Infusion of clinical-grade enriched regulatory T cells delays experimental xenogeneic graft-versus-host disease
Hannon, Muriel ; LECHANTEUR, Chantal ; et al
in Transfusion (in press)Detailed reference viewed: 24 (6 ULg)
Dendritic cells in Barrett's esophagus carcinogenesis: an inadequate microenvironment for antitumor immunity?
Somja, Joan ; Demoulin, Stéphanie ; RONCARATI, Patrick et al
in American Journal of Pathology (in press)Detailed reference viewed: 28 (6 ULg)
Human papillomavirus entry into NK cells requires CD16 expression and triggers cytotoxic activity and cytokine secretion
; ; Langers, Inge et al
Poster (2013, May)
Human papillomavirus (HPV) infections account for more than 50% of infection-linked cancers in women worldwide. The immune system controls, at least partially, viral infection and around 90% of HPV ... [more ▼]
Human papillomavirus (HPV) infections account for more than 50% of infection-linked cancers in women worldwide. The immune system controls, at least partially, viral infection and around 90% of HPV-infected women clear the virus within two years. However, it remains unclear which immune cells are implicated in this process and no study has evaluated the direct interaction between HPVs and NK cells, a key player in host resistance to viruses and tumors. We demonstrated an NK-cell infiltration in HPV- associated preneoplastic cervical lesions. Since HPVs cannot grow in vitro, virus-like particles (VLPs) were used as a model for studying the NK-cell response against the virus. Interestingly, NK cells displayed higher cytotoxic activity and cytokine production (TNF-a and IFN-g) in the presence of HPV-VLPs. Using flow cytometry and microscopy, we observed that NK-cell stimulation was linked to rapid VLP entry into these cells by macropinocytosis. Using CD16+ and CD16- NK-cell lines and a CD16-blocking antibody, we demonstrated that CD16 is necessary for HPV–VLP internalization, as well as for degranulation and cytokine production. Thus, we show for the first time that NK cells interact with HPVs and can participate in the immune response against HPV-induced lesions. [less ▲]Detailed reference viewed: 5 (0 ULg)
Clinical Utility of an Epigenetic Assay to Detect Occult Prostate Cancer in Histopathologically Negative Biopsies: Results of the MATLOC Study.
; ; DELVENNE, Philippe et al
in Journal of Urology (The) (2013), 189(3), 1110-1116
PURPOSE: Concern over possible false negative histopathology of prostate biopsies often leads to re-biopsy. A quantitative methylation-specific PCR (QMSP) assay panel, including GSTP1,APC and RASSF1 ... [more ▼]
PURPOSE: Concern over possible false negative histopathology of prostate biopsies often leads to re-biopsy. A quantitative methylation-specific PCR (QMSP) assay panel, including GSTP1,APC and RASSF1, could serve to increase the sensitivity to detect cancer over pathologic review alone, leading towards a high negative predictive value (NPV) and a decrease of unnecessary repeat biopsies. MATERIALS AND METHODS: The MATLOC (Methylation Analysis To Locate Occult Cancer) study blindly tested archived prostate biopsy needle core tissue samples of 498 subjects from the UK and Belgium with histopathologically negative prostate biopsies followed by either a positive (cases) or negative (controls) repeat biopsy within 30 months. The clinical performance of the epigenetic marker panel, emphasizing NPV, was assessed and cross-validated. Multivariate logistic regression was used to evaluate all risk factors. RESULTS: The epigenetic assay performed on the first, negative biopsies from this retrospective review cohort resulted in an NPV of 90% (95% CI, 87-93%). In a multivariate model, correcting for age, PSA, DRE and histopathological characteristics of the first biopsy, the epigenetic assay proved to be a significant, independent predictor of patient outcome with an odds ratio of 3.17 (95% CI, 1.81-5.53). CONCLUSIONS: A multiplex QMSP assay determining the methylation status of GSTP1,APC and RASSF1is strongly associated with the outcome of a repeat biopsy up to 30 months after an initial negative biopsy in men with suspicion of prostate cancer. The addition of this epigenetic assay could improve the prostate cancer diagnostic process and reduce unnecessary repeat biopsies. [less ▲]Detailed reference viewed: 13 (9 ULg)
Tumor microenvironment converts plasmacytoid dendritic cells into immunosuppressive/tolerogenic cells: insight into the molecular mechanisms
