63 results on '"André-Schmutz I"'
Search Results
2. Improving immune reconstitution while preventing GvHD in allogeneic stem cell transplantation
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Andre-Schmutz, I, Cortivo, L Dal, Fischer, A., and Cavazzana-Calvo, M.
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- 2005
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3. Haematopoietic stem cell transplantation in RAG immunodeficient mice: effect of Interleukin-7 treatment on increasing MHC incompatibility
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André-Schmutz, I., Bonhomme, D., Yates, F., Malassis, M., Seltz, F., Fischer, A., and Cavazzana-Calvo, M.
- Published
- 2004
4. AK2 deficiency compromises the mitochondrial energy metabolism required for differentiation of human neutrophil and lymphoid lineages
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Six, E, Lagresle-Peyrou, C, Susini, S, De Chappedelaine, C, Sigrist, N, Sadek, H, Chouteau, M, Cagnard, N, Fontenay, M, Hermine, Olivier, Chomienne, C, Reynier, Pascal, Fischer, Alain, André-Schmutz, I, Gueguen, Naïg, Cavazzana, M, Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chaire Médecine expérimentale (A. Fischer), and Collège de France (CdF (institution))
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Neutrophils ,Adenine Nucleotides ,Gene Expression Profiling ,Stem Cells ,Primary Cell Culture ,HL-60 Cells ,Cell Differentiation ,Leukopenia ,Oxidative Phosphorylation ,adenylate kinase ,mitochondria ,Gene Expression Regulation ,Gene Knockdown Techniques ,Mutation ,Humans ,Severe Combined Immunodeficiency ,CD34 ,Lymphocytes ,Antigens ,[SDV.MHEP]Life Sciences [q-bio]/Human health and pathology - Abstract
International audience; Reticular dysgenesis is a human severe combined immunodeficiency that is primarily characterized by profound neutropenia and lymphopenia. The condition is caused by mutations in the adenylate kinase 2 (AK2) gene, resulting in the loss of mitochondrial AK2 protein expression. AK2 regulates the homeostasis of mitochondrial adenine nucleotides (ADP, ATP and AMP) by catalyzing the transfer of high-energy phosphate. Our present results demonstrate that AK2-knocked-down progenitor cells have poor proliferative and survival capacities and are blocked in their differentiation toward lymphoid and granulocyte lineages. We also observed that AK2 deficiency impaired mitochondrial function in general and oxidative phosphorylation in particular - showing that AK2 is critical in the control of energy metabolism. Loss of AK2 disrupts this regulation and leads to a profound block in lymphoid and myeloid cell differentiation.
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- 2015
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5. Donor T lymphocyte infusion following ex vivo depletion of donor anti-host reactivity by a specific anti–interleukin-2 receptor P55 chain immunotoxin
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André-Schmutz, I, Le Deist, F, Hacein-Bey, S, Hamel, Y, Vitetta, E, Schindler, J, Fischer, A, and Cavazzana-Calvo, M
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- 2002
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6. Adoptive Immunotherapy with Donor Allodepleted T Cells.
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Dal Cortivo, L., Mahlaoui, N., Picard, C., Neven, B., Andre-Schmutz, I., Luby, J.M., Martinache, C., Paquet, T., Ledeist, F., Fischer, A., and Cavazzana-Calvo, M.
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- 2005
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7. Selective allodepletion.
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Cavazzana-Calvo, M. and André-Schmutz, I.
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STEM cells , *HEMATOPOIETIC stem cells , *BONE marrow cells , *TRANSPLANTATION of organs, tissues, etc. , *GRAFT rejection , *VIRUS diseases - Abstract
The article informs that GvHD, which was the main limitation of allogeneic hematopoietic stem cell transplantation (HSCT), has been almost completely eliminated by extensive depletion of donor T cells from the graft combined with profound immunosuppressive treatment. However, the consequence of these non-specific strategies is a long-lasting immunodeficiency associated with increased incidence of disease relapse, graft rejection and reactivation of viral infections. It informs that over the last 10-15 years a number of research teams in Europe and North America have worked out various alloselective approaches from first principles, through translational research to clinical trials.
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- 2005
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8. Gene therapy targeting haematopoietic stem cells for inherited diseases: progress and challenges.
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Cavazzana M, Bushman FD, Miccio A, André-Schmutz I, and Six E
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- Anemia, Sickle Cell genetics, Animals, Genetic Engineering, Humans, Severe Combined Immunodeficiency genetics, beta-Thalassemia genetics, Anemia, Sickle Cell therapy, Genetic Therapy methods, Genetic Vectors administration & dosage, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells cytology, Severe Combined Immunodeficiency therapy, beta-Thalassemia therapy
- Abstract
Pioneering gene therapy trials have shown that the genetic engineering of haematopoietic stem and progenitor cells can be an alternative to allogeneic transplantation in the treatment of primary immunodeficiencies. Early trials also highlighted the risk of insertional mutagenesis and oncogene transactivation associated with the first generation of gammaretroviral vectors. These events prompted the development of safer, self-inactivating lentiviral or gammaretroviral vectors. These lentiviral vectors have been successfully used to treat over 200 patients with 10 different haematological disorders (including primary immunodeficiencies, haemoglobinopathies and metabolic disorders) and for the generation of chimeric antigen receptor-T cells for cancer therapy. However, several challenges, such as effective reconstitution during inflammation, remain if gene therapy is to be extended to more complex diseases in which haematopoietic stem and progenitor cells can be altered by the disease environment. We discuss the progress made and future challenges for gene therapy and contrast gene therapy with gene-editing strategies.
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- 2019
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9. Loss of ARHGEF1 causes a human primary antibody deficiency.
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Bouafia A, Lofek S, Bruneau J, Chentout L, Lamrini H, Trinquand A, Deau MC, Heurtier L, Meignin V, Picard C, Macintyre E, Alibeu O, Bras M, Molina TJ, Cavazzana M, André-Schmutz I, Durandy A, Fischer A, Oksenhendler E, and Kracker S
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- Female, Germinal Center immunology, Germinal Center pathology, Humans, Immunologic Memory genetics, Male, Phosphatidylinositol 3-Kinases genetics, Phosphatidylinositol 3-Kinases immunology, Proto-Oncogene Proteins c-akt genetics, Proto-Oncogene Proteins c-akt immunology, Rho Guanine Nucleotide Exchange Factors deficiency, Rho Guanine Nucleotide Exchange Factors immunology, Siblings, T-Lymphocytes immunology, T-Lymphocytes pathology, rho-Associated Kinases genetics, rho-Associated Kinases immunology, rhoA GTP-Binding Protein genetics, B-Lymphocytes immunology, B-Lymphocytes pathology, Primary Immunodeficiency Diseases genetics, Primary Immunodeficiency Diseases immunology, Primary Immunodeficiency Diseases pathology, Signal Transduction genetics, Signal Transduction immunology
- Abstract
ARHGEF1 is a RhoA-specific guanine nucleotide exchange factor expressed in hematopoietic cells. We used whole-exome sequencing to identify compound heterozygous mutations in ARHGEF1, resulting in the loss of ARHGEF1 protein expression in 2 primary antibody-deficient siblings presenting with recurrent severe respiratory tract infections and bronchiectasis. Both ARHGEF1-deficient patients showed an abnormal B cell immunophenotype, with a deficiency in marginal zone and memory B cells and an increased frequency of transitional B cells. Furthermore, the patients' blood contained immature myeloid cells. Analysis of a mediastinal lymph node from one patient highlighted the small size of the germinal centers and an abnormally high plasma cell content. On the molecular level, T and B lymphocytes from both patients displayed low RhoA activity and low steady-state actin polymerization (even after stimulation of lysophospholipid receptors). As a consequence of disturbed regulation of the RhoA downstream target Rho-associated kinase I/II (ROCK), the patients' lymphocytes failed to efficiently restrain AKT phosphorylation. Enforced ARHGEF1 expression or drug-induced activation of RhoA in the patients' cells corrected the impaired actin polymerization and AKT regulation. Our results indicate that ARHGEF1 activity in human lymphocytes is involved in controlling actin cytoskeleton dynamics, restraining PI3K/AKT signaling, and confining B lymphocytes and myelocytes within their dedicated functional environment.
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- 2019
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10. Severe combined immunodeficiency in stimulator of interferon genes (STING) V154M/wild-type mice.
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Bouis D, Kirstetter P, Arbogast F, Lamon D, Delgado V, Jung S, Ebel C, Jacobs H, Knapp AM, Jeremiah N, Belot A, Martin T, Crow YJ, André-Schmutz I, Korganow AS, Rieux-Laucat F, and Soulas-Sprauel P
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- Agammaglobulinemia, Animals, Cell Differentiation genetics, Disease Models, Animal, Humans, Interferon Type I metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Receptor, Interferon alpha-beta genetics, B-Lymphocytes physiology, Inflammation genetics, Killer Cells, Natural immunology, Membrane Proteins genetics, Mutation genetics, Severe Combined Immunodeficiency genetics, T-Lymphocytes physiology
- Abstract
Background: Autosomal dominant gain-of-function mutations in human stimulator of interferon genes (STING) lead to a severe autoinflammatory disease called STING-associated vasculopathy with onset in infancy that is associated with enhanced expression of interferon-stimulated gene transcripts., Objective: The goal of this study was to analyze the phenotype of a new mouse model of STING hyperactivation and the role of type I interferons in this system., Methods: We generated a knock-in model carrying an amino acid substitution (V154M) in mouse STING, corresponding to a recurrent mutation seen in human patients with STING-associated vasculopathy with onset in infancy. Hematopoietic development and tissue histology were analyzed. Lymphocyte activation and proliferation were assessed in vitro. STING V154M/wild-type (WT) mice were crossed to IFN-α/β receptor (IFNAR) knockout mice to evaluate the type I interferon dependence of the mutant Sting phenotype recorded., Results: In STING V154M/WT mice we detected variable expression of inflammatory infiltrates in the lungs and kidneys. These mice showed a marked decrease in survival and developed a severe combined immunodeficiency disease (SCID) affecting B, T, and natural killer cells, with an almost complete lack of antibodies and a significant expansion of monocytes and granulocytes. The blockade in B- and T-cell development was present from early immature stages in bone marrow and thymus. In addition, in vitro experiments revealed an intrinsic proliferative defect of mature T cells. Although the V154M/WT mutant demonstrated increased expression of interferon-stimulated genes, the SCID phenotype was not reversed in STING V154M/WT IFNAR knockout mice. However, the antiproliferative defect in T cells was rescued partially by IFNAR deficiency., Conclusions: STING gain-of-function mice developed an interferon-independent SCID phenotype with a T-cell, B-cell, and natural killer cell developmental defect and hypogammaglobulinemia that is associated with signs of inflammation in lungs and kidneys. Only the intrinsic proliferative defect of T cells was partially interferon dependent., (Crown Copyright © 2018. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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11. Deletion 6q Drives T-cell Leukemia Progression by Ribosome Modulation.
