Publications (9)33.4 Total impact
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Article: In vivo and in vitro comparison of three different allografts vitalized with human mesenchymal stromal cells.
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ABSTRACT: Bone allografts are commonly used by orthopedists to provide a mechanical support and template for cellular colonization and tissue repair. There is an increasing demand for bone graft substitutes that are safe and easy to store but which are equally effective in supporting new bone growth. In this study, we compared three different human bone allografts: (1) the cryopreserved allograft (frozen), (2) the gamma-irradiated and cryopreserved allograft (γ-irradiated), and (3) the solvent dehydrated and γ-irradiated-processed bone allograft (Tutoplast(®) Process Bone [TPB]). Human mesenchymal stromal cells (hMSCs) have the potential to differentiate into osteogenic, chondrogenic, and adipogenic lineages. Our results showed that hMSC seeding efficiency was equivalent among the three bone allografts. However, differences were observed in terms of cell metabolism (viability), osteoblastic gene expression, and in vivo bone formation. Frozen allografts had the higher frequency of new bone formation in vivo (89%). Compared with frozen allografts, we demonstrated that TPB allografts allowed optimal hMSC viability, osteoblastic differentiation, and bone formation to occur in vivo (72%). Further, the frequency of successful bone formation was higher than that obtained with the γ-irradiated allograft (55%). Moreover, after hMSC osteoinduction, 100% of the TPB and frozen allografts formed bone in vivo whereas only 61% of the γ-irradiated allografts did. As healthcare teams around the world require bone-grafting scaffolds that are safe and easy to store, the TPB allograft appears to be a good compromise between efficient bone formation in vivo and convenient storage at room temperature.Tissue Engineering Part A 05/2012; 18(17-18):1921-31. · 4.64 Impact Factor -
Article: Intracoronary autologous mononucleated bone marrow cell infusion for acute myocardial infarction: results of the randomized multicenter BONAMI trial.
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ABSTRACT: Intracoronary administration of autologous bone marrow cells (BMCs) leads to a modest improvement in cardiac function, but the effect on myocardial viability is unknown. The aim of this randomized multicentre study was to evaluate the effect of BMC therapy on myocardial viability in patients with decreased left ventricular ejection fraction (LVEF) after acute myocardial infarction (AMI) and to identify predictive factors for improvement of myocardial viability. One hundred and one patients with AMI and successful reperfusion, LVEF ≤45%, and decreased myocardial viability (resting Tl201-SPECT) were randomized to either a control group (n = 49) or a BMC group (n = 52). Primary endpoint was improvement of myocardial viability 3 months after AMI. Baseline mean LVEF measured by radionuclide angiography was 36.3 ± 6.9%. Bone marrow cell infusion was performed 9.3 ± 1.7 days after AMI. Myocardial viability improved in 16/47 (34%) patients in the BMC group compared with 7/43 (16%) in the control group (P = 0.06). The number of non-viable segments becoming viable was 0.8 ± 1.1 in the control group and 1.2 ± 1.5 in the BMC group (P = 0.13). Multivariate analysis including major post-AMI prognostic factors showed a significant improvement of myocardial viability in BMC vs. control group (P = 0.03). Moreover, a significant adverse role for active smoking (P = 0.04) and a positive trend for microvascular obstruction (P = 0.07) were observed. Intracoronary autologous BMC administration to patients with decreased LVEF after AMI was associated with improvement of myocardial viability in multivariate-but not in univariate-analysis. A large multicentre international trial is warranted to further document the efficacy of cardiac cell therapy and better define a group of patients that will benefit from this therapy. Clinical Trial Registration Information: URL: http://www.clinicaltrials.gov. Unique identifier NCT00200707.European Heart Journal 12/2010; 32(14):1748-57. · 10.48 Impact Factor -
Article: Cell therapy of hip osteonecrosis with autologous bone marrow grafting.