Demoulin, Stéphanie ; Herfs, Michael ; Delvenne, Philippe et al
in Journal of Leukocyte Biology (2013), 93(3), 343-352
Human pDCs represent a rare population of circulating cells characterized by a rapid and massive TLR-dependent secretion of type I IFN in response to pathogenic agents or danger signals. Through their ... [more ▼]
Human pDCs represent a rare population of circulating cells characterized by a rapid and massive TLR-dependent secretion of type I IFN in response to pathogenic agents or danger signals. Through their capacity to bring together innate and adaptive immunity and to secrete soluble factors controlling cancer development, these cells could represent important actors in antitumor immunity. However, accumulating evidence suggests that pDCs recruited to the tumor microenvironment often display a nonactivated state and are associated with the development and maintenance of immunosuppression. Here, we present an overview of neoplastic lesions associated with an infiltration of immunosuppressive/ tolerogenic pDC. Moreover, as the proper response of pDC against cancer depends on a critical balance between immune-activating and immune-suppressing mechanisms, we summarize current knowledge about the molecular pathways developed by tumors to prevent antitumoral pDC immune responses. A better understanding of the mechanisms regulating pDC function in tumors could aid in the development of new therapies. Indeed, effective cancer vaccines or therapies could combine immunoactivating strategies (i.e., TLR agonists) with elimination of immune-suppressing mechanisms, leading to pDC reprogramming and thus, allowing tumor rejection in a clinical setting. [less ▲]Detailed reference viewed: 47 (15 ULg)
Role of Gamma Delta T cells in HPV-induced Cancer Progression
Van hede, Dorien ; ; et al
Poster (2013, January 28)Detailed reference viewed: 18 (3 ULg)
Cutaneous melanocytomas: a conceptual cluster of atypical and indolent melanocytic neoplasms.
PIERARD, Gérald ; FRANCHIMONT, Claudine ; HERMANNS, Trinh et al
in Expert Review of Dermatology (2013), 8Detailed reference viewed: 2 (1 ULg)
Ruthenium oligonucleotides, targeting HPV16 E6 oncogene, inhibit the growth of cervical cancer cells under illumination by a mechanism involving p53
Reschner, Anca ; BONTEMS, Sébastien ; et al
in Gene Therapy (2013), 20(4), 435-443Detailed reference viewed: 29 (4 ULg)
Human papillomavirus predicts the outcome following concomitant chemoradiotherapy in patients with head and neck squamous cell carcinomas.
; ; et al
in Oncology Reports (2013), 30(1), 371-6
We investigated the prevalence of human papillomavirus (HPV) in a clinical series of 72 patients with head and neck squamous cell carcinoma (HNSCC) using a retrospective and prospective study design. The ... [more ▼]
We investigated the prevalence of human papillomavirus (HPV) in a clinical series of 72 patients with head and neck squamous cell carcinoma (HNSCC) using a retrospective and prospective study design. The majority of patients were smokers and/or drinkers and were treated with concomitant chemoradiotherapy (CCR). Furthermore, we assessed the impact of HPV positivity on the response to CCR. Paraffin-embedded samples from HNSCC patients (n=72) were evaluated for the presence of HPV DNA using both GP5+/GP6+ consensus PCR and type-specific E6/E7 PCR to detect HPV types 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 53, 56, 58, 59, 66, 67 and 68. The type-specific E6/E7 PCR demonstrated that 20 out of 69 HNSCC patients (29%) presented with high-risk (HR) HPV types and that 5 of the 69 HNSCC patients (7%) presented with low-risk (LR) HPV types. Using the GP5+/GP6+ PCR, we observed that the rate of response was statistically lower in the HPV+ group (P=0.02). Concerning patient outcomes in terms of recurrence and survival, we observed that the prognosis was poorer for HPV+ patients. We showed for the first time that patients with HPV+ HNSCC present with a worse prognosis after CCR. This observation highlights the need for prospective studies with large numbers of patients and a detailed history of tobacco and alcohol consumption before validating HPV as a marker of prognosis following CCR. [less ▲]Detailed reference viewed: 13 (2 ULg)
Expression of type 2 orexin receptor in human endometrium and its epigenetic silencing in endometrial cancer.
