A Toubert

Paris Diderot University, Lutetia Parisorum, Île-de-France, France

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Publications (141)615.07 Total impact

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    ABSTRACT: Over the past 15 years, SCT has emerged as a promising treatment option for patients with severe autoimmune diseases (ADs). Mechanistic studies recently provided the proof-of-concept that restoration of immunological tolerance can be achieved by haematopoietic SCT in chronic autoimmunity through eradication of the pathologic, immunologic memory and profound reconfiguration of the immune system, that is, immune 'resetting'. Nevertheless, a number of areas remain unresolved and warrant further investigation to refine our understanding of the underlying mechanisms of action and to optimize clinical SCT protocols. Due to the low number of patients transplanted in each centre, it is essential to adequately collect and analyse biological samples in a larger cohort of patients under standardized conditions. The European society for blood and marrow transplantation Autoimmune Diseases and Immunobiology Working Parties have, therefore, undertaken a joint initiative to develop and implement guidelines for 'good laboratory practice' in relation to procurement, processing, storage and analysis of biological specimens for immune reconstitution studies in AD patients before, during and after SCT. The aim of this document is to provide practical recommendations for biobanking of samples and laboratory immune monitoring in patients with ADs undergoing SCT, both for routine supportive care purposes and investigational studies.Bone Marrow Transplantation advance online publication, 10 November 2014; doi:10.1038/bmt.2014.251.
    Bone marrow transplantation. 11/2014;
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    ABSTRACT: Immune reconstitution after allogeneic stem cell transplantation is a dynamic and complex process depending on the recipient and donor characteristics, on the modalities of transplantation and on the occurrence of graft-versus-host disease. Multivariate methods widely used for gene expression profiling, can simultaneously analyze the patterns of a great number of biological variables on a heterogeneous set of patients. Here we use these methods on flow cytometry assessment of up to 25 lymphocyte populations to analyze the global pattern of long-term immune reconstitution after transplantation. Immune patterns were most distinct from healthy controls at 6 months, and had not yet fully recovered as long as 2 years, after transplant. The two principal determinants of variability were linked to the balance of B and CD8+ T cells and of natural killer and B cells, respectively. Recipient's cytomegalovirus serostatus, cytomegalovirus replication, and chronic graft-versus-host disease were the main factors shaping the immune pattern 1 year after transplant. We identified a complex signature of under- and over-representation of immune populations dictated by recipient's cytomegalovirus seropositivity. Finally, we identified dimensions of variance in immune patterns as significant predictors of long-term non-relapse mortality, independently of chronic graft-versus-host disease.
    Haematologica 09/2014; · 5.94 Impact Factor
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    ABSTRACT: Using B-cell rearrangement excision circles measurements, we analyzed B-cell reconstitution in a cohort of 243 patients who underwent allogeneic stem cell transplantation. Acute and chronic graft vs. host disease (aGVHD and cGVHD) transiently increased B-cell replication but decreased overall B-cell neogenesis with a clear difference in term of kinetics. Moreover, impact of aGVHD in absence of cGVHD was transient, recovering at month 6 similar values than in patients who did not suffer from GVHD. Conversely, impact of cGVHD at month 12 in multivariate analysis was independent of previous aGVHD effect on B-cell output. Finally, we showed in patients affected with cGVHD a higher B-cell division rate that correlates with an elevated BAFF/CD19+ B cell ratio, supporting a B-cell hyperactivation state in vivo.
    Blood 09/2014; · 9.78 Impact Factor
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    ABSTRACT: The diverse aspects of Cutaneous T-cell lymphomas may impede the diagnosis of Sézary syndrome (SS) and mycosis fungoides (MF), in particular at early stages of the disease. We defined the CD158k/KIR3DL2 molecule as a first positive cell surface marker for Sézary cells (SCs). Here, we designed an optimized flow-cytometry gating strategy, allowing the definition of lymphocytes of different sizes and defects of cell surface markers. Quantification by cytomorphology, flow-cytometry or clonal evaluation, gave similar results at initial time points and during the evolution in a prospective study involving 64 consecutive cutaneous T-cell lymphoma or erythrodermic patients. We found that CD158k+T-cells and circulating CD4+T-cells from MF patients exhibited unexpected patterns of cell surface expression with a marked heterogeneity of circulating lymphocytes even at initial diagnosis. Taken together, our results show that a multistep gating of CD158k+ cells is reliable to assess tumor burden in case of SS and suggest that both circulating MF CD4+T-cells and CD158k+T-cells are not homogeneous distinct memory populations. Further phenotypic and functional characterization of such subsets is needed in order to better understand the underlying molecular mechanisms leading to the development of these diseases.Journal of Investigative Dermatology accepted article preview online, 26 August 2014. doi:10.1038/jid.2014.356.