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Gachet S, El-Chaar T, Avran D, Genesca E, Catez F, Quentin S, Delord M, Thérizols G, Briot D, Meunier G, Hernandez L, Pla M, Smits WK, Buijs-Gladdines JG, Van Loocke W, Menschaert G, André-Schmutz I, Taghon T, Van Vlierberghe P, Meijerink JP, Baruchel A, Dombret H, Clappier E, Diaz JJ, Gazin C, de Thé H, Sigaux F, and Soulier J
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- Animals, Cell Line, Tumor, Chromosomes, Human, Pair 6, Disease Progression, Gene Expression Profiling, Haploinsufficiency, Heterogeneous-Nuclear Ribonucleoproteins metabolism, Humans, Leukemia, T-Cell metabolism, Leukemia, T-Cell pathology, Mice, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma genetics, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma metabolism, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma pathology, RNA Interference, RNA, Long Noncoding metabolism, Transplantation, Heterologous, Chromosome Deletion, Heterogeneous-Nuclear Ribonucleoproteins genetics, Leukemia, T-Cell genetics, RNA, Long Noncoding genetics, Ribosomes metabolism
- Abstract
Deletion of chromosome 6q is a well-recognized abnormality found in poor-prognosis T-cell acute lymphoblastic leukemia (T-ALL). Using integrated genomic approaches, we identified two candidate haploinsufficient genes contiguous at 6q14, SYNCRIP (encoding hnRNP-Q) and SNHG5 (that hosts snoRNAs), both involved in regulating RNA maturation and translation. Combined silencing of both genes, but not of either gene alone, accelerated leukemogeneis in a Tal1/Lmo1/Notch1 -driven mouse model, demonstrating the tumor-suppressive nature of the two-gene region. Proteomic and translational profiling of cells in which we engineered a short 6q deletion by CRISPR/Cas9 genome editing indicated decreased ribosome and mitochondrial activities, suggesting that the resulting metabolic changes may regulate tumor progression. Indeed, xenograft experiments showed an increased leukemia-initiating cell activity of primary human leukemic cells upon coextinction of SYNCRIP and SNHG5. Our findings not only elucidate the nature of 6q deletion but also highlight the role of ribosomes and mitochondria in T-ALL tumor progression. SIGNIFICANCE: The oncogenic role of 6q deletion in T-ALL has remained elusive since this chromosomal abnormality was first identified more than 40 years ago. We combined genomic analysis and functional models to show that the codeletion of two contiguous genes at 6q14 enhances malignancy through deregulation of a ribosome-mitochondria axis, suggesting the potential for therapeutic intervention. This article is highlighted in the In This Issue feature, p. 1494 ., (©2018 American Association for Cancer Research.)
- Published
- 2018
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12. Plerixafor enables safe, rapid, efficient mobilization of hematopoietic stem cells in sickle cell disease patients after exchange transfusion.
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Lagresle-Peyrou C, Lefrère F, Magrin E, Ribeil JA, Romano O, Weber L, Magnani A, Sadek H, Plantier C, Gabrion A, Ternaux B, Félix T, Couzin C, Stanislas A, Tréluyer JM, Lamhaut L, Joseph L, Delville M, Miccio A, André-Schmutz I, and Cavazzana M
- Subjects
- Anemia, Sickle Cell metabolism, Anemia, Sickle Cell pathology, Anti-HIV Agents administration & dosage, Antigens, CD34 metabolism, Antisickling Agents administration & dosage, Benzylamines, Case-Control Studies, Cells, Cultured, Cohort Studies, Cyclams, Hematopoietic Stem Cells cytology, Humans, Hydroxyurea administration & dosage, Anemia, Sickle Cell therapy, Blood Transfusion, Hematopoietic Stem Cell Mobilization, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells drug effects, Hematopoietic Stem Cells metabolism, Heterocyclic Compounds administration & dosage
- Abstract
Sickle cell disease is characterized by chronic anemia and vaso-occlusive crises, which eventually lead to multi-organ damage and premature death. Hematopoietic stem cell transplantation is the only curative treatment but it is limited by toxicity and poor availability of HLA-compatible donors. A gene therapy approach based on the autologous transplantation of lentiviral-corrected hematopoietic stem and progenitor cells was shown to be efficacious in one patient. However, alterations of the bone marrow environment and properties of the red blood cells hamper the harvesting and immunoselection of patients' stem cells from bone marrow. The use of Filgrastim to mobilize large numbers of hematopoietic stem and progenitor cells into the circulation has been associated with severe adverse events in sickle cell patients. Thus, broader application of the gene therapy approach requires the development of alternative mobilization methods. We set up a phase I/II clinical trial whose primary objective was to assess the safety of a single injection of Plerixafor in sickle cell patients undergoing red blood cell exchange to decrease the hemoglobin S level to below 30%. The secondary objective was to measure the efficiency of mobilization and isolation of hematopoietic stem and progenitor cells. No adverse events were observed. Large numbers of CD34
+ cells were mobilized extremely quickly. Importantly, the mobilized cells contained high numbers of hematopoietic stem cells, expressed high levels of stemness genes, and engrafted very efficiently in immunodeficient mice. Thus, Plerixafor can be safely used to mobilize hematopoietic stem cells in sickle cell patients; this finding opens up new avenues for treatment approaches based on gene addition and genome editing. Clinicaltrials.gov identifier: NCT02212535 ., (Copyright © 2018 Ferrata Storti Foundation.)- Published
- 2018
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13. Inherited Immunodeficiency: A New Association With Early-Onset Childhood Panniculitis.
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Bader-Meunier B, Rieux-Laucat F, Touzot F, Frémond ML, André-Schmutz I, Fraitag S, and Bodemer C
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- B-Lymphocytes immunology, Bone Marrow Transplantation adverse effects, Child, Preschool, Female, Humans, Immunoglobulins, Intravenous therapeutic use, Immunologic Deficiency Syndromes therapy, Infant, Lymphocyte Specific Protein Tyrosine Kinase p56(lck) genetics, Male, Mutation, NF-kappa B p52 Subunit genetics, Nucleotidyltransferases genetics, Postoperative Complications, T-Lymphocytes immunology, Immunologic Deficiency Syndromes complications, Immunologic Deficiency Syndromes genetics, Panniculitis complications, Panniculitis immunology
- Abstract
We report on 4 children who presented with aseptic panniculitis associated with inherited immunodeficiency. Three patients had a B-cell immunodeficiency resulting from mutations in the TRNT1 and NF-κb2 genes (no mutation was found in the third patient), and 1 had a T-cell deficiency (mutation in the LCK gene). Panniculitis occurred before the age of 2 years in the 4 patients and preceded the onset of recurrent infections because of immunodeficiency in 2. It presented either as nodules, which resolved spontaneously within 1 to 2 weeks (3 patients), or chronic ulcerative lesions (1 patient) associated with unexplained fever and elevated acute phase reactants, without evidence of infection or high-titer autoantibodies. Febrile nodules relapsed in 2 patients, and recurrent attacks of unexplained fever (without relapse of panniculitis) occurred in the third. Skin biopsy revealed predominantly lympho-histiocytic or septal neutrophilic panniculitis in 1 and 3 patients, respectively. Panniculitis was associated with dermal involvement in the 4 patients. Patients with B-cell deficiency received monthly intravenous immunoglobulin replacement. Two patients who underwent bone marrow transplant died of bone marrow transplant-related complications. The 2 remaining patients had persistent, mild autoinflammatory disease, which did not require specific treatment. In these cases, the need for careful immunologic evaluation of patients who present with unexplained panniculitis, especially early-onset panniculitis before the age of 2 years, is highlighted., Competing Interests: POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose., (Copyright © 2018 by the American Academy of Pediatrics.)
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- 2018
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14. Generation of adult human T-cell progenitors for immunotherapeutic applications.
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Simons L, Ma K, de Chappedelaine C, Moiranghtem RD, Elkaim E, Olivré J, Susini S, Appourchaux K, Reimann C, Sadek H, Pellé O, Cagnard N, Magrin E, Lagresle-Peyrou C, Taghon T, Rausell A, Cavazzana M, and André-Schmutz I
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- Animals, Cell Differentiation physiology, Cells, Cultured, Humans, Immunotherapy methods, Mice, Receptors, Antigen, T-Cell immunology, Thymus Gland immunology, T-Lymphocytes immunology
- Published
- 2018
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15. Gene transfer into hematopoietic stem cells reduces HLH manifestations in a murine model of Munc13-4 deficiency.
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Soheili T, Durand A, Sepulveda FE, Rivière J, Lagresle-Peyrou C, Sadek H, de Saint Basile G, Martin S, Mavilio F, Cavazzana M, and André-Schmutz I
- Abstract
Patients with mutations in the UNC13D gene (coding for Munc13-4 protein) suffer from familial hemophagocytic lymphohistiocytosis type 3 (FHL3), a life-threatening immune and hyperinflammatory disorder. The only curative treatment is allogeneic hematopoietic stem cell (HSC) transplantation, although the posttreatment survival rate is not satisfactory. Here, we demonstrate the curative potential of UNC13D gene correction of HSCs in a murine model of FHL3. We generated a self-inactivating lentiviral vector, used it to complement HSCs from Unc13d -deficient (Jinx) mice, and transplanted the cells back into the irradiated Jinx recipients. This procedure led to complete reconstitution of the immune system (ie, to wild-type levels). The recipients were then challenged with lymphocytic choriomeningitis virus to induce hemophagocytic lymphohistiocytosis (HLH)-like manifestations. All the clinical and biological signs of HLH were significantly reduced in mice having undergone HSC UNC13D gene correction than in nontreated animals. This beneficial effect was evidenced by the correction of blood cytopenia, body weight gain, normalization of the body temperature, decreased serum interferon-γ level, recovery of liver damage, and decreased viral load. These improvements can be explained by the restoration of the CD8
+ T lymphocytes' cytotoxic function (as demonstrated here in an in vitro degranulation assay). Overall, our results demonstrate the efficacy of HSC gene therapy in an FHL-like setting of immune dysregulation., Competing Interests: Conflict-of-interest disclosure: The authors declare no competing financial interests.- Published
- 2017
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16. Neutropenia in Patients with Common Variable Immunodeficiency: a Rare Event Associated with Severe Outcome.