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ABSTRACT: One of the reasons for bone remodeling leading to an insufficient creeping substitution after osteonecrosis in the femoral head may be the small number of progenitor cells in the proximal femur and the trochanteric region. Because of this lack of progenitor cells, treatment modalities should stimulate and guide bone remodeling to sufficient creeping substitution to preserve the integrity of the femoral head. Core decompression with bone graft is used frequently in the treatment of osteonecrosis of the femoral head. In the current series, grafting was done with autologous bone marrow obtained from the iliac crest of patients operated on for early stages of osteonecrosis of the hip before collapse with the hypothesis that before stage of subchondral collapse, increasing the number of progenitor cells in the proximal femur will stimulate bone remodeling and creeping substitution and thereby improve functional outcome. Between 1990 and 2000, 342 patients (534 hips) with avascular osteonecrosis at early stages (Stages I and II) were treated with core decompression and autologous bone marrow grafting obtained from the iliac crest of patients operated on for osteonecrosis of the hip. The percentage of hips affected by osteonecrosis in this series of 534 hips was 19% in patients taking corticosteroids, 28% in patients with excessive alcohol intake, and 31% in patients with sickle cell disease. The mean age of the patients at the time of decompression and autologous bone marrow grafting was 39 years (range: 16-61 years). The aspirated marrow was reduced in volume by concentration and injected into the femoral head after core decompression with a small trocar. To measure the number of progenitor cells transplanted, the fibroblast colony forming unit was used as an indicator of the stroma cell activity. Patients were followed up from 8 to 18 years. The outcome was determined by the changes in the Harris hip score, progression in radiographic stages, change in volume determined by digitizing area of the necrosis on the different cuts obtained on MRI, and by the need for hip replacement. Total hip replacement was necessary in 94 hips (evolution to collapse) among the 534 hips operated before collapse (Stages I and II). Sixty-nine hips with stage I osteonecrosis of the femoral head at the time of surgery demonstrated total resolution of osteonecrosis based on preoperative and postoperative MRI studies; these hips did not show any changes on plain radiographs. Before treatment, these 69 osteonecrosis had only a marginal band like pattern as abnormal signal and a volume less than 20 cubic centimeters. The intralesional area had kept a normal signal as regards the signal of the femoral head outside the osteonecrosis area. For the 371 other hips without collapse at the most recent follow up (average 12 years), the mean preoperative volume of the osteonecrosis was 26 cm(3) (minimum 12, maximum 30 cm(3)). The mean volume of the abnormal signal measured on MRI at the most recent follow up (mean 12 years) was 12 cm(3). The abnormal signal persisting as a sequelae was seen on T1 images as an intralesional area of low intensity signal with a disappearance of the marginal band like pattern. According to our experience, best indication for the procedure is symptomatic hips with osteonecrosis without collapse. In some patients who had Steinberg stage III osteonecrosis (subchondral lucency, no collapse) successful outcomes (no further surgery) has been obtained between 5 to 10 years. Therefore in selected patients, even more advanced disease can be considered for core decompression. Patients who had the greater number of progenitor cells transplanted in their hips had better outcomes.Indian Journal of Orthopaedics 01/2009; 43(1):40-5. · 0.50 Impact Factor -
Article: Donor regulatory T cells identified by FoxP3 expression but also by the membranous CD4+CD127low/neg phenotype influence graft-versus-tumor effect after donor lymphocyte infusion.
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ABSTRACT: Regulatory T cells (Treg) play a pivotal role in the control of graft-versus-host disease (GVHD) and might also influence the graft-versus-tumor effect after allogeneic stem cell transplantation. We assessed this role after donor lymphocyte infusions (DLIs) by quantifying Treg in DLI products, using the CD25, Foxp3 but also the recently identified CD127 Treg markers. Compared with others, patients in durable complete remission of their malignancy after DLI had received a lower number of FoxP3CD25, FoxP3CD127, or CD4CD127 Treg cells (P=0.04). The CD4CD127 Treg content of DLI remained significantly correlated with the hematologic response in multivariate analysis (P=0.05). Treg may thus inhibit graft-versus-tumor effect after DLI, a setting where the antitumoral effect observed is only driven by T-cell-mediated cytotoxicity, independently of any other associated treatment. In comparison with the intracytoplasmic Foxp3 marker, the membranous CD4CD127 phenotype of Treg could be particularly relevant to manipulate this cell-population, to increase the antitumoral response in strategies of allogeneic or autologous immunotherapy.Journal of immunotherapy (Hagerstown, Md.: 1997) 11/2008; 31(9):806-11. · 3.20 Impact Factor -
Article: Peptides derived from the onconeural HuD protein can elicit cytotoxic responses in HHD mouse and human.
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ABSTRACT: Anti-Hu syndrome is a paraneoplastic neurologic disease seemingly associated with an efficient antitumoral immune response against HuD protein expressed by both small cell lung cancer (SCLC) and neurons. Since anti-Hu antibodies are not pathogenic, and oligoclonal CD8(+) T cells infiltrate neoplastic and nervous tissues, we examined MHC class I-restricted immunogenicity of human HuD. Among 14 HuD-derived peptides potentially immunogenic in HLA-A*0201 restriction, 10 had actual in vitro binding capacity to the HLA molecule, 8 elicited specific cytotoxic T lymphocytes (CTLs) in a humanized murine model after peptidic vaccination, 2 also elicited specific CTLs in healthy humans, and 1 was naturally processed and presented to the immune system.Journal of Neuroimmunology 10/2003; 142(1-2):93-100. · 2.96 Impact Factor -
Article: Severe decrease in peripheral blood dendritic cells in hairy cell leukaemia.