Dehan, Pierre ; ; et al
in Journal of Clinical Endocrinology and Metabolism (2013), 98(4), 1549-57
CONTEXT: Orexins A and B are neuropeptides that bind and activate 2 types of receptors. In addition to direct action in the brain, the orexinergic system has broader implications in peripheral organs, and ... [more ▼]
CONTEXT: Orexins A and B are neuropeptides that bind and activate 2 types of receptors. In addition to direct action in the brain, the orexinergic system has broader implications in peripheral organs, and it has been proposed to have a role in the induction of apoptosis. There are very few data on the endometrium. OBJECTIVE: The expression and epigenetic regulation of type 2 orexin receptor (OX2R) was investigated in the human endometrium as well as in endometrial endometrioid carcinoma (EEC). METHODS: OX2R localization was studied by immunohistochemistry in normal endometrium (n = 24) and in EEC (n = 32). The DNA methylation status of a CpG island located in the first exon of OX2R was analyzed by bisulfite sequencing in normal (n = 18), EEC (n = 34), and 3 endometrial cell lines. On the latter, mRNA expression and Western blotting as well as in vitro induction with orexin were performed. RESULTS: Expression of the OX2R protein was detected in normal endometrial epithelia, whereas it was frequently lacking in EEC. This loss was associated with hypermethylation of OX2R in EEC in comparison with normal endometrium (median CpG methylation percentages of 48.85% and 5.85%, respectively). In cell lines, hypermethylation correlated with weak OX2R expression. Additionally, in vitro treatment of the 3 EEC cell lines with orexins A and B did not result in proliferation change CONCLUSIONS: Altogether our data provide evidence for the epigenetic silencing of OX2R in EEC. The implication of the OX2R loss in tumoral progression remains to be elucidated. [less ▲]Detailed reference viewed: 1 (1 ULg)
Characterization of spontaneous collagen fibrillogenesis in a cell-free and tension-free environment.
PIERARD, Gérald ; Hermanns-Lê, Trinh ; Delvenne, Philippe et al
in Clinical & Experimental Dermatology (2013)
The collagen fibril packing that forms threads and bundles is poorly defined, despite the fact that it is important for distinct aspects of the adventitial and reticular dermis. The present study explored ... [more ▼]
The collagen fibril packing that forms threads and bundles is poorly defined, despite the fact that it is important for distinct aspects of the adventitial and reticular dermis. The present study explored an in vitro fibrillogenesis model using the property of heat polymerization. The process was performed on glass slides with mixtures of collagen I and III, and the material was viewed by scanning electron microscopy. In all instances, collagen I and III formed fibrils with regular sizes. The formation of threads was influenced by the relative proportions of collagen I and III; increasing the relative proportion of collagen I resulted in the formation of threads showing increasing variations in thickness. These findings are in line with the differential presentation and compositions of the different parts of the dermis. The possible interventions of stromal cells and of other macromoleules of the extracellular matrix were not considered in this study. [less ▲]Detailed reference viewed: 9 (1 ULg)
Novel cooperation between CX3CL1 and CCL26 inducing NK cell chemotaxis via CX3CR1: a possible mechanism for NK cell infiltration of the allergic nasal tissue.
EL SHAZLY, Amr ; ; et al
in Clinical & Experimental Allergy : Journal of the British Society for Allergy & Clinical Immunology (2013), 43(3), 322-31
BACKGROUND: Recent data indicated that natural killer (NK) cells and chemokines could play a pivotal role in nasal inflammation. CX3CR1, the only receptor for fractalkine/CX3CL1, is abundantly expressed ... [more ▼]
BACKGROUND: Recent data indicated that natural killer (NK) cells and chemokines could play a pivotal role in nasal inflammation. CX3CR1, the only receptor for fractalkine/CX3CL1, is abundantly expressed by NK cells, and was recently shown to also be a receptor for eotaxin-3/CCL26. However, no reports explored the NK cells-CX3CL1-CCL26 axis via CX3CR1 in allergy. OBJECTIVE: Our goals were first to determine specifically NK cell recruitment pattern in nasal tissue of allergic chronic rhinosinusitis (ACRS) and non-allergic chronic rhinosinusitis (NACRS) patients in comparison with healthy controls, and secondly, to investigate the function of CX3CR1 in NK cell migration. METHODS: Immunohistochemistry, microchemotaxis chambers, flow cytometry and confocal microscopy were used in this study. RESULTS: Herein, we showed that NK cells infiltrated the epithelial layers of nasal tissue only in ACRS patients and not in NACRS patients or controls. NK cells were also more numerous in the stroma of the nasal tissue from ACRS patients compared with NACRS patients or controls. This migration could be mediated by both CX3CL1 and CCL26, as these two chemokines induced NK cell migration. Moreover, both molecules also stimulated cytoskeleton changes and F-actin reorganisation in NK cells. Chemotaxis and cytoskeleton changes were sensitive to genistein, a tyrosine kinase inhibitor. By flow cytometry, we demonstrated that a single antigen nasal provocation challenge increased the expression of CX3CR1 on NK cells in allergic rhinitis (AR) patients. The function of this receptor was associated with a significant augmentation of NK cell chemotaxis against the optimal doses of CX3CL1 and CCL26. CONCLUSIONS AND CLINICAL RELEVANCE: Our results highlight a novel role for CX3CR1 in NK cell migration that may contribute to the NK cell trafficking to the allergic upper airway. This could be mediated largely by CX3CL1 and CCL26 stimulation of the tyrosine kinase pathway. [less ▲]Detailed reference viewed: 10 (1 ULg)
Dendritic cells in Barrett's carcinogenesis: an inadequate environment for antitumor immunity?