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Guffroy A, Mourot-Cottet R, Gérard L, Gies V, Lagresle C, Pouliet A, Nitschké P, Hanein S, Bienvenu B, Chanet V, Donadieu J, Gardembas M, Karmochkine M, Nove-Josserand R, Martin T, Poindron V, Soulas-Sprauel P, Rieux-Laucat F, Fieschi C, Oksenhendler E, André-Schmutz I, and Korganow AS
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- Adolescent, Adult, Child, Child, Preschool, Common Variable Immunodeficiency blood, Common Variable Immunodeficiency genetics, Common Variable Immunodeficiency immunology, Comorbidity, Female, France epidemiology, Humans, Immunoglobulins blood, Infant, Infant, Newborn, Leukocyte Count, Male, Middle Aged, Neutropenia blood, Neutropenia genetics, Neutropenia immunology, Exome Sequencing, Young Adult, Common Variable Immunodeficiency epidemiology, Neutropenia epidemiology
- Abstract
Background: Common variable immunodeficiency (CVID) is characterized by infections and hypogammaglobulinemia. Neutropenia is rare during CVID., Methods: The French DEFI study enrolled patients with primary hypogammaglobulinemia. Patients with CVID and neutropenia were retrospectively analyzed., Results: Among 473 patients with CVID, 16 patients displayed neutropenia (lowest count [0-1400]*10
6 /L). Sex ratio (M/F) was 10/6. Five patients died during the follow-up (11 years) with an increased percentage of deaths compared to the whole DEFI group (31.3 vs 3.4%, P < 0.05). Neutropenia was diagnosed for 10 patients before 22 years old. The most frequent symptoms, except infections, were autoimmune cytopenia, i.e., thrombopenia or anemia (11/16). Ten patients were affected with lymphoproliferative diseases. Two patients were in the infection only group and the others belonged to one or several other CVID groups. The median level of IgG was 2.6 g/L [0.35-4.4]. Most patients presented increased numbers of CD21low CD38low B cell, as already described in CVID autoimmune cytopenia group. Neutropenia was considered autoimmune in 11 cases. NGS for 52 genes of interest was performed on 8 patients. No deleterious mutations were found in LRBA, CTLA4, and PIK3. More than one potentially damaging variant in other genes associated with CVID were present in most patients arguing for a multigene process., Conclusion: Neutropenia is generally associated with another cytopenia and presumably of autoimmune origin during CVID. In the DEFI study, neutropenia is coupled with more severe clinical outcomes. It appears as an "alarm bell" considering patients' presentation and the high rate of deaths. Whole exome sequencing diagnosis should improve management.- Published
- 2017
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17. B cells differentiate in human thymus and express AIRE.
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Gies V, Guffroy A, Danion F, Billaud P, Keime C, Fauny JD, Susini S, Soley A, Martin T, Pasquali JL, Gros F, André-Schmutz I, Soulas-Sprauel P, and Korganow AS
- Subjects
- B-Lymphocytes metabolism, Female, Humans, Infant, Infant, Newborn, Male, AIRE Protein, B-Lymphocytes cytology, Cell Differentiation physiology, Thymus Gland cytology, Transcription Factors biosynthesis
- Published
- 2017
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18. Gene Therapy with Hematopoietic Stem Cells: The Diseased Bone Marrow's Point of View.
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Cavazzana M, Ribeil JA, Lagresle-Peyrou C, and André-Schmutz I
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- Animals, Bone Marrow Diseases pathology, Humans, Bone Marrow pathology, Bone Marrow Diseases therapy, Genetic Therapy, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells cytology
- Abstract
When considering inherited diseases that can be treated by gene transfer into hematopoietic stem cells (HSCs), there are only two in which the HSC and progenitor cell distribution inside the bone marrow and its microenvironment are exactly the same as in a healthy subject: metachromatic leukodystrophy (MLD) and adrenoleukodystrophy (ALD). In all other settings [X-linked severe combined immunodeficiency (X-SCID), adenosine deaminase deficiency, Wiskott-Aldrich syndrome, and β-hemoglobinopathies], the bone marrow content of the different stem and precursor cells and the cells' relationship with the stroma have very specific characteristics. These peculiarities can influence the cells' harvesting and behavior in culture, and the postgraft uptake and further behavior of the gene-modified hematopoietic/precursor cells. In the present mini-review, we shall briefly summarize these characteristics and outline the possible consequences and challenges., Competing Interests: Author Disclosure Statement No competing financial interests exist.
- Published
- 2017
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19. Gene-corrected human Munc13-4-deficient CD8+ T cells can efficiently restrict EBV-driven lymphoproliferation in immunodeficient mice.
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Soheili T, Rivière J, Ricciardelli I, Durand A, Verhoeyen E, Derrien AC, Lagresle-Peyrou C, de Saint Basile G, Cosset FL, Amrolia P, André-Schmutz I, and Cavazzana M
- Subjects
- Animals, CD8-Positive T-Lymphocytes pathology, Genetic Therapy, Herpesvirus 4, Human genetics, Humans, Membrane Proteins deficiency, Mice, Mice, SCID, Transduction, Genetic, CD8-Positive T-Lymphocytes immunology, Epstein-Barr Virus Infections genetics, Epstein-Barr Virus Infections immunology, Epstein-Barr Virus Infections pathology, Herpesvirus 4, Human immunology, Lymphohistiocytosis, Hemophagocytic genetics, Lymphohistiocytosis, Hemophagocytic immunology, Lymphohistiocytosis, Hemophagocytic pathology, Lymphoproliferative Disorders genetics, Lymphoproliferative Disorders immunology, Lymphoproliferative Disorders pathology, Lymphoproliferative Disorders virology, Membrane Proteins immunology
- Published
- 2016
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20. X-linked primary immunodeficiency associated with hemizygous mutations in the moesin (MSN) gene.
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Lagresle-Peyrou C, Luce S, Ouchani F, Soheili TS, Sadek H, Chouteau M, Durand A, Pic I, Majewski J, Brouzes C, Lambert N, Bohineust A, Verhoeyen E, Cosset FL, Magerus-Chatinet A, Rieux-Laucat F, Gandemer V, Monnier D, Heijmans C, van Gijn M, Dalm VA, Mahlaoui N, Stephan JL, Picard C, Durandy A, Kracker S, Hivroz C, Jabado N, de Saint Basile G, Fischer A, Cavazzana M, and André-Schmutz I
- Subjects
- Adolescent, Adult, Aged, Cell Adhesion, Cell Movement, Child, Child, Preschool, Genetic Association Studies, Humans, Lymphocyte Count, Male, Pedigree, CD8-Positive T-Lymphocytes immunology, Chromosomes, Human, X genetics, Immunologic Deficiency Syndromes genetics, Infections genetics, Microfilament Proteins genetics, Mutation genetics
- Abstract
Background: We investigated 7 male patients (from 5 different families) presenting with profound lymphopenia, hypogammaglobulinemia, fluctuating monocytopenia and neutropenia, a poor immune response to vaccine antigens, and increased susceptibility to bacterial and varicella zoster virus infections., Objective: We sought to characterize the genetic defect involved in a new form of X-linked immunodeficiency., Methods: We performed genetic analyses and an exhaustive phenotypic and functional characterization of the lymphocyte compartment., Results: We observed hemizygous mutations in the moesin (MSN) gene (located on the X chromosome and coding for MSN) in all 7 patients. Six of the latter had the same missense mutation, which led to an amino acid substitution (R171W) in the MSN four-point-one, ezrin, radixin, moesin domain. The seventh patient had a nonsense mutation leading to a premature stop codon mutation (R533X). The naive T-cell counts were particularly low for age, and most CD8
+ T cells expressed the senescence marker CD57. This phenotype was associated with impaired T-cell proliferation, which was rescued by expression of wild-type MSN. MSN-deficient T cells also displayed poor chemokine receptor expression, increased adhesion molecule expression, and altered migration and adhesion capacities., Conclusion: Our observations establish a causal link between an ezrin-radixin-moesin protein mutation and a primary immunodeficiency that could be referred to as X-linked moesin-associated immunodeficiency., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)- Published
- 2016
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21. Alterations of circulating lymphoid committed progenitor cellular metabolism after allogeneic stem cell transplantation in humans.
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Glauzy S, Peffault de Latour R, André-Schmutz I, Lachuer J, Servais S, Socié G, Clave E, and Toubert A
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- Adult, Biomarkers, Female, Graft vs Host Disease diagnosis, Graft vs Host Disease etiology, Humans, Immunophenotyping, Male, Middle Aged, Phenotype, Transplantation, Homologous, Young Adult, Energy Metabolism, Hematopoietic Stem Cell Transplantation adverse effects, Lymphoid Progenitor Cells metabolism
- Abstract
Lymphoid-committed CD34(+)lin(-)CD10(+)CD24(-) progenitors undergo a rebound at month 3 after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the absence of acute graft-versus-host disease (aGVHD). Here, we analyzed transcriptional programs of cell-sorted circulating lymphoid-committed progenitors and CD34(+)Lin(-)CD10(-) nonlymphoid progenitors in 11 allo-HSCT patients who had (n = 5) or had not (n = 6) developed grade 2 or 3 aGVHD and in 7 age-matched healthy donors. Major upregulated pathways include protein synthesis, energy production, cell cycle regulation, and cytoskeleton organization. Notably, genes from protein biogenesis, translation machinery, and cell cycle (CDK6) were overexpressed in progenitors from patients in the absence of aGVHD compared with healthy donors and patients affected by aGVHD. Expression of many genes from the mitochondrial oxidative phosphorylation metabolic pathway leading to ATP production were more specifically increased in lymphoid-committed progenitors in the absence of aGVHD. This was also the case for genes involved in cell mobilization such as those regulating Rho GTPase activity. In all, we found that circulating lymphoid-committed progenitors undergo profound changes in metabolism, favoring cell proliferation, energy production, and cell mobilization after allo-HSCT in humans. These mechanisms are abolished in the case of aGVHD or its treatment, indicating a persistent cell-intrinsic defect after exit from the bone marrow., (Copyright © 2016 ISEH - International Society for Experimental Hematology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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22. Gene Therapy for X-Linked Severe Combined Immunodeficiency: Where Do We Stand?
