and cellular interactions mediated by CD54 are likely to play a role in the capacity of GCDC to stimulate allogenic PBMC proliferation.

CD11c Antigen↗
PubMed2005

Does psychological characteristic influence physicians' communication styles? Impact of physicians' locus of control on interviews with a cancer patient and a relative.

CONTEXT: Physicians' psychological characteristics may influence their communication styles and may thus interfere with patient-centred communication. OBJECTIVE: Our aim was to test the hypothesis that, in interviews with a cancer patient and a relative, physicians with an "external" locus of control (LOC; who believe that life outcomes are controlled by external forces such as luck, fate or others) have a communication style different from that of physicians with an "internal" LOC (who believe that life outcomes are controlled by their own characteristics or actions). DESIGN, SETTING, PARTICIPANTS AND INTERVENTION: Eighty-one voluntary physicians practising in the field of oncology were recorded while performing an actual and a simulated interview with a cancer patient and a relative. MAIN OUTCOME MEASURES: Physicians' communication skills were assessed using the Cancer Research Campaign Workshop Evaluation Manual. Physicians' LOC was assessed using the Rotter I-E scale. The communication skills of the upper and lower quartiles of physicians in respect of their scores on this scale were compared using Student's t test. RESULTS: In actual interviews, physicians with an "external" LOC talked more to the relative (P=0.017) and used more utterances with an assessment function (P=0.010) than physicians with an "internal" LOC. In simulated interviews, physicians with an "external" LOC used less utterances that give premature information (P=0.031) and used more utterances with a supportive function, such as empathy and reassurance (P=0.029), than physicians with an "internal" LOC. CONCLUSION: These results provide evidence that physicians' LOC can influence their communication styles. Physicians' awareness of this influence constitutes a step towards a tailoring of their communication skills to every patient's and relative's concerns and needs and thus towards a patient-centred communication.

Adult↗
PubMed2005

Factors that influence physicians' detection of distress in patients with cancer: can a communication skills training program improve physicians' detection?

BACKGROUND: No study to date has assessed the impact of skills acquisition after a communication skills training program on physicians' ability to detect distress in patients with cancer. METHODS: First, the authors used a randomized design to assess the impact, on physicians' ability to detect patients' distress, of a 1-hour theoretical information course followed by 2 communication skills training programs: a 2.5-day basic training program and the same training program consolidated by 6 3-hour consolidation workshops. Then, contextual, patient, and communication variables or factors associated with physicians' detection of patients' distress were investigated. After they attended the basic communication skills training program, physicians were assigned randomly to consolidation workshops or to a waiting list. Interviews with a cancer patient were recorded before training, after consolidation workshops for the group that attended consolidation workshops, and approximately 5 months after basic training for the group that attended basic training without the consolidation workshops. Patient distress was recorded with the Hospital Anxiety and Depression Scale before the interviews. Physicians rated their patients' distress on a visual analog scale after the interviews. Physicians' ability to detect patients' distress was measured through computing differences between physicians' ratings of patients' distress and patients' self-reported distress. Communication skills were analyzed according to the Cancer Research Campaign Workshop Evaluation Manual. RESULTS: Fifty-eight physicians were evaluable. Repeated-measures analysis of variance showed no statistically significant changes over time and between groups in physicians' ability to assess patient distress. Mixed-effects modeling showed that physicians' detection of patients' distress was associated negatively with patients' educational level (P = 0.042) and with patients' self-reported distress (P < 0.000). Mixed-effects modeling also showed that physicians' detection of patient distress was associated positively with physicians breaking bad news (P = 0.022) and using assessment skills (P = 0.015) and supportive skills (P = 0.045). CONCLUSIONS: Contrary to what was expected, no change was observed in physicians' ability to detect distress in patients with cancer after a communication skills training programs, regardless of whether physicians attended the basic training program or the basic training program followed by the consolidation workshops. The results indicated a need for further improvements in physicians' detection skills through specific training modules, including theoretical information about factors that interfere with physicians' detection and through role-playing exercises that focus on assessment and supportive skills that facilitate detection.

Communication↗
PubMed2005

Physicians' communication with a cancer patient and a relative: a randomized study assessing the efficacy of consolidation workshops.