Somja, Joan ; Demoulin, Stéphanie ; RONCARATI, Patrick et al
Conference (2013)Detailed reference viewed: 14 (4 ULg)
Evaluation of a new biocompatible poly(N-(morpholino ethyl methacrylate)-based copolymer for the delivery of ruthenium oligonucleotides, targeting HPV16 E6 oncogene
Reschner, Anca ; ; et al
in Journal of Biomedical Nanotechnology (2013), 9
This study investigates the use of a new biocompatible block copolymer poly(2-(dimethylamino)ethyl methacrylate-N-(morpholino)ethyl methacrylate (PDMAEMA-b-PMEMA) for the delivery of a particular ... [more ▼]
This study investigates the use of a new biocompatible block copolymer poly(2-(dimethylamino)ethyl methacrylate-N-(morpholino)ethyl methacrylate (PDMAEMA-b-PMEMA) for the delivery of a particular antisense oligonucleotide targeting E6 gene from human papilloma virus. This antisense oligonucleotide was derivatized with a polyazaaromatic RuII complex which, under visible illumination, is able to produce an irreversible crosslink with the complementary targeted sequence. The purpose of this study is to determine whether by the use of a suitable transfection agent, it is possible to increase the efficiency of the antisense oligonucleotide targeting E6 gene, named Ru-P-4. In a recent study, we showed that Oligofectamine® transfected Ru-P-4 antisense oligonucleotide failed to inhibit efficiently the growth of cervical cancer cell line SiHa, contrarily to the Ru-P-6 antisense oligonucleotide, another sequence also targeting the E6 gene. The ability of PDMAEMA-b-PMEMA to form polyplexes with optimal physicochemical characteristics was investigated first. Then the ability of the PDMAEMA-b-PMEMA/Ru-P-4 antisense oligonucleotide polyplexes to transfect two keratinocyte cell lines (SiHa and HaCat) and the capacity of polyplexes to inhibit HPV16 + cervical cancer cell growth was evaluated. PDMAEMA-b-PMEMA base polyplexes at the optimal molar ratio of polymer nitrogen atoms to DNA phosphates (N/P), were able to deliver Ru-P-4 antisense oligonucleotide and to induce a higher growth inhibition in human cervical cancer SiHa cells, compared to other formulations based on Oligofectamine®. [less ▲]Detailed reference viewed: 31 (9 ULg)
Echocardiographic integrated backscatter for detecting progression and regression of aortic valve calcifications in rats.
; ; et al
in Cardiovascular Ultrasound (2013), 11(1), 4
ABSTRACT: BACKGROUND: Calcification is an independent predictor of mortality in calcific aortic valve disease (CAVD). The aim of this study was to evaluate the use of non-invasive, non-ionizing ... [more ▼]
ABSTRACT: BACKGROUND: Calcification is an independent predictor of mortality in calcific aortic valve disease (CAVD). The aim of this study was to evaluate the use of non-invasive, non-ionizing echocardiographic calibrated integrated backscatter (cIB) for monitoring progression and subsequent regression of aortic valvular calcifications in a rat model of reversible renal failure with CAVD, compared to histology. METHODS: 28 male Wistar rats were prospectively followed during 21 weeks. Group 1 (N=14) was fed with a 0.5% adenine diet for 9 weeks to induce renal failure and CAVD. Group 2 (N=14) received a standard diet. At week 9, six animals of each group were killed. The remaining animals of group 1 (N=8) and group 2 (N=8) were kept on a standard diet for an additional 12 weeks. cIB of the aortic valve was calculated at baseline, 9 and 21 weeks, followed by measurement of the calcified area (Ca Area) on histology. RESULTS: At week 9, cIB values and Ca Area of the aortic valve were significantly increased in the adenine-fed rats compared to baseline and controls. After 12 weeks of adenine diet cessation, cIB values and Ca Area of group 1 decreased compared to week 9, while there was no longer a significant difference compared to age-matched controls of group 2. CONCLUSIONS: cIB is a non-invasive tool allowing quantitative monitoring of CAVD progression and regression in a rat model of reversible renal failure, as validated by comparison with histology. This technique might become useful for assessing CAVD during targeted therapy. [less ▲]Detailed reference viewed: 13 (3 ULg)
Interleukin-32 expression is associated with a poorer prognosis in head and neck squamous cell carcinoma.