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Cavazzana M, Six E, Lagresle-Peyrou C, André-Schmutz I, and Hacein-Bey-Abina S
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- B-Lymphocytes immunology, B-Lymphocytes pathology, Clinical Trials as Topic, Gammaretrovirus immunology, Genetic Vectors immunology, Hematopoietic Stem Cell Transplantation, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells immunology, Humans, Killer Cells, Natural immunology, Killer Cells, Natural pathology, Lentivirus immunology, Patient Safety, Retroviridae immunology, T-Lymphocytes immunology, T-Lymphocytes pathology, Virus Integration genetics, X-Linked Combined Immunodeficiency Diseases genetics, X-Linked Combined Immunodeficiency Diseases immunology, X-Linked Combined Immunodeficiency Diseases pathology, Gammaretrovirus genetics, Genetic Therapy methods, Genetic Vectors chemistry, Lentivirus genetics, Retroviridae genetics, X-Linked Combined Immunodeficiency Diseases therapy
- Abstract
More than 20 years ago, X-linked severe combined immunodeficiency (SCID-X1) appeared to be the best condition to test the feasibility of hematopoietic stem cell gene therapy. The seminal SCID-X1 clinical studies, based on first-generation gammaretroviral vectors, demonstrated good long-term immune reconstitution in most treated patients despite the occurrence of vector-related leukemia in a few of them. This gene therapy has successfully enabled correction of the T cell defect. Natural killer and B cell defects were only partially restored, most likely due to the absence of a conditioning regimen. The success of these pioneering trials paved the way for the extension of gene-based treatment to many other diseases of the hematopoietic system, but the unfortunate serious adverse events led to extensive investigations to define the retrovirus integration profiles. This review puts into perspective the clinical experience of gene therapy for SCID-X1, with the development and implementation of new generations of safer vectors such as self-inactivating gammaretroviral or lentiviral vectors as well as major advances in integrome knowledge.
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- 2016
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23. An in vivo genetic reversion highlights the crucial role of Myb-Like, SWIRM, and MPN domains 1 (MYSM1) in human hematopoiesis and lymphocyte differentiation.
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Le Guen T, Touzot F, André-Schmutz I, Lagresle-Peyrou C, France B, Kermasson L, Lambert N, Picard C, Nitschke P, Carpentier W, Bole-Feysot C, Lim A, Cavazzana M, Callebaut I, Soulier J, Jabado N, Fischer A, de Villartay JP, and Revy P
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- B-Lymphocytes cytology, Cell Differentiation, Hematopoiesis genetics, Humans, Infant, Lymphopenia genetics, Male, Mutation, T-Lymphocytes cytology, Trans-Activators, Ubiquitin-Specific Proteases, DNA-Binding Proteins genetics, Immunologic Deficiency Syndromes genetics, Transcription Factors genetics
- Abstract
Background: Myb-Like, SWIRM, and MPN domains 1 (MYSM1) is a metalloprotease that deubiquitinates the K119-monoubiquitinated form of histone 2A (H2A), a chromatin marker associated with gene transcription silencing. Likewise, it has been reported that murine Mysm1 participates in transcription derepression of genes, among which are transcription factors involved in hematopoietic stem cell homeostasis, hematopoiesis, and lymphocyte differentiation. However, whether MYSM1 has a similar function in human subjects remains unclear. Here we describe a patient presenting with a complete lack of B lymphocytes, T-cell lymphopenia, defective hematopoiesis, and developmental abnormalities., Objectives: We sought to characterize the underlying genetic cause of this syndrome., Methods: We performed genome-wide homozygosity mapping, followed by whole-exome sequencing., Results: Genetic analysis revealed that this novel disorder is caused by a homozygous MYSM1 missense mutation affecting the catalytic site within the deubiquitinase JAB1/MPN/Mov34 (JAMM)/MPN domain. Remarkably, during the course of our study, the patient recovered a normal immunohematologic phenotype. Genetic analysis indicated that this improvement originated from a spontaneous genetic reversion of the MYSM1 mutation in a hematopoietic stem cell., Conclusions: We here define a novel human immunodeficiency and provide evidence that MYSM1 is essential for proper immunohematopoietic development in human subjects. In addition, we describe one of the few examples of spontaneous in vivo genetic cure of a human immunodeficiency., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
- Published
- 2015
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24. AK2 deficiency compromises the mitochondrial energy metabolism required for differentiation of human neutrophil and lymphoid lineages.
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Six E, Lagresle-Peyrou C, Susini S, De Chappedelaine C, Sigrist N, Sadek H, Chouteau M, Cagnard N, Fontenay M, Hermine O, Chomienne C, Reynier P, Fischer A, André-Schmutz I, Gueguen N, and Cavazzana M
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- Adenine Nucleotides metabolism, Adenylate Kinase deficiency, Antigens, CD34 genetics, Antigens, CD34 metabolism, Cell Differentiation, Gene Expression Profiling, Gene Expression Regulation, Gene Knockdown Techniques, HL-60 Cells, Humans, Leukopenia enzymology, Leukopenia pathology, Lymphocytes pathology, Mitochondria enzymology, Mitochondria pathology, Mutation, Neutrophils pathology, Oxidative Phosphorylation, Primary Cell Culture, Severe Combined Immunodeficiency enzymology, Severe Combined Immunodeficiency pathology, Stem Cells pathology, Adenylate Kinase genetics, Leukopenia genetics, Lymphocytes enzymology, Mitochondria genetics, Neutrophils enzymology, Severe Combined Immunodeficiency genetics, Stem Cells enzymology
- Abstract
Reticular dysgenesis is a human severe combined immunodeficiency that is primarily characterized by profound neutropenia and lymphopenia. The condition is caused by mutations in the adenylate kinase 2 (AK2) gene, resulting in the loss of mitochondrial AK2 protein expression. AK2 regulates the homeostasis of mitochondrial adenine nucleotides (ADP, ATP and AMP) by catalyzing the transfer of high-energy phosphate. Our present results demonstrate that AK2-knocked-down progenitor cells have poor proliferative and survival capacities and are blocked in their differentiation toward lymphoid and granulocyte lineages. We also observed that AK2 deficiency impaired mitochondrial function in general and oxidative phosphorylation in particular - showing that AK2 is critical in the control of energy metabolism. Loss of AK2 disrupts this regulation and leads to a profound block in lymphoid and myeloid cell differentiation.
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- 2015
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25. Comparing genotoxic signatures in cord blood cells from neonates exposed in utero to zidovudine or tenofovir.
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Vivanti A, Soheili TS, Cuccuini W, Luce S, Mandelbrot L, Lechenadec J, Cordier AG, Azria E, Soulier J, Cavazzana M, Blanche S, and André-Schmutz I
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- Aneuploidy, Female, Gene Expression, HIV Infections drug therapy, HIV Infections genetics, HIV Infections transmission, Humans, Infant, Newborn, Maternal-Fetal Exchange, Pregnancy, Pregnancy Complications, Infectious virology, Anti-HIV Agents therapeutic use, Fetal Blood drug effects, Hematopoietic Stem Cells drug effects, Infectious Disease Transmission, Vertical prevention & control, Pregnancy Complications, Infectious drug therapy, Tenofovir therapeutic use, Zidovudine therapeutic use
- Abstract
Objectives: Zidovudine and tenofovir are the two main nucleos(t)ide analogs used to prevent mother-to-child transmission of HIV. In vitro, both drugs bind to and integrate into human DNA and inhibit telomerase. The objective of the present study was to assess the genotoxic effects of either zidovudine or tenofovir-based combination therapies on cord blood cells in newborns exposed in utero., Design: We compared the aneuploid rate and the gene expression profiles in cord blood samples from newborns exposed either to zidovudine or tenofovir-based combination therapies during pregnancy and from unexposed controls (n = 8, 9, and 8, respectively)., Methods: The aneuploidy rate was measured on the cord blood T-cell karyotype. Gene expression profiles of cord blood T cells and hematopoietic stem and progenitor cells were determined with microarrays, analyzed in a gene set enrichment analysis and confirmed by real-time quantitative PCRs., Results: Aneuploidy was more frequent in the zidovudine-exposed group (26.3%) than in the tenofovir-exposed group (14.2%) or in controls (13.3%; P < 0.05 for both). The transcription of genes involved in DNA repair, telomere maintenance, nucleotide metabolism, DNA/RNA synthesis, and the cell cycle was deregulated in samples from both the zidovudine and the tenofovir-exposed groups., Conclusion: Although tenofovir has a lower clastogenic impact than zidovudine, gene expression profiling showed that both drugs alter the transcription of DNA repair and telomere maintenance genes.
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- 2015
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26. RUNX1-dependent RAG1 deposition instigates human TCR-δ locus rearrangement.
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Cieslak A, Le Noir S, Trinquand A, Lhermitte L, Franchini DM, Villarese P, Gon S, Bond J, Simonin M, Vanhille L, Reimann C, Verhoeyen E, Larghero J, Six E, Spicuglia S, André-Schmutz I, Langerak A, Nadel B, Macintyre E, Payet-Bornet D, and Asnafi V
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- Animals, Base Sequence, Binding Sites genetics, Cell Differentiation, Cell Line, DNA genetics, DNA metabolism, HEK293 Cells, Humans, Kinetics, Lymphopoiesis, Mice, Molecular Sequence Data, Species Specificity, T-Lymphocyte Subsets cytology, VDJ Recombinases metabolism, Core Binding Factor Alpha 2 Subunit metabolism, Gene Rearrangement, delta-Chain T-Cell Antigen Receptor, Homeodomain Proteins metabolism, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism
- Abstract
V(D)J recombination of TCR loci is regulated by chromatin accessibility to RAG1/2 proteins, rendering RAG1/2 targeting a potentially important regulator of lymphoid differentiation. We show that within the human TCR-α/δ locus, Dδ2-Dδ3 rearrangements occur at a very immature thymic, CD34(+)/CD1a(-)/CD7(+dim) stage, before Dδ2(Dδ3)-Jδ1 rearrangements. These strictly ordered rearrangements are regulated by mechanisms acting beyond chromatin accessibility. Importantly, direct Dδ2-Jδ1 rearrangements are prohibited by a B12/23 restriction and ordered human TCR-δ gene assembly requires RUNX1 protein, which binds to the Dδ2-23RSS, interacts with RAG1, and enhances RAG1 deposition at this site. This RUNX1-mediated V(D)J recombinase targeting imposes the use of two Dδ gene segments in human TCR-δ chains. Absence of this RUNX1 binding site in the homologous mouse Dδ1-23RSS provides a molecular explanation for the lack of ordered TCR-δ gene assembly in mice and may underlie differences in early lymphoid differentiation between these species., (© 2014 Cieslak et al.)
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- 2014
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27. The BLNK adaptor protein has a nonredundant role in human B-cell differentiation.
