Publications (10)43.84 Total impact
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Article: Upregulation of Adhesion Molecules on Leukemia Targets Improves the Efficacy of Cytotoxic T Cells Transduced With Chimeric Anti-CD19 Receptor.
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ABSTRACT: T lymphocytes engineered to express chimeric antigen receptors (CARs) interact directly with cell surface molecules, bypassing MHC antigen presentation dependence. We generated human anti-CD19ζ CAR cytotoxic T lymphocytes and cytokine-induced killer cells and studied their sensitivity to the expression of adhesion molecules for the killing of primary B-lineage acute lymphoblastic leukemia (B-ALL) targets. Despite a very low basal expression of surface adhesion molecules, B-ALL blasts were lysed by the anti-CD19ζ-CAR transduced effectors as expected. We next investigated the regulatory role of adhesion molecules during CAR-mediated cytolysis. The blocking of these accessory molecules strongly limited the chimeric effector's cytotoxicity. Thereafter, B-ALL cells surface adhesion molecule level expression was induced by IFN-γ or by the combined use of CD40L and IL-4 and the cells were submitted to anti-CD19ζ-CAR transduced effectors lysis. Upregulation of adhesion molecules expression by blasts potentiated their killing. The improved cytotoxicity observed was dependent on target surface expression of adhesion molecules, particularly CD54. Taken together, these results indicate that adhesion molecules, and principally CD54, are involved in the efficiency of recognition by effector chimeric ζ. These observations have potential implications for the design of immunotherapy treatment approaches for hematological malignancies and tumors based on the adoption of CAR effector cells.Journal of immunotherapy (Hagerstown, Md.: 1997) 04/2013; 36(3):181-9. · 3.20 Impact Factor -
Article: HLA-A(*)0201(+) Plasmacytoid Dendritic Cells Provide a Cell-Based Immunotherapy for Melanoma Patients.
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ABSTRACT: Several sources of evidence suggest that tumor-specific T cells have the potential to control melanoma tumors. Current active and adoptive therapeutic approaches to elicit such T cells are either not sufficiently clinically efficient or require fastidious processes that impede their extensive clinical use. As plasmacytoid dendritic cells (pDCs) have a crucial role in triggering antitumor immunity especially in melanoma, we explored their potential as a cell-based approach for melanoma immunotherapy. An irradiated human HLA-A(*)0201(+) pDC line loaded with peptides derived from the major melanoma tumor antigens, MelA/MART-1, gp100/pmel17, tyrosinase, and MAGE-A3, was used to trigger functional multi-specific T cells ex vivo from peripheral blood mononuclear cells and tumor-infiltrating lymphocytes from stage I-IV HLA-A(*)0201(+) melanoma patients. pDCs loaded with melanoma-derived peptides promptly induced high levels of melanoma tumor-specific T cells from both sources. pDC-primed central/effector memory antitumor T cells were highly functional as indicated by the specific IFNγ secretion and membrane CD107 expression upon stimulation. Cells also exhibited strong cytotoxicity toward semi-allogeneic melanoma cells and patient-derived tumor cells. The simple design and potent efficacy of this promising approach provides a preclinical basis for the development of a pDC-based vaccine and an alternative means to produce tumor-specific T cells for adoptive cellular immunotherapy in melanoma patients.Journal of Investigative Dermatology 06/2012; 132(10):2395-406. · 6.31 Impact Factor -
Article: Photochemotherapy induces a faster apoptosis of alloreactive activated T cells than of nonalloreactive resting T cells in graft versus host disease.