; Mouallif, Mustapha ; Hubert, Pascale et al
in Molecular Carcinogenesis (2013)
Head and neck squamous cell carcinoma (HNSCC) represent the sixth most common malignancy diagnosed worldwide. Patient's survival is low due the high frequency of tumor recurrence. Inflammation promotes ... [more ▼]
Head and neck squamous cell carcinoma (HNSCC) represent the sixth most common malignancy diagnosed worldwide. Patient's survival is low due the high frequency of tumor recurrence. Inflammation promotes carcinogenesis as well as the formation of metastasis. Indeed, proinflammatory mediators are known to stimulate the expression of specific transcription factors such as Snai1 and to increase the ability of tumor cells to migrate into distant organs. The atypical interleukin-32 (IL32) was mainly described to exacerbate inflammatory responses in rheumatoid arthritis and inflammatory bowel diseases. IL32 is expressed in various cancers but its role in HNSCC physiology is still unexplored. Here, we analyzed the expression of IL32 and its implication on HNSCC aggressiveness. We showed that patients with tumor expressing high amounts of IL32 exhibit decreased disease-free periods (20.5 mo vs. 41 mo, P = 0.0041) and overall survival (P = 0.0359) in comparison with individuals with weak IL32 tumor expression. This overexpression was negatively correlated with gender (P = 0.0292) and p53 expression (P = 0.0307). In addition, in vitro data linked IL32 expression to metastasis formation since IL32 inhibition decreased Snai1 expression and tumor cell migration in a Boyden chamber assay. Our data provide new insight into the role of IL32 in HNSCC aggressiveness. (c) 2013 Wiley Periodicals, Inc. [less ▲]Detailed reference viewed: 17 (4 ULg)
Role of γδ T cells in HPV-induced cancer progression
Van hede, Dorien ; ; et al
Poster (2012, December 10)Detailed reference viewed: 16 (4 ULg)
Oncogenic human papillomavirus could directly interact with Natural Killer cells
; Bastin, Renaud ; Boniver, Jacques et al
Poster (2012, December 10)Detailed reference viewed: 11 (9 ULg)
Role of γδ T cells in the tumoural progression of HPV-associated lesions
Van hede, Dorien ; ; et al
Conference (2012, November 09)Detailed reference viewed: 11 (1 ULg)
Infusion of third party mesenchymal stem cells (MSC) after kidney and liver transplantation: a phase I-II, open-label, clinical study
DETRY, Olivier ; DELBOUILLE, Marie-Hélène ; LECHANTEUR, Chantal et al
Conference (2012, October 19)
MSC cells have demonstrated significant immunosuppressive effects in various in vivo and in vitro studies. This study aims to be the first evaluation of the safety and tolerability of third party MSC ... [more ▼]
MSC cells have demonstrated significant immunosuppressive effects in various in vivo and in vitro studies. This study aims to be the first evaluation of the safety and tolerability of third party MSC infusion after cadaveric kidney and liver transplantation in a prospective phase I-II study, taking advantage of our centre expertise and experience in MSC use in graft-versus-host disease (GVHD) after bone marrow transplantation and using an already functioning GMP-compliant laboratory producing clinical-grade MSC. Secondary end-points will help to evaluate the immunosuppressive potential of MSC after organ transplantation, and the opportunity to develop larger randomised, controlled, phase III trials. After successful transplantation, 10 liver and 10 kidney transplant recipients under standard immunosuppression (tacrolimus, MMF, steroids) will receive an intravenous infusion of 1.5-3x106/kg of third-party MSC on post-operative day 3±2. These patients will be prospectively compared to 10 liver and 10 kidney recipients who meet the inclusion criteria but deny MSC infusion. Safety will be assessed by recording side effects, including opportunistic infections and cancers. Immunosuppressive potential will be evaluated by rejection episode rates, by graft/patient survivals, by immunohistology of 3-months kidney and 6-month liver graft biopsies and by in vitro evaluation of the immunity profile of the recipients. In a second step, reduction (kidney) and progressive weaning (liver) of immunosuppression will be attempted in recipients who received MSC. This ongoing study is supported by research grants from the CHU of Liège, University of Liège, and by the Senior Clinical Research Grant from ESOT. The first patients were included and treated in early 2012, and final results expected in late 2013. [less ▲]Detailed reference viewed: 47 (4 ULg)