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Lagresle-Peyrou C, Millili M, Luce S, Boned A, Sadek H, Rouiller J, Frange P, Cros G, Cavazzana M, André-Schmutz I, and Schiff C
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- Adaptor Proteins, Signal Transducing genetics, Agammaglobulinemia genetics, Agammaglobulinemia pathology, Animals, B-Lymphocytes pathology, B-Lymphocytes transplantation, Bone Marrow immunology, Bone Marrow pathology, Cell Differentiation, Gene Expression, Genetic Complementation Test, Humans, Immunoglobulin kappa-Chains genetics, Immunoglobulin kappa-Chains immunology, Mice, Mice, Inbred NOD, Mice, SCID, Mutation, Protein Precursors genetics, Protein Precursors immunology, Receptors, Antigen, B-Cell genetics, Receptors, Antigen, B-Cell immunology, Single-Domain Antibodies genetics, Single-Domain Antibodies immunology, Transplantation, Heterologous, Adaptor Proteins, Signal Transducing immunology, Agammaglobulinemia immunology, B-Lymphocytes immunology
- Abstract
Background: Expression of the pre-B-cell receptor (pre-BCR) by pre-BII cells constitutes a crucial checkpoint in B-cell differentiation. Mutations that affect the pre-B-cell receptor result in early B-cell differentiation blockades that lead to primary B-cell immunodeficiencies. BLNK adaptor protein has a key role in the pre-B-cell receptor signaling cascade, as illustrated by the abnormal B-cell development in the 4 patients with BLNK gene defects reported to date. However, the BLNK protein's precise function in human B-cell differentiation has not been completely specified., Methods: B-cell development, including IgVH and Vk chain repertoires analysis, was studied in the bone marrow of a new case of BLNK deficiency in vitro and in vivo., Results: Here, we report on a patient with agammaglobulinemia, with a total absence of circulating B cells. We detected a homozygous mutation in BLNK, which leads to the complete abrogation of BLNK protein expression. In the bone marrow, we identified a severe differentiation blockade at the pre-BI- to pre-BII-cell transition. IgVH gene rearrangements and selection of the IgH repertoire were normal, whereas the patient's pre-BI cells showed very restricted usage of the IgVκ repertoire. Complementation of bone marrow progenitors from the patient with the BLNK gene and transplantation into NOD/SCID/γcko mice allowed the complete restoration of B-cell differentiation and a normal usage of the IgVκ genes., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)
- Published
- 2014
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28. CXCR4-related increase of circulating human lymphoid progenitors after allogeneic hematopoietic stem cell transplantation.
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Glauzy S, André-Schmutz I, Larghero J, Ezine S, Peffault de Latour R, Moins-Teisserenc H, Servais S, Robin M, Socié G, Clave E, and Toubert A
- Subjects
- Adolescent, Adult, Aged, Antigens, CD34 metabolism, Bone Marrow Cells immunology, Chemokine CXCL12 metabolism, Child, Down-Regulation immunology, Female, Host vs Graft Reaction immunology, Humans, Male, Middle Aged, Neprilysin metabolism, Receptors, CXCR4 genetics, T-Lymphocytes immunology, T-Lymphocytes metabolism, Thymus Gland immunology, Transplantation, Homologous adverse effects, Young Adult, Hematopoietic Stem Cell Transplantation adverse effects, Receptors, CXCR4 metabolism, T-Lymphocytes cytology
- 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.
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- 2014
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29. Genotoxic signature in cord blood cells of newborns exposed in utero to a Zidovudine-based antiretroviral combination.
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André-Schmutz I, Dal-Cortivo L, Six E, Kaltenbach S, Cocchiarella F, Le Chenadec J, Cagnard N, Cordier AG, Benachi A, Mandelbrot L, Azria E, Bouallag N, Luce S, Ternaux B, Reimann C, Revy P, Radford-Weiss I, Leschi C, Recchia A, Mavilio F, Cavazzana M, and Blanche S
- Subjects
- Adult, Antigens, CD34 genetics, Antigens, CD34 metabolism, Cell Cycle genetics, DNA Repair genetics, Drug Combinations, Female, Fetal Blood cytology, Fetal Blood physiology, Gene Expression Profiling methods, HIV Infections drug therapy, HIV Infections genetics, HIV Infections metabolism, Hematopoietic Stem Cells cytology, Hematopoietic Stem Cells metabolism, Humans, Infant, Newborn, Infectious Disease Transmission, Vertical, Karyotyping methods, Maternal-Fetal Exchange physiology, Pregnancy, Pregnancy Complications, Infectious drug therapy, Pregnancy Complications, Infectious metabolism, Pregnancy Complications, Infectious virology, Prenatal Exposure Delayed Effects, Stem Cells metabolism, Transcriptome genetics, Young Adult, Zidovudine pharmacokinetics, Anti-HIV Agents adverse effects, Fetal Blood drug effects, Hematopoietic Stem Cells drug effects, Zidovudine adverse effects
- Abstract
Background: The genotoxicity of zidovudine has been established in experimental models. The objective of the study was to identify genotoxicity markers in cord blood cells from newborns exposed in utero to antiretroviral (ARV) combinations containing zidovudine., Methods: Cells were investigated by karyotyping and gene expression analysis of the CD34(+) hematopoietic stem/progenitor cell (HPC) compartment., Results: Karyotyping of the cord blood cells from 15 ARV-exposed newborns and 12 controls revealed a higher proportion of aneuploid cells in the exposed group (median, 18.8% [interquartile range, 10.0%-26.7%] vs 6.6% [interquartile range, 3.1%-11.7%]; P < .001). All chromosomes were involved, with a random distribution of these alterations. Gene expression profiling of CD34(+) HPCs from 7 ARV-exposed and 6 control newborns revealed that >300 genes were significantly upregulated or downregulated by at least 1.5-fold in the exposed group (P < .05 for all comparisons). Significant alterations of genes involved in cell cycle control, mitotic checkpoints, and DNA repair were identified. Although this study does not allow discrimination between the roles of each of the 3 drugs, both cytogenetic and transcriptional findings are similar to those in cellular experiments that used zidovudine alone., Conclusions: The cord blood cells, including hematopoietic stem cells, from newborns exposed in utero to a zidovudine-based ARV combination present cytogenetic and transcriptional abnormalities compatible with DNA damage.
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- 2013
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30. Haematopoietic stem cell transplantation for SCID patients: where do we stand?
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Cavazzana-Calvo M, André-Schmutz I, and Fischer A
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- Cord Blood Stem Cell Transplantation, Cytokines immunology, Europe epidemiology, Genetic Therapy, Graft Rejection immunology, Graft vs Host Disease epidemiology, Graft vs Host Disease prevention & control, Histocompatibility, Humans, Infant, Infant, Newborn, Lymphocyte Subsets immunology, Lymphocyte Subsets pathology, Lymphocyte Subsets transplantation, Lymphocyte Transfusion, Lymphopoiesis, Neonatal Screening, Severe Combined Immunodeficiency classification, Severe Combined Immunodeficiency diagnosis, Severe Combined Immunodeficiency epidemiology, Severe Combined Immunodeficiency genetics, Severe Combined Immunodeficiency immunology, Thymus Gland embryology, Thymus Gland immunology, Thymus Gland pathology, Tissue Donors, Transplantation, Homologous, Treatment Outcome, United States epidemiology, Hematopoietic Stem Cell Transplantation mortality, Severe Combined Immunodeficiency surgery
- Abstract
Severe combined immunodeficiencies (SCIDs) correspond to the most severe form of primary immunodeficiency. The extreme severity of the clinical presentation in SCID has legitimately led physicians to consider these conditions as medical emergencies. Hundreds of patients worldwide have undergone allogeneic haematopoietic stem cell transplantation (HCST) in the last 40 years. The complete absence of the T cell compartment in SCID prompted the development (starting in the early 1980s) of haploidentical, parental HSCT for the many patients who do not have a human leucocyte antigen (HLA)-identical sibling. Despite the undeniable progress made in this field over recent years, the long-lasting immunodeficiency that follows partially HLA-incompatible transplantation is still responsible for a mortality rate of 30% at one year post-transplantation. New approaches for reconstituting T cell compartments more rapidly are under intense preclinical development and are discussed herein., (© 2012 Blackwell Publishing Ltd.)
- Published
- 2013
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31. Amniotic fluid stem cells restore the muscle cell niche in a HSA-Cre, Smn(F7/F7) mouse model.
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Piccoli M, Franzin C, Bertin E, Urbani L, Blaauw B, Repele A, Taschin E, Cenedese A, Zanon GF, André-Schmutz I, Rosato A, Melki J, Cavazzana-Calvo M, Pozzobon M, and De Coppi P
- Subjects
- Amniotic Fluid metabolism, Animals, Disease Models, Animal, Female, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Muscle, Skeletal physiopathology, Muscular Atrophy, Spinal pathology, Muscular Atrophy, Spinal physiopathology, Random Allocation, Stem Cells metabolism, Survival of Motor Neuron 1 Protein genetics, Amniotic Fluid cytology, Muscle, Skeletal cytology, Muscular Atrophy, Spinal genetics, Muscular Atrophy, Spinal surgery, Stem Cell Niche physiology, Stem Cell Transplantation methods, Stem Cells cytology
- Abstract
Mutations in the survival of motor neuron gene (SMN1) are responsible for spinal muscular atrophy, a fatal neuromuscular disorder. Mice carrying a homozygous deletion of Smn exon 7 directed to skeletal muscle (HSA-Cre, Smn(F7/F7) mice) present clinical features of human muscular dystrophies for which new therapeutic approaches are highly warranted. Herein we demonstrate that tail vein transplantation of mouse amniotic fluid stem (AFS) cells enhances the muscle strength and improves the survival rate of the affected animals. Second, after cardiotoxin injury of the Tibialis Anterior, only AFS-transplanted mice efficiently regenerate. Most importantly, secondary transplants of satellite cells (SCs) derived from treated mice show that AFS cells integrate into the muscle stem cell compartment and have long-term muscle regeneration capacity indistinguishable from that of wild-type-derived SC. This is the first study demonstrating the functional and stable integration of AFS cells into the skeletal muscle, highlighting their value as cell source for the treatment of muscular dystrophies., (Copyright © 2012 AlphaMed Press.)
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- 2012
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32. MST1 mutations in autosomal recessive primary immunodeficiency characterized by defective naive T-cell survival.