BACKGROUND: Although patients with cancer are often accompanied by a relative during medical interviews, to the authors' knowledge little is known regarding the efficacy of communication skills training programs on physicians' communication skills in this context. The objective of the current study was to assess the efficacy of 6 consolidation workshops, 3 hours in length, that were conducted after a 2.5-day basic training program. METHODS: After attending the basic training program, physicians were assigned randomly to consolidation workshops or to a waiting list. Training efficacy was assessed through simulated and actual interviews that were recorded on an audio tape at baseline, after consolidation workshops for the consolidation-workshops group, and 5 months after the end of basic training for the waiting-list group. Communication skills were assessed according to the Cancer Research Campaign Workshop Evaluation Manual. Patients' and relatives' perceptions of and satisfaction with physicians' communication performance were assessed using a 15-item questionnaire. RESULTS: Sixty-two physicians completed the training program. Compared with physicians who participated to the basic training program, when addressing the patient, physicians who were randomized to the consolidation workshops used more open, open directive, and screening questions (P = 0.011 in simulated patient interviews and P = 0.005 in actual patient interviews) and elicited and clarified psychologic concerns more often (P = 0.006 in simulated patient interviews and P < 0.001 in actual patient interviews). When they addressed the relative, physicians who were randomized to the consolidation workshops gave less premature information (P = 0.032 in simulated patient interviews and P < 0.001 in actual patient interviews). When they addressed the patient and the relative simultaneously, physicians who were randomized to the consolidation workshops used more empathy, educated guesses, alerting to reality, confronting, negotiating, and summarizing (P = 0.003 in simulated patient interviews and P = 0.024 in actual patient interviews). Patients, but not relatives, who interacted with physicians in the consolidation-workshops group were more satisfied globally with the interviews (P = 0.022). CONCLUSIONS: Six 3-hour consolidation workshops resulted in improved communication skills addressed to patients and to relatives. The current results showed that the transfer of skills addressing relatives' concerns remained limited and that consolidation workshops should focus even more systematically on the practice of three-person interviews.

Communication↗
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

[Prevalence of Epstein-Barr virus in non-Hodgkin's lymphomas in central region of Tunisia].

The purpose of this study was to evaluate the prevalence of EBV in non-Hodgkin's lymphomas occuring in non-immunocopromised patients in Tunisia through a series of 126 cases. EBV was investigated by EBER oligonucleotide in situ hybridization (ISH) and LMP1-immunohistochemistry. Serological study of EBV has been performed before therapy in 28 patients. EBV was detected in tumor cells by ISH in 28/126 (22.2%) cases. Variable proportions of tumor cells were positive. LMP1 was identified in only 8 cases. EBV was more frequently observed in T-cell lymphomas (9/24 patients; 37.5%) than in B-cell lymphomas (19/102 patients; 18.6%) (p=0.04). There was a strong relationship between EBV and small intestine lymphomas (6/8 patients; 75%) and T/NK nasal type lymphomas (3/3 patients; 100%). EBV serological reactivation was noted in 7/13 patients in clinical stages III/IV and in only 1/10 patients in stages I/II (p=0.03). In conclusion, the prevalence of EBV in Tunisian non-Hodgkin's lymphomas is low but variable depending on the histological type and anatomical location with a predilection for small intestine and nasal lymphomas.

Epstein-Barr Virus Infections↗
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↗
PubMed2005

Differential expression of vascular endothelial growth factor and its receptors in hematopoietic and fatty bone marrow: evidence that neuropilin-1 is produced by fat cells.

Vascular endothelial growth factor (VEGF), its receptors (VEGFR-1, VEGFR-2) and neuropillin-1 (NRP-1) are expressed at variable levels in bone marrow. NRP-1expression is higher in fatty bone marrow than in hematopoietic marrow. Adipocytes are responsible for NRP-1 expression suggesting that they may play a role in hematopoiesis by producing NRP-1 or that NRP-1 may regulate adipocyte activity.

Adipocytes↗
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

Distinct clonal origin in two cases of Hodgkin's lymphoma variant of Richter's syndrome associated With EBV infection.

Occurrence of an aggressive lymphoma in patients with chronic lymphocytic leukemia (CLL), clinically referred to as Richter's syndrome, occasionally manifests as a lymphoproliferation resembling Hodgkin's lymphoma (HL) and often containing the Epstein-Barr virus (EBV). Only a limited number of HL variants have been subject to informative analysis regarding their clonal relationship to the CLL, with evidence of a same clonal origin in some cases and of clonally unrelated neoplasms in other cases. In this paper, we performed a detailed pathologic, virologic, and molecular analysis of two cases of Richter's syndrome with HL features. The first case occurred in a 65-year-old man with a 5-year history of CLL as a mediastinal and supraclavicular mass histologically diagnosed as lymphocyte depleted HL with no background CLL. The second case occurred in a 78-year-old woman with a 4-year history of CLL as an inguinal mass with a composite histologic appearance comprising areas of CLL, areas of CLL with Hodgkin Reed-Sternberg cells, and areas of HL. Both patients had received fludarabine therapy. The HRS cells were CD20-/CD30+/CD15-/J-chain- in case no. 1 and CD20+/-/CD30+/CD15-/J-chain- in case no. 2. In both cases, the Hodgkin's Reed-Sternberg cells (HRS) were positive for type A EBV, and a 30-bp deletion of the LMP-1 gene was detected in case no. 2. Using microdissection and polymerase chain reaction amplification of the immunoglobulin heavy chain gene (IgH) complementarity determining region III of each cell type, we demonstrated a distinct clonal origin for the CLL cells and the HRS in both cases. These cases bring support to the hypothesis that EBV+ HL in CLL patients occurs as unrelated secondary neoplasms most likely as the result of the immune depression associated with CLL and also raise the question of a possible causal role of fludarabine.

Aged↗
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↗