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2.
J Allergy Clin Immunol ; 135(5): 1303-9.e1-3, 2015 May.
Article in English | MEDLINE | ID: mdl-25282016

ABSTRACT

BACKGROUND: Combined immunodeficiencies (CIDs) form a heterogeneous group of inherited conditions that affect the development, function, or both of T cells. The treatment of CIDs with allogeneic hematopoietic stem cell transplantation (HSCT) is complicated by a high incidence of life-threatening infections and an increased risk of graft-versus-host disease (GVHD). OBJECTIVE: In view of the growing evidence that alloreactivity is mainly derived from human naive T cells, the selective depletion of naive T cells from allografts might constitute a way of reducing alloreactivity while maintaining memory T-cell responsiveness to pathogens. METHODS: Five consecutive patients with CIDs and chronic viral infections underwent an allogeneic, HLA-mismatched HSCT. Given the patients' infection status and the potential risk of severe GVHD in the mismatched setting, the CD34(-) fraction of the allograft was depleted of naive T cells by using magnetic CD45RA beads. RESULTS: Engraftment occurred in 4 of the 5 patients. No severe GVHD occurred. In the 4 engrafted patients viral infections were cleared within 2 months of the HSCT, and both cellular and humoral immunity were re-established within a year of the HSCT. An early T-cell response against viral pathogens was documented in 2 patients. CONCLUSION: The present pilot study shows that clinical-grade depletion of naive T cells from an allograft through the use of magnetic CD45RA beads seems to be a feasible and efficacious option for the treatment of patients with CIDs at high risk of GVHD, infection, or both in an HLA-mismatched setting.


Subject(s)
HLA Antigens/immunology , Hematopoietic Stem Cell Transplantation , Immunologic Deficiency Syndromes/immunology , Immunologic Deficiency Syndromes/therapy , Lymphocyte Depletion , Child, Preschool , Follow-Up Studies , Graft Survival/immunology , Graft vs Host Disease/etiology , Graft vs Host Disease/prevention & control , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Immunoglobulin A/immunology , Immunoglobulin G/immunology , Immunoglobulin M/immunology , Immunologic Deficiency Syndromes/diagnosis , Immunologic Deficiency Syndromes/metabolism , Infant , Leukocyte Common Antigens/metabolism , T-Lymphocyte Subsets/immunology , T-Lymphocyte Subsets/metabolism , Transplantation Conditioning , Transplantation, Homologous , Treatment Outcome
3.
J Infect Dis ; 208(2): 235-43, 2013 Jul 15.
Article in English | MEDLINE | ID: mdl-23559464

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.


Subject(s)
Anti-HIV Agents/adverse effects , Fetal Blood/drug effects , Hematopoietic Stem Cells/drug effects , Zidovudine/adverse effects , 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
4.
Transfusion ; 53(3): 564-9, 2013 Mar.
Article in English | MEDLINE | ID: mdl-22725259

ABSTRACT

BACKGROUND: This report describes the specific kinetics of the peripheral blood (PB) CD34+ cell concentration in a selected group of very poor stem cell mobilizer patients treated with granulocyte-colony-stimulating factor (G-CSF) and plerixafor and determines the kinetics' impact on apheresis. STUDY DESIGN AND METHODS: All patients had previously experienced at least two failures of mobilization (without use of plerixafor). The present salvage therapy consisted in the administration of 10 µg/kg/day G-CSF for 5 days added to a dose of plerixafor administered at between 5 a.m. and 6 a.m. on Day 5. The PB CD34+ cell counts were tested every 3 hours thereafter. Apheresis was initiated as soon as the PB CD34+ cell count reached 10 × 10(6) /L. RESULTS: A PB CD34+ cell count higher than 10 × 10(6) /L was observed as soon as 3 hours after plerixafor administration in 10 of the 11 patients who reached this threshold at some point in the monitoring process. Interestingly, all patients presented an early decrease in the PB CD34+ cell count 8 to 12 hours after plerixafor administration (below 10 × 10(6) /L for seven patients). CONCLUSION: Had such patients been tested for PB CD34+ cell mobilization according to conventional criteria (i.e., 11 hr after plerixafor administration), apheresis would not have been performed at the optimal timing. For very poor stem cell mobilizer patients, early monitoring of PB CD34+ cell count may be required for the optimal initiation of apheresis.