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Nehme NT, Schmid JP, Debeurme F, André-Schmutz I, Lim A, Nitschke P, Rieux-Laucat F, Lutz P, Picard C, Mahlaoui N, Fischer A, and de Saint Basile G
- Subjects
- Adolescent, Cell Survival genetics, Cells, Cultured, Child, Child, Preschool, Family, Female, Genes, Recessive physiology, Humans, Immunologic Deficiency Syndromes blood, Intracellular Signaling Peptides and Proteins, Male, Pedigree, T-Lymphocytes immunology, Immunologic Deficiency Syndromes genetics, Immunologic Deficiency Syndromes immunology, Mutation physiology, Protein Serine-Threonine Kinases genetics, T-Lymphocytes physiology
- Abstract
The molecular mechanisms that underlie T-cell quiescence are poorly understood. In the present study, we report a primary immunodeficiency phenotype associated with MST1 deficiency and primarily characterized by a progressive loss of naive T cells. The in vivo consequences include recurrent bacterial and viral infections and autoimmune manifestations. MST1-deficient T cells poorly expressed the transcription factor FOXO1, the IL-7 receptor, and BCL2. Conversely, FAS expression and the FAS-mediating apoptotic pathway were up-regulated. These abnormalities suggest that increased cell death of naive and proliferating T cells is the main mechanism underlying this novel immunodeficiency. Our results characterize a new mechanism in primary T-cell immunodeficiencies and highlight a role of the MST1/FOXO1 pathway in controlling the death of human naive T cells.
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- 2012
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33. Cytokines and culture medium have a major impact on human in vitro T-cell differentiation.
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Six EM, Benjelloun F, Garrigue A, Bonhomme D, Morillon E, Rouiller J, Cacavelli L, Blondeau J, Beldjord K, Hacein-Bey-Abina S, Cavazzana-Calvo M, and André-Schmutz I
- Subjects
- Adjuvants, Immunologic pharmacology, Cells, Cultured, Coculture Techniques, Cytokines immunology, Hematopoietic Stem Cells immunology, Humans, Interleukin-7 pharmacology, Stem Cell Factor pharmacology, Stromal Cells immunology, Cell Differentiation drug effects, Culture Media, Conditioned pharmacology, Cytokines pharmacology, T-Lymphocytes cytology, T-Lymphocytes drug effects
- Abstract
An important proof of principle has been achieved with the development of an in vitro T-cell differentiation assay based on the coculture of hematopoietic progenitors with the OP9-Delta1 stromal cell line. The original murine T cell differentiation assay has since been adapted for human T-cell differentiation, however with lower efficiency. The choice of both medium and cytokines is crucial in this assay, therefore our work has been focused on these two factors. The use of freshly reconstituted medium, the optimization of interleukine-7 (IL-7) concentration, and the addition of stem cell factor (SCF) have allowed to improve the proliferation of progenitors and T-cell precursors as well as the yield of double positive CD4+CD8+ T cells, and mature γδ and αβ T cells. These optimizations make the OP9-Delta1 system sensitive enough to perform both quantitative and qualitative assays with various type of progenitors, including those transduced by a retroviral vector. The improved OP9-Delta1 assay therefore constitutes an extremely useful test for basic research purposes and for translational medicine., (Copyright © 2011 Elsevier Inc. All rights reserved.)
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- 2011
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34. Advances in adoptive immunotherapy to accelerate T-cellular immune reconstitution after HLA-incompatible hematopoietic stem cell transplantation.
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Reimann C, Dal Cortivo L, Hacein-Bey-Abina S, Fischer A, André-Schmutz I, and Cavazzana-Calvo M
- Subjects
- Histocompatibility Testing, Humans, T-Lymphocytes cytology, T-Lymphocytes transplantation, Hematopoietic Stem Cell Transplantation, Immunotherapy, Adoptive trends, T-Lymphocytes immunology
- Abstract
Although partially HLA-mismatched hematopoietic stem cell transplantation (HSCT) has become an important therapeutic option for children with primary immunodeficiencies, delayed reconstitution of the T-cell compartment remains a major clinical concern. Adoptive immunotherapies to provide recipients with a protective and diverse T-cell repertoire in the months following HSCT are warranted. In order to improve T-cell reconstitution after T-cell-depleted HSCT, different strategies are currently being studied. Some are based on administration of modified mature T cells (e.g., allodepleted T cells or pathogen-specific T cells). Others aim at accelerating de novo thymopoiesis from donor-derived hematopoietic stem cells in vivo via the administration of thymopoietic agents or the transfer of large numbers of T-cell precursors generated ex vivo. The present article will provide a brief summary of recent advances in the field of allodepletion and adoptive transfer of pathogen-specific T cells and a detailed discussion of strategies for enhancing thymopoiesis in vivo.
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- 2010
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35. Immune reconstitution after haematopoietic stem cell transplantation: obstacles and anticipated progress.
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Cavazzana-Calvo M, André-Schmutz I, Dal Cortivo L, Neven B, Hacein-Bey-Abina S, and Fischer A
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- Adoptive Transfer, Antigens, CD34 immunology, Graft vs Host Disease prevention & control, Graft vs Host Disease therapy, Humans, T-Lymphocytes cytology, T-Lymphocytes transplantation, Thymus Gland cytology, Thymus Gland immunology, Transplantation Immunology, Graft vs Host Disease immunology, Hematopoietic Stem Cell Transplantation, T-Lymphocytes immunology
- Abstract
Improvement of immune reconstitution after haematopoietic stem cell transplantation (HSCT) is a key issue determining the clinical outcome of this widely used therapeutic approach. To this end, new strategies have been prompted by recent discoveries in immunology. In the setting of human leukocyte antigen (HLA) geno(pheno)identical HSCT, better prevention and treatment of acute and chronic graft-versus-host disease (GvHD) could significantly attenuate the thymic epithelium damage responsible for delayed and incomplete T-cell reconstitution. In a haploidentical setting, methods that would significantly accelerate neothymopoiesis in the months following injection of highly purified CD34+ cells are warranted. If these objectives could be achieved, the haploidentical procedure would become more readily available to patients affected by acquired or inherited disorders of the haematopoietic system.
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- 2009
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36. Human and murine amniotic fluid c-Kit+Lin- cells display hematopoietic activity.
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Ditadi A, de Coppi P, Picone O, Gautreau L, Smati R, Six E, Bonhomme D, Ezine S, Frydman R, Cavazzana-Calvo M, and André-Schmutz I
- Subjects
- Animals, Female, Gene Expression Profiling, Gene Expression Regulation, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Humans, Kinetics, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Phenotype, Amniotic Fluid metabolism, Cell Lineage, Hematopoiesis, Proto-Oncogene Proteins c-kit metabolism
- Abstract
We have isolated c-Kit(+)Lin(-) cells from both human and murine amniotic fluid (AF) and investigated their hematopoietic potential. In vitro, the c-Kit(+)Lin(-) population in both species displayed a multilineage hematopoietic potential, as demonstrated by the generation of erythroid, myeloid, and lymphoid cells. In vivo, cells belonging to all 3 hematopoietic lineages were found after primary and secondary transplantation of murine c-Kit(+)Lin(-) cells into immunocompromised hosts, thus demonstrating the ability of these cells to self-renew. Gene expression analysis of c-Kit(+) cells isolated from murine AF confirmed these results. The presence of cells with similar characteristics in the surrounding amnion indicates the possible origin of AF c-Kit(+)Lin(-) cells. This is the first report showing that cells isolated from the AF do have hematopoietic potential; our results support the idea that AF may be a new source of stem cells for therapeutic applications.
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- 2009
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37. Mesenchymal stromal cells can be derived from bone marrow CD133+ cells: implications for therapy.
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Pozzobon M, Piccoli M, Ditadi A, Bollini S, Destro R, André-Schmutz I, Masiero L, Lenzini E, Zanesco L, Petrelli L, Cavazzana-Calvo M, Gazzola MV, and De Coppi P
- Subjects
- AC133 Antigen, Antigens, CD, Bone Marrow Cells cytology, Cell Lineage, Cell Proliferation, Glycoproteins, Humans, Karyotyping, Mesenchymal Stem Cell Transplantation, Mesenchymal Stem Cells cytology, Molecular Sequence Data, Peptides, Stromal Cells cytology, Bone Marrow Cells physiology, Cell Differentiation physiology, Cell- and Tissue-Based Therapy, Mesenchymal Stem Cells physiology, Stromal Cells physiology
- Abstract
It is known that the bone marrow (BM) CD133(+) cells play an important role in the hematopoietic compartment, but this is not their only role. The cells indeed can take part in vascular reconstitution when they become endothelial cells (EC), in skeletal muscle fiber regeneration when there is a switch in muscle precursors, and to cardiomyocyte phenotypic conversion when differentiating in cardiomyocytes-like cells. While the role in hematopoiesis and vasculogenesis of the selected cells is well established, their ability to differentiate along multiple non-EC lineages has not yet been fully elucidated. The goal of this study is to assert whether human CD133(+)BM-derived cells are able to differentiate in vitro, besides to blood cells, cell lineages pertinent to the mesoderm germ layers. To this end, we isolated CD133(+) cells using a clinically approved methodology and compared their differentiation potential to that of hematopoietic progenitor cells (HPCs) and mesenchymal stem cells (MSCs) obtained from the same BM samples. In our culture conditions, CD133 expression was consistently decreased after passage 2, as well as the expression of the stemness markers c-kit and OCT4, whereas expression of Stage Specific Embryonic Antigen 4 (SSEA4) remained consistent in all different conditions. Expanded CD133 were also positive for HLA-ABC, but negative for HLA-DR, in accordance with what has been previously reported for MSCs. Moreover, CD133(+) cells from human BM demonstrated a wide range of differentiation potential, encompassing not only mesodermal but also ectodermal (neurogenic) cell lineages. CD133 antigen could be potentially used to select a cell population with similar characteristics as MSCs for therapeutic applications.
- Published
- 2009
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38. Shortening the immunodeficient period after hematopoietic stem cell transplantation.
- Author
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André-Schmutz I, Six E, Bonhomme D, Rouiller J, Dal Cortivo L, Fischer A, and Cavazzana-Calvo M
- Subjects
- Animals, Bone Marrow Cells immunology, Bone Marrow Cells metabolism, Hematopoietic Stem Cells immunology, Hematopoietic Stem Cells metabolism, Humans, Immunotherapy, Adoptive, Lymphopoiesis, Mice, Precursor Cells, T-Lymphoid metabolism, Receptors, Notch immunology, Receptors, Notch metabolism, Hematopoietic Stem Cell Transplantation adverse effects, Immunologic Deficiency Syndromes etiology, Immunologic Deficiency Syndromes therapy, Precursor Cells, T-Lymphoid immunology
- Abstract
The delayed reconstitution of the T-lymphoid compartment represents a major clinical challenge after HLA-mismatched hematopoietic stem cell transplantation. The generation of new T lymphocytes deriving from transplanted hematopoietic stem cells requires several months, a period associated with an increased risk of opportunistic infections and relapses. Recently, the early steps of human lymphopoiesis and the nature of the thymus-seeding progenitors were described. Moreover several scientific groups succeeded to generate T-cell precursors from murine and human hematopoietic stem cells in vitro by transitory exposition to Notch-ligands. Here we summarize and discuss these results and their possible usage in the development of new cell therapies to shorten the immunodeficient period following hematopoietic stem cell transplantation.