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ABSTRACT: Graft versus host disease (GvHD) is the main complication after hematopoietic stem-cell transplantation.Extracorporeal photochemotherapy (ECP) is a cell therapy currently used for the treatment of T-cell–mediated diseases and seems as a valuable second-line therapy for patients suffering from steroid-refractory acute or chronic GvHD. ECP induces the apoptosis of treated cells and is believed to elicit a specific immune regulation of alloreactive T cells through repeated apoptotic T-cell infusions. However, its mechanisms of action have not yet been elucidated. In GvHD,alloreactive but not non alloreactive T cells are continuously activated by their environment. We hypothesized that ECP has a differential apoptotic effect on activated compared with resting T cells. The ECP-induced apoptosis of resting and activated T cells from patients with chronic GvHD was assessed.The kinetic of apoptosis was also evaluated using several triggers of T-cell activation such as mitogenic or antigen specific activation. The influence of survival cytokines (interleukin-2, -7, and -15) was also evaluated. Activated T cells from patients with chronic GvHD underwent apoptosis faster than resting T cells. This phenomenon was confirmed using mitogenic and antigen-specific activated T cells from healthy donors and cannot be delayed by protective cytokines. ECP induces a faster apoptosis of alloreactive activated T cells than of non alloreactive resting T cells in GvHD and more generally of activated T cells than of resting T cells. These novel findings provide new insights about the ECP-induced specific control of pathogenic T cells in GvHD.Transplantation 12/2010; 90(11):1232-8. · 4.00 Impact Factor -
Article: Photochemotherapy induces the apoptosis of monocytes without impairing their function.
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ABSTRACT: Extracorporeal photopheresis (ECP) is a powerful therapy currently used to treat various hematological disorders as in graft versus host disease. Clinical data clearly demonstrate its efficacy and immunomodulation toward the pathogenic T cells. However, ECP mechanism of action is still poorly understood. Monocytes represent up to 30% of the total amount of treated cells and are known to play an important role in adaptive immunity. However, data from previous reports analyzing the effect of psoralen and UV-A irradiation (PUVA) on their functions are heterogeneous. In this study, we focused on the effect of PUVA on human monocytes functions in adaptive immunity. Purified human monocytes were treated in vitro by PUVA. We measured their kinetic of apoptosis after the treatment. We also determine whether their phenotype and functionalities were modified. Finally, we assessed the functionalities of PUVA-treated monocytes-derived dendritic cells (DC). PUVA treatment sentenced purified monocytes to die in 6 days and immediately altered their migratory capacities without impairing their ability of endocytosis. It also up-regulated co-stimulatory molecules and production of inflammatory cytokines on activation and consequently stimulated allogeneic or autologous T cells as efficiently as untreated monocytes. Moreover, PUVA-treated monocytes retained their ability to differentiate into fully functional DC that maturated and stimulated T cells as well as normal DC. Our data demonstrate that monocytes undergo apoptosis and loose a part of their migratory capacity after ECP and the surviving cell functionalities are not impaired, suggesting that monocytes have a minor effect on ECP-mediated immunomodulation.Transplantation 03/2010; 89(5):492-9. · 4.00 Impact Factor -
Article: A novel cancer vaccine strategy based on HLA-A*0201 matched allogeneic plasmacytoid dendritic cells.
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ABSTRACT: The development of effective cancer vaccines still remains a challenge. Despite the crucial role of plasmacytoid dendritic cells (pDCs) in anti-tumor responses, their therapeutic potential has not yet been worked out. We explored the relevance of HLA-A*0201 matched allogeneic pDCs as vectors for immunotherapy. Stimulation of PBMC from HLA-A*0201(+) donors by HLA-A*0201 matched allogeneic pDCs pulsed with tumor-derived peptides triggered high levels of antigen-specific and functional cytotoxic T cell responses (up to 98% tetramer(+) CD8 T cells). The pDC vaccine demonstrated strong anti-tumor therapeutic in vivo efficacy as shown by the inhibition of tumor growth in a humanized mouse model. It also elicited highly functional tumor-specific T cells ex-vivo from PBMC and TIL of stage I-IV melanoma patients. Responses against MelA, GP100, tyrosinase and MAGE-3 antigens reached tetramer levels up to 62%, 24%, 85% and 4.3% respectively. pDC vaccine-primed T cells specifically killed patients' own autologous melanoma tumor cells. This semi-allogeneic pDC vaccine was more effective than conventional myeloid DC-based vaccines. Furthermore, the pDC vaccine design endows it with a strong potential for clinical application in cancer treatment. These findings highlight HLA-A*0201 matched allogeneic pDCs as potent inducers of tumor immunity and provide a promising immunotherapeutic strategy to fight cancer.PLoS ONE 01/2010; 5(5):e10458. · 4.09 Impact Factor -
Article: Exploration of the lysis mechanisms of leukaemic blasts by chimaeric T-cells.