    The Journal of investigative dermatology. 08/2014;
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    ABSTRACT: Natural killer cells are the first lymphocyte subset to reconstitute, and play a major role in early immunity after allogeneic hematopoietic stem cell transplantation. Cells expressing the activating receptor NKG2C seem crucial in the resolution of cytomegalovirus episodes, even in the absence of T-cells. We prospectively investigated Natural Killer cells reconstitution in a cohort of 439 adult recipients who underwent non T-cell depleted allogeneic hematopoietic stem cell transplantation between 2005 and 2012. Freshly collected blood samples were analyzed 3, 6, 12 and 24 months after transplantation. Data were studied with respect to conditioning regimen, source of stem cells, underlying disease, occurrence of Graft-versus-Host Disease, and profiles of cytomegalovirus reactivation. In multivariate analysis, we show that the absolute numbers of CD56brightNatural killer cells at month 3 were significantly higher after myeloablative than after reduced intensity conditioning. Acute Graft-versus-Host Disease impaired reconstitution of total and CD56dimNatural killer cells at month 3. In contrast, high Natural killer cell count at month 3 was associated with a lower incidence of chronic Graft-versus-Host Disease, independently from a previous episode of acute Graft-versus-Host Disease and stem cell source. NKG2C+CD56dim and total Natural killer cell count at M3 was lower in patients reactivating CMV between month 0 and month 3, but expanded greatly afterwards. These cells were also less numerous in patients who experienced subsequent reactivation between month 3 and month 6. Our results advocate a direct role of NKG2C-expressing Natural killer cells in the early control of cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation.
    Haematologica 08/2014; · 5.94 Impact Factor
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    ABSTRACT: Acute myeloid leukemia (AML) cells are killed by allogeneic NK cells. However, autologous NK cells from AML patients express decreased levels of activating receptors, and show reduced cytotoxicity. Here, we investigated how interactions between NK and AML cells might cause loss of NK cell activity in patients. Our results show that AML cell lines and primary blasts alter the NK cell phenotype, reducing their cytotoxic potential upon prolonged contact. Down-regulation of NK-cell-activating receptors was contact-dependent and correlated with conjugate formation. Time-lapse imaging of HL60 AML cell line and NK-cell interactions showed a high proportion of non-cytolytic contacts. Studies of NK-cell immunological synapses revealed a defect in lytic synapse formation. Namely, despite correct F-actin and LFA-1 recruitment, polarization of lytic granules toward primary blasts or AML cell lines was reduced. The NK-AML cell line synapses showed impairment of CD3ζ recruitment. Attempts to correct these synapse defects by cytokine stimulation of NK cells improved conjugate formation, but not granule polarization. Pre-treatment of AML cell lines with the immuno-modulating molecule lenalidomide significantly enhanced granule polarization. We speculate that combining immunomodulatory drugs and cytokines could increase AML cell sensitivity to autologous NK cells and reinforce the activity of allogeneic NK cells in adoptive immunotherapy.This article is protected by copyright. All rights reserved
    European Journal of Immunology 07/2014; · 4.97 Impact Factor
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    ABSTRACT: Activating anti-angiotensin type 1 receptor antibodies (AT1R-AA) have been described in patients with systemic scleroderma, an auto-immune disorder with clinical fibrotic features. Chronic graft-versus-host disease (cGvHD) after hematopoietic stem cell transplantation may have clinical fibrotic features, whose pathogenesis may be similar with systemic sclerosis.