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ABSTRACT: Clinical studies in hairy cell leukaemia (HCL) have linked the frequent occurrence of infections due to intracellular pathogens and a profound monocytopenia. More recently, dendritic cells (DC), a subset of which are related to monocytes, were shown to be the professional antigen-presenting cells which stimulate the adaptive immune response. Using membrane markers and flow cytometry, we determined in peripheral blood whether various DC subsets and monocytes were impaired in HCL. Lymphoid and myeloid DC were virtually absent in five HCL patients with active disease. After treatment, both DC and monocytes recovered slowly. The decrease in DC suggests that defective antigen presentation could affect susceptibility to intracellular pathogens in HCL.British Journal of Haematology 04/2002; 116(3):595-7. · 4.94 Impact Factor -
Article: Multiple co-stimulatory signals are required for triggering proliferation of T cells from human secondary lymphoid tissue
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ABSTRACT: Vaccine-based therapies are being developed for a variety of cancers and their efficacy will be determined by their ability to stimulate T cells in the secondary lymphoid tissue. We found that T cells isolated from human secondary lymphoid organs (LT-T), in contrast to peripheral blood T cells (PB-T) are hyporesponsive to cross-linked anti-CD3 mAb (CD3c) even in the presence of exogenous IL-2. Using mAb to trigger CD2 and CD28 co-stimulatory molecules, we found that such dual co-stimulation of LT-T induces profound and sustained responses including CD25 expression, IL-2 secretion and proliferation. Different levels of co-stimulation produced a hierarchical pattern of responses in LT-T, which correlated with the degree of CD3–TCR down-regulation. Mature antigen-presenting cells (APC) restored the capacity of LT-T to proliferate to stimulation of the CD3–TCR complex. Blocking studies demonstrated that optimal proliferation was critically dependent on co-stimulation via CD2 and CD28 engaged by their ligands on the APC. Therefore, LT-T have increased co-stimulatory requirements as compared to PB-T, i.e. multiple co-stimulatory signals coupled to CD3–TCR triggering. Furthermore, LT-T were found to be dependent on APC for survival, in contrast to PB-T. Clearly, LT-T do not behave in a comparable way to PB-T and in vitro experiments assessing novel cancer vaccines should therefore use LT-T as the most appropriate population of responder T cells.International Immunology 05/2001; · 3.41 Impact Factor -
Article: IL-12 secreting dendritic cells are required for optimum activation of human secondary lymphoid tissue T cells.
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ABSTRACT: Successful immunization requires that mature dendritic cells (mDCs) prime T cells in secondary lymphoid tissue (LT). Previously, the authors have shown that LT T cell activation has an increased costimulatory threshold for a proliferative response as compared with peripheral blood (PB) T cells. Therefore, to optimize mDC immunogenicity, DC maturation was studied using LT T cells as responders. While mDCs obtained with soluble CD40Ligand (sCD40L) or a sCD40L/IFNgamma combination similarly expressed the CD83 and CCR7 molecules on their membrane, only the latter secreted IL-12. sCD40L/IFNgamma mDCs, as compared with sCD40L mDCs, enhanced allogeneic LT T cell proliferation, LT CD4+ cell IFNgamma production and LT CD8+ cell cytotoxicity. Enhancement could be predominantly ascribed to IL-12 secreted by sCD40L/IFNgamma mDCs and to additional costimulatory signals as shown remarkably in the IFNgamma response when IL-12 was neutralized. Therefore, in addition to their membrane phenotype, mDCs to be used in immunization protocols should be assessed for IL-12 secretion as a surrogate marker for an optimum costimulatory potential.Journla of Immunotherapy 25(4):324-33. · 3.27 Impact Factor -
Article: Adenoviral transduction of human ‘clinical grade’ immature dendritic cells enhances costimulatory molecule expression and T-cell stimulatory capacity
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ABSTRACT: The therapeutic use of dendritic cells (DC) in antigen-specific anti-tumor vaccines, requires sufficient numbers of functional DC, the preparation of which should comply with the code of Good Manufacturing Practice. In addition, the expression of tumor specific antigen should be possible in these DC. As a preclinical step, the method reported here was developed in healthy volunteers. Monocytes (Mo) were isolated by leukapheresis from 12 donors, purified by elutriation and then cultured for 6 days in sealed bags in AIM-V serum free medium with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-13 (IL-13). Between 6×108 and 1×109 immature DC (iDC) could be differentiated from one leukapheresis. Cells displayed a characteristic iDC phenotype (CD1a+, CD14−, CD80+, CD86+, HLA DR+, CD83−), and had potent allogeneic and antigen dependent autologous T cell-stimulatory capacity. Moreover, iDC could be further differentiated into mature DC by CD40 ligation as assessed by CD83 expression and the upregulation of HLA-DR and costimulatory molecules. After infection with a recombinant adenovirus encoding for beta-galactosidase (βGal), 50% to 80% of iDC expressed βGal without toxicity. Adenovirus infection increased the expression of both costimulatory molecules and CD83, and also increased allogeneic stimulatory capacity. Thus, the method developed here allows us to use large numbers of functional iDC as will be required for therapeutic uses in man. These DC can express a transgenic protein.Journal of Immunological Methods.
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2012
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Université Paris-Est Créteil Val de Marne - Université Paris 12
Créteil, Ile-de-France, France
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