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ABSTRACT: Adoptive transfer of specific cytotoxic T lymphocytes (CTL) and Cytokine Induced Killer Cells (CIK) following genetic engineering of T-cell receptor zeta hold promising perspective in immunotherapy. In the present work we focused on the mechanisms of anti-tumor action of effectors transduced with an anti-CD19 chimaeric receptor in the context of B-lineage acute lymphoblastic leukemia (B-ALL). Primary B-ALL blasts were efficiently killed by both z-CD19 CTL and z-CD19 CIK effectors. The use of death receptor mediated apoptosis of target cells was excluded since agonists molecules of Fas and TRAIL-receptors failed to induce cell death. Perforin/granzyme pathway was found to be the mechanism of chimaeric effectors mediated killing. Indeed, cytolytic effector molecules perforin as well as granzymes were highly expressed by CTL and CIK. CD19 specific stimulation of transduced effectors was associated with degranulation as attested by CD107 membrane expression and high IFN-gamma and TNF-alpha release. Moreover inhibitors of the perforin-based cytotoxic pathway, Ca(2+)-chelating agent EGTA and Concanamycin A, almost completely abrogated B-ALL blast killing. In conclusion we show that the cytolysis response of z-CD19 chimaeric effectors is predominantly mediated via perforin/granzyme pathway and is independent of death receptors signaling in primary B-ALL.Journal of Biomedicine and Biotechnology 01/2010; 2010:234540. · 2.44 Impact Factor -
Article: Immunomonitoring of graft-versus-host minor histocompatibility antigen correlates with graft-versus-host disease and absence of relapse after graft.
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ABSTRACT: After HLA-identical hematopoietic stem cell transplantation, minor histocompatibility (mH) antigen alloreactivity plays a dominant role in the development of graft-versus-host disease (GVHD) and graft versus leukemia (GVL). We have analyzed the mH alloreactivity (enzyme-linked immunospot [ELISpot] for interferon-gamma[IFN-gamma] assay) from 24 donor/recipient pairs over a period of 2 years of follow-up and correlated such alloreactivity with the development of GVHD or absence of relapse. Circulating specific T cells anti-mH with multimer HLA-peptides were also studied. We show by ELISpot IFN-gamma assay that alloreactivity during the first 3 months from donor versus recipient or donor versus mismatched identified mH antigens is associated with acute GVHD and GVL effect. In addition, we demonstrate that the donor-versus-recipient reactivity observed after the third month is highly associated with chronic GVHD and GVL (p = 0.0007). Finally, we show by multimer HLA-peptide assay that mH epitope-specific T cells present after 3 months are statistically related to the GVL effect. Our results provide a robust method to monitor mH antigen graft-versus-host reaction and suggest that current identified mH have predictive value on GVHD and GVL.Transfusion 10/2009; 50(2):418-28. · 3.22 Impact Factor -
Article: Phenotype frequencies of autosomal minor histocompatibility antigens display significant differences among populations.
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ABSTRACT: Minor histocompatibility (H) antigens are allogeneic target molecules having significant roles in alloimmune responses after human leukocyte antigen-matched solid organ and stem cell transplantation (SCT). Minor H antigens are instrumental in the processes of transplant rejection, graft-versus-host disease, and in the curative graft-versus-tumor effect of SCT. The latter characteristic enabled the current application of selected minor H antigens in clinical immunotherapeutic SCT protocols. No information exists on the global phenotypic distribution of the currently identified minor H antigens. Therefore, an estimation of their overall impact in human leukocyte antigen-matched solid organ and SCT in the major ethnic populations is still lacking. For the first time, a worldwide phenotype frequency analysis of ten autosomal minor H antigens was executed by 31 laboratories and comprised 2,685 randomly selected individuals from six major ethnic populations. Significant differences in minor H antigen frequencies were observed between the ethnic populations, some of which appeared to be geographically correlated.PLoS Genetics 07/2007; 3(6):e103. · 8.69 Impact Factor -
Article: Minor histocompatibility antigen DDX3Y induces HLA-DQ5-restricted T cell responses with limited TCR-Vbeta usage both in vivo and in vitro.