    Transplantation 05/2014; · 3.78 Impact Factor
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    ABSTRACT: Previous studies on regulatory T-cell (Treg) reconstitution after allogeneic hematopoietic SCT (HSCT) have suggested that, within the GVHD process, imbalance between effector T cells and Tregs may be more important than the absolute numbers of circulating Tregs. No study has analyzed naive vs memory Treg reconstitution in a longitudinal cohort with large numbers of patients. The reconstitution of total and subsets of Treg was prospectively analyzed by flow cytometry in 185 consecutive recipients at 3, 6, 12 and 24 months after allogeneic HSCT. The levels of total, naive and memory Tregs increased, mainly within the memory subset, but remained lower than healthy controls up to 2 years after transplantation. Reduced-intensity conditioning and peripheral blood (PBSC) as the source of stem cells were associated with better 3-month reconstitution. In multivariate analysis, PBSC, recipient age ⩽25 and no anti-thymoglobulin in the conditioning regimen were associated with a better Treg reconstitution. Naive Treg long-term reconstitution was mainly influenced by recipient age. Whereas prior acute GVHD impaired Treg reconstitution, Treg subsets (absolute numbers and frequencies relative to CD4(+) T-cell subsets) at 3, 6 and 12 months after HSCT were not associated with the occurrence of a later episode of chronic GVHD.Bone Marrow Transplantation advance online publication, 19 May 2014; doi:10.1038/bmt.2014.105.
    Bone marrow transplantation. 05/2014;
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    ABSTRACT: Despite the effectiveness of immunosuppressive drugs, kidney transplant recipients still face late graft dysfunction. Thus, it is necessary to identify biomarkers to detect the first pathologic events and guide therapeutic target development. Previously, we identified differences in the T-cell receptor Vβ repertoire in patients with stable graft function. In this prospective study, we assessed the long-term effect of CD8(+) T-cell differentiation and function in 131 patients who had stable graft function. In 45 of 131 patients, a restriction of TCR Vβ diversity was detected and associated with the expansion of terminally differentiated effector memory (TEMRA; CD45RA(+)CCR7(-)CD27(-)CD28(-)) CD8(+) T cells expressing high levels of perforin, granzyme B, and T-bet. This phenotype positively correlated with the level of CD57 and the ability of CD8(+) T cells to secrete TNF-α and IFN-γ. Finally, 47 of 131 patients experienced kidney dysfunction during the median 15-year follow-up period. Using a Cox regression model, we found a 2-fold higher risk (P=0.06) of long-term graft dysfunction in patients who had increased levels of differentiated TEMRA CD8(+) T cells at inclusion. Collectively, these results suggest that monitoring the phenotype and function of circulating CD8(+) T cells may improve the early identification of at-risk patients.
    Journal of the American Society of Nephrology 03/2014; · 8.99 Impact Factor
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    British Journal of Haematology 02/2014; · 4.94 Impact Factor
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    ABSTRACT: Although hypereosinophilia associated with chronic graft-versus-host disease (GvHD) has long been recognized, biological data on this phenomenon are scarce. In this paper, we describe hypereosinophilia (HE) together with a clonal T-cell expansion in patients with chronic GvHD, versus control patients with acute or chronic GvHD, but without HE. These clonal expansions shared a CD8+, TC1 phenotype rather than a CD4+ TH2 profile. In contrast to the drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome, these allogeneic CD8+ clones do not recognize the epitopes of herpes viruses. Furthermore, these TC1 closnes do not produce interleukin 17 as described in the DRESS syndrome.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 01/2014; · 3.15 Impact Factor
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    ABSTRACT: Mismatched unrelated donor (MMUD) or umbilical cord blood (UCB) can be chosen as alternative donors for allogeneic stem cell transplantation but might be associated with long lasting immune deficiency. Sixty-six patients who underwent a first transplantation from either UCB or 9/10 MMUD (n= 36) and who survived beyond 3 months were evaluated. Immune reconstitution was prospectively assessed at sequential time points after transplantation. NK, B, CD4+ and CD8+T cells and their subsets as well as regulatory T cells (Treg) were studied. Detailed analyses on infections occurring after 3 months were also assessed. The 18-month cumulative incidences of infection-related death