- Published
- 2009
- Full Text
- View/download PDF
39. Lymphoid-affiliated genes are associated with active histone modifications in human hematopoietic stem cells.
- Author
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Maës J, Maleszewska M, Guillemin C, Pflumio F, Six E, André-Schmutz I, Cavazzana-Calvo M, Charron D, Francastel C, and Goodhardt M
- Subjects
- ADP-ribosyl Cyclase 1 metabolism, Acetylation, Antigens, CD19 metabolism, Antigens, CD34 metabolism, Cell Differentiation, Cell Lineage, Fetal Blood cytology, Hematopoietic Stem Cells cytology, Humans, Lymphocytes cytology, Myeloid Cells cytology, Myeloid Cells metabolism, Satellite Cells, Skeletal Muscle cytology, Satellite Cells, Skeletal Muscle metabolism, Genes, Hematopoietic Stem Cells metabolism, Histones metabolism, Lymphocytes metabolism
- Abstract
To address the role of chromatin structure in the establishment of hematopoietic stem cell (HSC) multilineage potential and commitment to the lymphoid lineage, we have analyzed histone modifications at a panel of lymphoid- and myeloid-affiliated genes in multipotent and lineage-committed hematopoietic cells isolated from human cord blood. Our results show that many B- and T-lymphoid genes, although silent in HSCs, are associated with acetylated histones H3 and H4. We also detected histone H3 lysine 4 methylation but not repressive lysine 9 or 27 methylation marks at these loci, indicative of an open chromatin structure. Interestingly, the relative level of H3 lysine 4 dimethylation to trimethylation at B-specific loci was high in multipotent CD34(+)CD38(lo) progenitors and decreased as they become actively transcribed in B-lineage cells. In vitro differentiation of CD34(+) cells toward the erythroid, granulocyte, and T-cell lineages resulted in a loss of histone acetylation at nonlineage-associated genes. This study provides evidence that histone modifications involved in chromatin decondensation are already in place at lymphoid-specific genes in primary human HSCs, supporting the idea that these genes are "primed" for expression before lineage commitment. This permissive chromatin structure is progressively lost as the stem cell differentiates.
- Published
- 2008
- Full Text
- View/download PDF
40. HIV-1 Nef protein expression in human CD34+ progenitors impairs the differentiation of an early T/NK cell precursor.
- Author
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Dorival C, Brizzi F, Lelièvre JD, Sol-Foulon N, Six E, Henry A, André-Schmutz I, Cavazzana-Calvo M, Coulombel L, Estaquier J, Schwartz O, and Lévy Y
- Subjects
- Antigens, CD34 metabolism, Cell Differentiation, Genes, nef, HIV-1 genetics, HIV-1 physiology, Hematopoietic Stem Cells immunology, Hematopoietic Stem Cells pathology, Humans, Killer Cells, Natural immunology, Killer Cells, Natural pathology, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets pathology, Transduction, Genetic, nef Gene Products, Human Immunodeficiency Virus genetics, HIV-1 pathogenicity, Hematopoietic Stem Cells virology, Killer Cells, Natural virology, T-Lymphocyte Subsets virology, nef Gene Products, Human Immunodeficiency Virus physiology
- Abstract
HIV-1 impairs the production of T cells, through mechanisms that are still unknown. Here, we investigated the effect of the expression of HIV-1 Nef on the T-cell potential of human hematopoietic CD34(+) precursors. Those progenitors were transduced by using lentiviral vectors expressing Nef and cultured on OP9-DL1 cells allowing the differentiation of T cell from human hematopoietic precursors. We demonstrate that Nef impairs the generation of a CD3epsilon(+)CD5(+) CD1a(+) precursor stage that has initiated a D-J rearrangement of the TCRbeta locus. Onward stages of T-cell development were also affected with a quantitative reduction of CD4(+) intraCD3epsilon(+) Immature single positive cells (ISP), Double Positive (DP) CD4(+)CD8(+) TCRalphabeta T cells and CD56(+) NK cells. But B cell production was not affected. Limiting dilution analyses demonstrated a significant reduction in the frequency of T/NK progenitors among Nef-expressing CD34(+) cells. Altogether, these data demonstrate that Nef interferes with the differentiation of a primitive lymphoid human precursor with a T/NK potential.
- Published
- 2008
- Full Text
- View/download PDF
41. A human postnatal lymphoid progenitor capable of circulating and seeding the thymus.
- Author
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Six EM, Bonhomme D, Monteiro M, Beldjord K, Jurkowska M, Cordier-Garcia C, Garrigue A, Dal Cortivo L, Rocha B, Fischer A, Cavazzana-Calvo M, and André-Schmutz I
- Subjects
- Antigens, CD34 biosynthesis, Bone Marrow Cells metabolism, CD24 Antigen biosynthesis, CD3 Complex biosynthesis, Cells, Cultured, Flow Cytometry, Gene Expression Profiling, Humans, Leukocytes, Mononuclear metabolism, Neprilysin biosynthesis, Phenotype, Reverse Transcriptase Polymerase Chain Reaction, Stem Cells cytology, Stem Cells metabolism, Thymus Extracts metabolism, Thymus Gland metabolism
- Abstract
Identification of a thymus-seeding progenitor originating from human bone marrow (BM) constitutes a key milestone in understanding the mechanisms of T cell development and provides new potential for correcting T cell deficiencies. We report the characterization of a novel lymphoid-restricted subset, which is part of the lineage-negative CD34(+)CD10(+) progenitor population and which is distinct from B cell-committed precursors (in view of the absence of CD24 expression). We demonstrate that these Lin(-)CD34(+)CD10(+)CD24(-) progenitors have a very low myeloid potential but can generate B, T, and natural killer lymphocytes and coexpress recombination activating gene 1, terminal deoxynucleotide transferase, PAX5, interleukin 7 receptor alpha, and CD3epsilon. These progenitors are present in the cord blood and in the BM but can also be found in the blood throughout life. Moreover, they belong to the most immature thymocyte population. Collectively, these findings unravel the existence of a postnatal lymphoid-polarized population that is capable of migrating from the BM to the thymus.
- Published
- 2007
- Full Text
- View/download PDF
42. [Cell therapy for inherited diseases of the hematopoietic system].
- Author
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Cavazzana-Calvo M, Dal-Cortivo L, André-Schmutz I, Hacein-Bey Abina S, and Fischer A
- Subjects
- Animals, Graft Rejection physiopathology, HLA Antigens immunology, HLA Antigens physiology, History, 20th Century, Humans, Immunologic Deficiency Syndromes therapy, Hematologic Diseases genetics, Hematologic Diseases therapy, Hematopoiesis physiology, Hematopoietic System physiology, Stem Cell Transplantation history
- Abstract
Cell therapy was born in 1968 with the first allogeneic transplantation of hematopoietic stem cells for two immune deficiency disorders: the Wiskott-Aldrich syndrome and the Severe Combined ImmunoDeficiency (SCID). From this pioneering experience, thousands of patients affected with inherited or acquired diseases of the hematopoietic system have benefited from this therapeutic approach. Unfortunately, immunologic obstacles, represented by the compatibility in the major histocompatibility HLA system, still dictate today important limitations for a larger therapeutic utilization of hematopoietic stem cells (HSC). In this review, we have summarized the difficulties and the scientific advances leading us to improve the clinical results; the therapeutic research's track for primary immunodeficiencies is also discussed.
- Published
- 2007
- Full Text
- View/download PDF
43. [Human hematopoiesis: from CD34 cells to T lymphocytes].
- Author
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Cavazzana-Calvo M, Six E, André-Schmutz I, and Coulombel L
- Subjects
- Animals, Antigens, CD34 analysis, Bone Marrow Cells cytology, Cell Differentiation, Cell Lineage, Cell Movement, Cytokines physiology, Gene Expression Regulation, Developmental, Gene Rearrangement, T-Lymphocyte, Hematopoietic Stem Cell Transplantation, Humans, Immunologic Deficiency Syndromes genetics, Immunologic Deficiency Syndromes pathology, Leukemia-Lymphoma, Adult T-Cell pathology, Liver embryology, Lymphocytes cytology, Mice, Receptors, Notch antagonists & inhibitors, Receptors, Notch genetics, Receptors, Notch physiology, Thymus Gland cytology, Thymus Gland embryology, Transcription Factors physiology, Hematopoiesis physiology, Hematopoietic Stem Cells cytology, T-Lymphocytes cytology
- Abstract
Hematopoietic stem cell (HSC) has two key-properties : the self-renewal and the multipotentiality which guarantee the homeostasis of the hematopoietic system all along the lifespan. Inside this system, T lymphocytes are particular for several reasons. First and foremost, their differentiation takes place in a different organ from the one where the immature progenitors are generated and expanded. This implies the migration of an immature progenitor from the fetal liver and later on from the bone marrow to the thymus. Secondly, T cell differentiation is characterized by thymic selection and generation of T lymphocytes with a diverse repertoire able to answer to all foreign antigens one can meet. These complicated mechanisms underlying the T cell differentiation, completely different from those characterizing the myeloid system, at least partially explain our limited knowledge on human T cell lymphopoiesis. Finally, T cell differentiation pathway shows the particularity of profound ontogenic changes with the huge production of lymphoid progenitors during the fetal and the first years of life which declines during the ageing period. Recently, the discovery of new hematopoietic cytokines, the discovery of genes involved in primary immunodeficiencies and the detailed description of the role of Notch receptors have strongly developed our knowledge on T cell lymphopoiesis. In this review, we will attempt to describe where we stand in the description of this fundamental process and to underline the unresolved questions. The knowledge of this process is crucial, since it will lead us to set up new protocols with the aim to speed up immunological reconstitution after HLA partially compatible HSC and to treat the lymphocytopenia of patients affected by HIV.
- Published
- 2007
- Full Text
- View/download PDF
44. [Notch ligands Delta and lymphoid development niches].