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ABSTRACT: In vitro stimulation of human female T cells with male HLA-identical dendritic cells resulted in the generation of HLA-DQB1*0501/0502-restricted minor histocompatibility H-Y antigen-specific CD4(+) T cell clones. Two clones generated from different HLA-identical pairs were analyzed. Use of HLA-DQ5-expressing female Epstein-Barr virus transformed B lymphoblastoid cell lines transfected with various H-Y genes and loaded with overlapping peptides demonstrated that both T cell clones are specific for a peptide encoded by DDX3Y. Previously, an HLA-DQ5-restricted T cell clone specific for the same peptide was isolated from a patient with graft-versus-host disease. Thus, we compared the T cell receptor (TCR) rearrangements of the 2 in vitro generated T cell clones and the ex vivo isolated T cell clone. All 3 clones shared the same TCRBV5-4* gene segment and 2 of 3 clones also used similar TCR-Valpha segments. Our results suggest that T cells recognizing the HLA-DQ5/DDX3Y T cell epitope might be characterized by a relatively limited TCR-beta repertoire. The differences in the junctional TCR-beta region had no effect on the antigen specificity, but altered the capacity of the TCR to distinguish the HLA-DQ5/DDX3Y complex from its allelic counterpart. The results also demonstrate that in vitro stimulation of T cells with allogeneic HLA-identical dendritic cells may facilitate the characterization of in vivo, potentially relevant HLA class II-restricted minor H epitopes.Biology of Blood and Marrow Transplantation 12/2006; 12(11):1114-24. · 3.87 Impact Factor -
Article: Allogeneic reaction induces dendritic cell maturation through proinflammatory cytokine secretion.
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ABSTRACT: A bone marrow transplantation conditioning regimen is known to activate host dendritic cells (DC), which then become able to initiate graft-versus-host disease (GVHD) by presenting alloantigens. In this article, the authors addressed whether the alloreaction could reciprocally maintain DC in an activation state through secretion of proinflammatory cytokines. Skin biopsy specimens from GVHD patients were analyzed for the presence of DC. Supernatants collected from primary major histocompatibility antigen (allogeneic mixed leukocyte reaction [MLR] supernatant [SN]) or secondary minor histocompatibility antigen-mismatched mixed lymphocyte reactions were used to culture cytokine-promoted immature (im) DC. DC phenotype, function, and migration were analyzed. Immunostaining from GVHD skin biopsy specimens showed a deficit of Langerhans cells (LC) in the epidermis but the presence of mature DC in the dermis. Because LC should have recovered in the epidermis by this time, the authors then addressed whether the allogeneic reaction could maintain DC in an activation and migratory state, through secretion of inflammatory cytokines. With this aim, cytokine-mediated imDC were exposed to alloMLR-SN for 2 days. The authors observed that DC increased their expression of CD80, CD86, CD40, and human leukocyte antigen (HLA)-DR and neoexpressed CD83, DC-LAMP/CD208, and CCR7. At the functional level, alloMLR-SN-treated DC lost their ability to capture dextran, improved their allostimulatory capacity, and migrated in response to macrophage inflammatory protein 3beta. Interestingly, SN collected from secondary HLA-identical but minor histocompatibility antigen-mismatched MLR induced almost equivalent DC phenotypic maturation. The authors' results show that the allogeneic reaction leads to maturation and migration of DC through proinflammatory cytokine secretion. This might contribute to the impairment of LC reconstitution in the skin of patients with GVHD.Transplantation 02/2004; 77(2):267-75. · 4.00 Impact Factor
Top co-authors
Top Journals
Institutions
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2013
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Azienda Ospedaliera San Gerardo
Monza, Lombardy, Italy
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2012
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Université Joseph Fourier - Grenoble 1
Grenoble, Rhone-Alpes, France
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2010
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INSERM, GIP CYCERON
Caen, Basse-Normandie, France
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2004–2010
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Etablissement Français du Sang (EFS)
Paris, Ile-de-France, France
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