were 8 and 3%, and of infections were 72 and 57% after MMUD and UCB transplantation, respectively. Rates of infection per 12 patient-month were roughly 2 overall (1 for bacterial, 0.9 for viral and 0.3 for fungal infections). Memory, naïve CD4+ and CD8+T cells, naïve B cells and Treg cells reconstitution between the 2 sources was roughly similar. Absolute CD4+T cells hardly reached 500 per μL by one year post transplantation and most B cells were of naïve phenotype. Correlations between immune reconstitution and infection were then performed by multivariate analyses. Low CD4+ and high CD8+T cells absolute counts at 3 months were linked to increased risks of overall and viral (but not bacterial) infections. When assessing for the naïve/memory phenotypes at 3 months among the CD4+ T cell compartment, higher percentages of memory subsets were protective against late infections: central memory CD4+T cells protected against overall and bacterial infections; late effector memory CD4+T cells protected against overall, bacterial and viral infections. At the opposite, high percentage of effector- and late effector-memory subsets at 3 months among the CD8+ T cell compartment predicted higher risks for viral infections. Patients transplanted from alternative donors represent a population with very high risk of infection. Detailed phenotypic analysis of immune reconstitution may help to evaluate infection risk and to adjust infection prophylaxis.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 01/2014; · 3.15 Impact Factor
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    ABSTRACT: Immune recovery after profound lymphopenia is a major challenge in many clinical situations, such as allogeneic hematopoietic stem cell transplantation (allo-HSCT). Recovery depends, in a first step, on hematopoietic lymphoid progenitors production in the bone marrow (BM). In this study, we characterized CD34+Lin-CD10+ lymphoid progenitors in the peripheral blood of allo-HSCT patients. Our data demonstrate a strong recovery of this population 3 months after transplantation. This rebound was abolished in patients who developed acute graft-versus-host disease (aGVHD). A similar recovery profile was found for both CD24+ and CD24- progenitor subpopulations. CD34+lin-CD10+CD24- lymphoid progenitors sorted from allo-HSCT patients preserved their T cell potentiel according to in vitro T-cell differentiation assay and the expression profile of 22 genes involved in T-cell differentiation and homing. CD34+lin-CD10+CD24- cells from patients without aGVHD had reduced CXCR4 gene expression, consistent with an enhanced egress from the BM. CCR7 gene expression was reduced in patients after allo-HSCT, as were its ligands CCL21 and CCL19. This reduction was particularly marked in patients with aGVHD, suggesting a possible impact on thymic homing. Thus, the data presented here identify this population as an important early step in T cell reconstitution in humans and so, an important target when seeking to enhance immune reconstitution.
    PLoS ONE 01/2014; 9(3):e91492. · 3.53 Impact Factor
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    ABSTRACT: HLA-A*31:01 was reported to be associated with carbamazepine (CBZ)-induced severe cutaneous adverse reactions (SCAR), including drug reaction with eosinophilia and systemic symptoms (DRESS), Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). We conducted an international study using consensus diagnosis criteria to enroll a total of 93 patients with CBZ-SCAR from Europe or Asia. We found that HLA-A*31:01 showed a significant association with CBZ-DRESS in Europeans (P<0.001; odds ratio (OR) (95% confidence interval (CI))=57.6 (11.0-340)), and the strong association was also found in Chinese (P<0.001; OR (95% CI)=23.0 (4.2-125)). However, HLA-A*31:01 had no association with CBZ-SJS/TEN in neither Chinese nor Europeans. By comparison, HLA-B*15:02 showed a strong association with CBZ-SJS/TEN in Chinese (P<0.001, OR (95% CI)=58.1 (17.6-192)). A meta-analysis of this and other published studies confirmed that in all populations, HLA-A*31:01 had an extremely strong association with CBZ-DRESS (P<0.001, a pooled OR (95% CI)=13.2 (8.4-20.8)), but a much weaker association with CBZ-SJS/TEN (P=0.01, OR (95% CI)=3.94 (1.4-11.5)). Our data revealed that HLA-A*31:01 is a specific predictor for CBZ-DRESS but not for CBZ-SJS/TEN. More studies are needed to investigate the genetic determinant of CBZ-SJS/TEN in Europeans. Considering the potential clinical utility, the cost-effectiveness of the combined HLA-A*31:01 and HLA-B*15:02 genetic test to prevent CBZ-SCAR in Chinese needs further investigation.The Pharmacogenomics Journal advance online publication, 10 December 2013; doi:10.1038/tpj.2013.40.