- Author
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Six E, André Schmutz I, and Cavazzana-Calvo M
- Subjects
- Animals, Drosophila Proteins physiology, Fetal Blood cytology, Humans, Infant, Newborn, Ligands, Models, Animal, Models, Biological, Lymphatic System physiology, Nerve Tissue Proteins physiology, Receptors, Cell Surface physiology, Receptors, Notch physiology, Signal Transduction
- Published
- 2007
- Full Text
- View/download PDF
45. Bone marrow transplantation attenuates the myopathic phenotype of a muscular mouse model of spinal muscular atrophy.
- Author
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Salah-Mohellibi N, Millet G, André-Schmutz I, Desforges B, Olaso R, Roblot N, Courageot S, Bensimon G, Cavazzana-Calvo M, and Melki J
- Subjects
- Animals, Antigens, CD34 immunology, Bone Marrow Cells cytology, Cell Proliferation, Gene Expression Regulation, Green Fluorescent Proteins metabolism, Hepatocyte Growth Factor genetics, Mice, Mice, Mutant Strains, Muscle Fibers, Skeletal cytology, Muscle Fibers, Skeletal pathology, Muscle, Skeletal cytology, Muscle, Skeletal pathology, Muscle, Skeletal physiology, PAX7 Transcription Factor metabolism, RNA, Messenger genetics, RNA, Messenger metabolism, Receptors, Notch genetics, Regeneration, Satellite Cells, Skeletal Muscle cytology, Satellite Cells, Skeletal Muscle pathology, Vascular Endothelial Growth Factor A genetics, Bone Marrow Transplantation methods, Muscular Atrophy, Spinal pathology, Muscular Diseases pathology, Muscular Dystrophy, Animal pathology, Phenotype
- Abstract
Bone marrow (BM) transplantation was performed on a muscular mouse model of spinal muscular atrophy that had been created by mutating the survival of motor neuron gene (Smn) in myofibers only. This model is characterized by a severe myopathy and progressive loss of muscle fibers leading to paralysis. Transplantation of wild-type BM cells following irradiation at a low dose (6 Gy) improved motor capacity (+85%). This correlated with a normalization of myofiber number associated with a higher number of regenerating myofibers (1.6-fold increase) and an activation of CD34 and Pax7 satellite cells. However, BM cells had a very limited capacity to replace or fuse to mutant myofibers (2%). These data suggest that BM transplantation was able to attenuate the myopathic phenotype through an improvement of skeletal muscle regeneration of recipient mutant mice, a process likely mediated by a biological activity of BM-derived cells. This hypothesis was further supported by the capacity of muscle protein extracts from transplanted mutant mice to promote myoblast proliferation in vitro (1.6-fold increase). In addition, a tremendous upregulation of hepatocyte growth factor (HGF), which activates quiescent satellite cells, was found in skeletal muscle of transplanted mutants compared with nontransplanted mutants. Eventually, thanks to the Cre-loxP system, we show that BM-derived muscle cells were strong candidates harboring this biological activity. Taken together, our data suggest that a biological activity is likely involved in muscle regeneration improvement mediated by BM transplantation. HGF may represent an attractive paracrine mechanism to support this activity.
- Published
- 2006
- Full Text
- View/download PDF
46. Severe combined immunodeficiency. A model disease for molecular immunology and therapy.
- Author
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Fischer A, Le Deist F, Hacein-Bey-Abina S, André-Schmutz I, Basile Gde S, de Villartay JP, and Cavazzana-Calvo M
- Subjects
- Genetic Therapy, Hematopoietic Stem Cell Transplantation, Humans, Immune Tolerance, Models, Immunological, Severe Combined Immunodeficiency genetics, T-Lymphocytes immunology, Severe Combined Immunodeficiency immunology, Severe Combined Immunodeficiency therapy
- Abstract
Severe combined immunodeficiencies (SCIDs) consist of genetically determined arrest of T-cell differentiation. Ten different molecular defects have now been identified, which all lead to early death in the absence of therapy. Transplantation of allogeneic hematopoietic stem cells (HSCT) can restore T-cell development, thus saving the lives of SCID patients. In this review, the different characteristics of HSCT are discussed along with the available data regarding the long-term outcome. Transient thymopoiesis caused by an exhaustion of donor progenitor cells and possibly a progressive loss of thymus function can lead to a progressive decline in T-cell functions. The preliminary results of gene therapy show the correction of two SCID conditions. Based on the assumption that long-lasting pluripotent progenitor cells are transduced, these data suggest that gene therapy could overcome the long-term recurrence of the T-cell immunodeficiency. SCID is thus a disease model for experimental therapy in the hematopoietic system.
- Published
- 2005
- Full Text
- View/download PDF
47. IL-7 effect on immunological reconstitution after HSCT depends on MHC incompatibility.
- Author
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André-Schmutz I, Bonhomme D, Yates F, Malassis M, Selz F, Fischer A, and Cavazzana-Calvo M
- Subjects
- Animals, B-Lymphocytes immunology, Disease Models, Animal, Female, Lymph Nodes immunology, Male, Mice, Mice, Inbred Strains, Recombinant Proteins therapeutic use, T-Lymphocytes immunology, Thymus Gland immunology, Hematopoietic Stem Cell Transplantation, Interleukin-7 therapeutic use, Major Histocompatibility Complex immunology
- Abstract
Considerable progress has been recently accomplished in the management of patients who have undergone haplo-incompatible haematopoietic stem cell transplantation (HSCT) in terms of intake and prevention of graft-versus-host disease. Nevertheless haplo-incompatible HSCT is a procedure limited to a small number of patients because of the long-lasting immunodeficiency that is responsible for more than 50% of deaths within the first 3 months. Interleukin (IL)-7, which plays a unique and key role in T-cell development both in the mouse and in the human, is particularly attractive for attempting to speed up T-cell reconstitution. However, controversial results have been obtained after bone marrow graft in murine and primate models. To elucidate the impact of IL-7 treatment, we have performed HSCT in irradiated murine recombination activating gene (RAG) immunodeficient recipients, using donors that exhibited increased major histocompatibilty complex (MHC) incompatibility. Although irradiation performed prior to HSCT lead to a profound defect in the thymic stromal cells responsible for IL-7 production, IL-7 treatment had no significant effect on immune reconstitution in the MHC compatible and partially compatible settings. Interestingly, in the MHC fully incompatible setting in which only one-third of the recipients demonstrated active thymopoiesis, probably because of the rejection of donor cells by host natural killer cells, IL-7 treatment had a beneficial effect on T-cell development.
- Published
- 2004
- Full Text
- View/download PDF
48. Gene transfer for activation of CMV specific T cells.
- Author
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André-Schmutz I, Dal Cortivo L, Hamel Y, and Cavazzana-Calvo M
- Subjects
- Antigen-Presenting Cells immunology, Antigens, Viral genetics, Antigens, Viral immunology, B-Lymphocytes immunology, B-Lymphocytes virology, Cytomegalovirus genetics, Cytomegalovirus immunology, Cytomegalovirus Infections prevention & control, Dendritic Cells immunology, Genes, Transgenic, Suicide immunology, Genetic Vectors genetics, Graft vs Host Disease prevention & control, Graft vs Host Disease therapy, Herpesvirus 4, Human genetics, Humans, Immunocompromised Host immunology, Leukocytes, Mononuclear immunology, Phosphoproteins genetics, Phosphoproteins immunology, T-Lymphocytes, Cytotoxic immunology, Thymidine Kinase genetics, Transfection, Vaccination, Viral Matrix Proteins genetics, Viral Matrix Proteins immunology, Cytomegalovirus Infections therapy, Genetic Therapy methods, Immunotherapy methods, T-Lymphocytes immunology
- Abstract
Cytomegalovirus (CMV) is responsible for significant morbidity and mortality in immunocompromised patients undergoing allogeneic hematopoietic stem cell transplantation. The limitations of antiviral drugs and a better understanding of the cellular immune response to CMV has lead to the development of alternative therapies that restore host cellular immunity to CMV. Infusion of donor T lymphocytes results in variable protection against CMV but a high incidence of graft-versus-host disease in the allogeneic setting. To prevent this complication and further improve anti-CMV immune response, several groups have developed new approaches, such as the introduction of a suicide gene to control alloreactivity against the host or the selective activation of CMV-specific T cells by antigen-presenting cells expressing CMV antigens introduced by gene transfer. Depending on the target cells and the strategy chosen, adenovirus, retrovirus or poxviruses derived vectors are used for gene transfer. The protocols as well as the preclinical and clinical results obtained in the field of anti-CMV immunotherapy using gene transfer are reported and discussed.
- Published
- 2004
- Full Text
- View/download PDF
49. [The bone marrow: a reserve of stem cells able to repair various tissues?].
- Author
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Cavazzana-Calvo M, Lagresle C, André-Schmutz I, and Hacein-Bey-Abina S
- Subjects
- Animals, Antigens, CD34, Bone Marrow Transplantation, Cell Division, Humans, Stem Cells, Bone Marrow Cells physiology, Hematopoietic Stem Cells physiology
- Abstract
Hematopoietic stem cells (HSC) have been widely used for autologous and allodeneic transplantation during decades, although little was known about their migration, survival, self-renewal and differentiation process. Their sorting by the CD34(+) marker they express at the cell surface in human has been challenged by the recent discovery of HSC in the CD34(-) compartment that may precede CD34(+) HSC in the differentiation process. Until recently, stem cells present in the bone marrow were thought to be specific for hematopoiesis. Some experiments including clinical trials showing the formation of various tissues, muscle, neural cells and hepatocytes for instance, after transplantation of medullar cells, have challenged this dogma. In fact, the proofs of such a transdifferentiation process by HSC are still missing and the observations may result from the differentiation of other mulipotent stem cells present in the bone marrow, such as mesenchymal stem cells and more primitive multipotent adult progenitor cells (MAPC) and side population (SP) cells., (Copyright John Libbey Eurotext 20003.)
- Published
- 2004
50. Medical perspectives of adults and embryonic stem cells.
- Author
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Cavazzana-Calvo M, André-Schmutz I, Lagresle C, and Fischer A
- Subjects
- Adult, Cell Differentiation, Embryo, Mammalian, Genetic Diseases, Inborn therapy, Hematologic Neoplasms therapy, Humans, Stem Cell Transplantation trends, Bone Marrow Transplantation, Hematopoietic Stem Cells cytology, Stem Cell Transplantation ethics, Stem Cells cytology
- Abstract
In the last 30 years, allogeneic bone marrow transplantation has become the treatment of choice for many hematologic malignancies or inherited disorders and a number of changes have been registered in terms of long-term survival rate of transplanted patients as well as of available sources of hematopoietic stem cell (HSC). In parallel to the publication of better results in HSC transplantation, several recent discoveries have opened a scientific and ethical debate on the therapeutical potential of stem cells isolated from adult or embryonic tissues. One of the major discoveries in this field is the capacity of bone marrow-derived stem cells to treat a genetic liver disease in a mouse model, thus justifying the concept of transdifferentiation of adult stem cell and raising hopes on its possible therapeutical applications. We have tried here to summarise the advances in this field and to discuss the limits of these biological data.
- Published
- 2002
- Full Text
- View/download PDF
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