    The Pharmacogenomics Journal 12/2013; · 5.13 Impact Factor
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    ABSTRACT: ABSTRACT Whether the efficacy of lenalidomide in the treatment of multiple myeloma (MM) is due to direct tumor toxicity only or to additional immunomodulatory effects is unclear. We studied the effect of lenalidomide treatment on T-cell immune reconstitution in MM patients who had undergone autologous peripheral blood stem cell transplantation (ASCT). Twenty-nine newly diagnosed MM patients received induction therapy followed by high-dose melphalan and ASCT. After ASCT, 11 patients received lenalidomide consolidation therapy for 2 months followed by maintenance therapy until disease progression. The remaining 18 patients received no treatment. Serial analysis of thymic output, as given by numbers of T-cell receptor excision circles (sjTREC), and T-cell phenotyping was performed until 18 months post-ASCT. Lenalidomide impaired long-term thymic T-cell reconstitution, decreased CD4+ and CD8+ CD45RA+CCR7- effector-terminal T-cell absolute counts and increased CD4+CD25+CD127-/low regulatory T-cells. Lenalidomide consolidation and long-term maintenance therapy, administered post-ASCT, may have a potentially negative impact on immune surveillance.
    Leukemia & lymphoma 11/2013; · 2.61 Impact Factor
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    ABSTRACT: A soluble isoform of MHC class I chain-related molecule A (soluble MICA), generated by proteolytic shedding from the membrane-bound MICA of various tumor cells, has been shown to downregulate both the expression of natural killer group 2-member D receptor and the cytotoxic function of effectors cells and was postulated as a mechanism for tumor immune evasion. Its effect on the expression of cytokines by the effector cells remained unexplored. Here we demonstrate that the sMICA molecules upregulate interferon gamma expression by interleukin-12/interleukin-18-activated CD3(-)CD56(+) natural killer cells, witnessing the pro-inflammatory effect of soluble MICA. Overall, these data are in line with our previous observations that the raised serum levels of soluble MICA, following allogeneic hematopoietic stem cell transplantation, confer susceptibility to and the presence of pre-transplantation anti-MICA antibodies in the patient's serum confer protection against chronic graft versus host disease.
    Human immunology 08/2013; · 2.55 Impact Factor
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    ABSTRACT: Crohn's disease (CD) is an inflammatory pathology of the mucosal intestine that results from uncontrolled immune response towards commensal microbes. Clonal expansions of T cells have been found in patients with CD suggesting an antigen-specific stimulation of pathogenic T cells. Here we show, using T-cell receptor repertoire analysis by real-time PCR, that oligoclonal expansions are found in both CD8+ and CD4+ T cells in the blood and intestinal mucosa of CD patients. The majority of CD4+ T-cell-expanded clones are CD4+NKG2D+ T cells. These clonal expansions were found in both inflamed and neighboring healthy tissue and were persisting during the course of the disease. The presence of these CD4+NKG2D+ T-cell clones at the macroscopically normal edge of the surgical resection might be predictive of inflammation relapse post surgery.Mucosal Immunology advance online publication, 14 August 2013; doi:10.1038/mi.2013.51.
    Mucosal Immunology 08/2013; · 7.54 Impact Factor
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    ABSTRACT: We, and others, previously reported the expansion of CD5+CD19+ B-cells after allogeneic hematopoietic stem cell transplantation (HSCT). Recently the equivalent of the B1 cells in mice have been described in human as CD20+CD27+CD43+CD70- B cells. Here we report that while 20% of CD5+CD19+ cells in controls were CD43+, over 75% of CD5+CD19+ were CD43 positive in patients whether or not they previously developed chronic GvHD (p=0.0001). CD5+CD19+ B cells, CD5+CD43+CD19+ B cells and B1 cells counts were significantly decreased in patients who previously developed chronic GvHD and this effect of GvHD affected CD5+ and CD5- similarly within the B1 cell subset. Thus our results strongly suggest that the previously reported expansion of the CD5+CD19+ population might be related to an expansion of the B1 cell subset, and that B1 cell reconstitution was impaired in patients who developed chronic GvHD.
    Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 03/2013; · 3.15 Impact Factor
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    ABSTRACT: Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin's lymphoma in adults. It is generally treated by a combination of chemotherapy and CD20-specific monoclonal antibodies, such as rituximab, which act, at least partially, by activating antibody-dependent cell-mediated cytotoxicity (ADCC). ADCC involves NK cells, particularly the CD56(dim) NK-cell subset expressing CD16, the low affinity Fcγ receptor. Here we show that CD16 expression levels are decreased in a cohort of 36 newly-diagnosed DLBCL patients compared with those in 20 healthy controls (HCs). CD137, a costimulatory molecule expressed on activated NK cells, was also expressed at lower levels in patients compared with controls. Cells sampled from our cohort also showed severely reduced degranulation activity when challenged with rituximab-coated tumor cells, which could not be corrected by stimulation with high doses of IL-2. These results suggest that rituximab-induced NK-cell ADCC could be defective in some DLBCL patients at diagnosis. These patients should be closely monitored and attempts made to improve their NK-cell function.
    European Journal of Immunology 02/2013; · 4.97 Impact Factor
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    ABSTRACT: Patients with Type 2 diabetes (T2D) are highly susceptible to infection and have an increased incidence of some tumors, possibly due to immune system dysfunction. In the innate cellular immune system, Natural Killer (NK) lymphocytes are important effectors responsible for controlling infections and combating tumor development. We analyzed NK cell subsets in 51 patients with long-standing T2D. Compared with healthy blood donors, diabetic patients showed a profound decrease in both NKG2D-positive NK cells (44% vs. 55.5%, P<0.01) and NKp46-positive cells (26% vs. 50%, P<0.01). Decreased expression of these receptors was associated with functional defects, such as reduced NK degranulation capacity when challenged with the tumor target cell line K562 (10.3 vs. 15.8%, P<0.05). This defect could be restored in vitro by stimulating NK cells from T2D patients with IL-15 (P<0.05). NKG2D expression was found to be negatively correlated with HBA1c level (r = -0.50; P = 0.009), suggesting that sustained hyperglycemia could directly influence NK cell defects. We demonstrated that endoplasmic reticulum (ER) stress, an important mediator in diabetes-associated complications, was inducible in vitro in normal NK cells and that tunicamycin treatment resulted in a significant decrease in NKG2D expression (P<0.05). Furthermore, markers of the Unfolded Protein Response (UPR) BiP, PDI and sXBP1 mRNAs were significantly increased in NK cells from T2D patients (P<0.05, P<0.01, P<0.05, respectively), indicating that ER stress is activated in vivo through both PERK and IRE1 sensors. These results demonstate for the first time defects in NK cell-activating receptors NKG2D and NKp46 in T2D patients, and implicate the UPR pathway as a potential mechanism. These defects may contribute to susceptibility to infections and malignancies and could be targetted therapeutically.
    PLoS ONE 01/2013; 8(4):e62418. · 3.53 Impact Factor

Publication Stats

2k Citations
615.07 Total Impact Points

Institutions

  • 2008–2014
    • Paris Diderot University
      Lutetia Parisorum, Île-de-France, France
  • 1996–2014
    • French Institute of Health and Medical Research
      Lutetia Parisorum, Île-de-France, France
  • 2013
    • Assistance Publique – Hôpitaux de Paris
      Lutetia Parisorum, Île-de-France, France
  • 2011
    • Pierre and Marie Curie University - Paris 6
      • Centre de recherche des Cordeliers - UMR_S 872
      Paris, Ile-de-France, France
  • 1998–2009
    • Unité Inserm U1077
      Caen, Lower Normandy, France
  • 2006
    • Centre Hospitalier de Versailles
      Versailles, Île-de-France, France
  • 2001–2005
    • Institut Universitaire de France
      Lutetia Parisorum, Île-de-France, France
  • 1988
    • Centre d'Immunologie de Marseille-Luminy
      Marsiglia, Provence-Alpes-Côte d'Azur, France