Subject(s)
Antigens, CD34/metabolism , Blood Component Removal/methods , Hematopoietic Stem Cell Mobilization/methods , Heterocyclic Compounds/administration & dosage , Adult , Aged , Antigens, CD34/blood , Benzylamines , Blood Cell Count , Blood Cells/metabolism , Cyclams , Drug Administration Schedule , Drug Synergism , Female , Granulocyte Colony-Stimulating Factor/administration & dosage , Granulocyte Colony-Stimulating Factor/pharmacology , Heterocyclic Compounds/pharmacology , Humans , Male , Middle Aged , Multiple Myeloma/drug therapy , Multiple Myeloma/therapy , Peripheral Blood Stem Cell Transplantation , Time Factors , Treatment Failure
6.
Stem Cells ; 30(8): 1771-80, 2012 Aug.
Article in English | MEDLINE | ID: mdl-22689616

ABSTRACT

Slow T-cell reconstitution is a major clinical concern after transplantation of cord blood (CB)-derived hematopoietic stem cells. Adoptive transfer of in vitro-generated T-cell progenitors has emerged as a promising strategy for promoting de novo thymopoiesis and thus accelerating T-cell reconstitution. Here, we describe the development of a new culture system based on the immobilized Notch ligand Delta-like-4 (DL-4). Culture of human CD34(+) CB cells in this new DL-4 system enabled the in vitro generation of large amounts of T-cell progenitor cells that (a) displayed the phenotypic and molecular signatures of early thymic progenitors and (b) had high T lymphopoietic potential. When transferred into NOD/SCID/γc(-/-) (NSG) mice, DL-4 primed T-cell progenitors migrated to the thymus and developed into functional, mature, polyclonal αß T cells that subsequently left the thymus and accelerated T-cell reconstitution. T-cell reconstitution was even faster and more robust when ex vivo-manipulated and nonmanipulated CB samples were simultaneously injected into NSG mice (i.e., a situation reminiscent of the double CB transplant setting). This work provides further evidence of the ability of in vitro-generated human T-cell progenitors to accelerate T-cell reconstitution and also introduces a feeder-cell-free culture technique with the potential for rapid, safe transfer to a clinical setting.


Subject(s)
Hematopoietic Stem Cells/cytology , Intercellular Signaling Peptides and Proteins/immunology , T-Lymphocytes/cytology , Adaptor Proteins, Signal Transducing , Animals , Calcium-Binding Proteins , Cell Differentiation/physiology , Hematopoietic Stem Cell Transplantation/methods , Hematopoietic Stem Cells/immunology , Humans , Immunotherapy , Intercellular Signaling Peptides and Proteins/genetics , Lymphopoiesis/physiology , Mice , Mice, Inbred NOD , Mice, SCID , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/immunology , T-Lymphocytes/immunology
7.
Cytotherapy ; 14(2): 232-9, 2012 Feb.
Article in English | MEDLINE | ID: mdl-22040109

ABSTRACT

BACKGROUND AIMS: Endothelial progenitor cells (EPC) have been proposed for autologous angiogenic therapy. The objectives of this study were to quantify EPC in the peripheral blood and bone marrow mononuclear cells (BM-MNC) of patients with critical limb ischemia that had received BM-MNC as a cell therapy product, and to study the putative relationship between the presence of EPC and the process of neovascularization in toe or transmetatarsal amputation specimens. METHODS: Early and late endothelial progenitor cells (CFU-EC and ECFC) were cultivated and quantified according to published methods in peripheral blood and BM-MNC from patients with critical limb ischemia (CLI; n = 11) enrolled in the OPTIPEC trial ( http://clinicaltrials.gov/ct2/show/NCT00377897 ) to receive BM-MNC as a cell therapy product. RESULTS: Eight out of the 11 patients had undergone amputations. Three of the patients displayed a neoangiogenic process that was associated with a higher number of CFU-EC in BM-MNC, while CD3+ , CFU-GM and CD34+ in BM-MNC, and EPC in peripheral blood, did not correlate with the appearance of newly formed vessels. As expected, circulating CFU-EC and ECFC counts were significantly lower in CLI patients compared with age-matched controls. CONCLUSIONS: In patients with critical limb ischemia, EPC in peripheral blood were decreased compared with healthy individuals. However, in BM-MNC we found that relative numbers of CFU-EC could be used as an indicator to discriminate patients with neoangiogenic processes. These results need to be confirmed in a randomized study.


Subject(s)
Bone Marrow Cells/cytology , Cell- and Tissue-Based Therapy/methods , Endothelial Cells/cytology , Extremities/pathology , Ischemia/pathology , Ischemia/therapy , Stem Cell Transplantation/methods , Stem Cells/cytology , Aged , Amputation, Surgical , Biomarkers , Endothelial Cells/transplantation , Humans , Leukocytes, Mononuclear/cytology , Middle Aged , Neovascularization, Physiologic , Treatment Outcome
8.
Adv Ther ; 28(4): 304-10, 2011 Apr.
Article in English | MEDLINE | ID: mdl-21400232

ABSTRACT

INTRODUCTION: Mobilization techniques for autologous peripheral blood stem cell (PBSC) collection include chemotherapy followed by hematopoietic growth factors, such as granulocyte colony-stimulating factor (G-CSF). Biosimilar versions of G-CSF are now available in Europe. METHODS: In this study, 40 patients with a hematological malignancy scheduled to receive biosimilar G-CSF (Zarzio(®) Sandoz Biopharmaceuticals, Paris, France) following first-cycle chemotherapy for treatment and autologous PBSC mobilization were prospectively included at a single center. These patients were compared with a historical control group who had been treated with G-CSF (Neupogen(®) Paris, France) at the same center according to the same clinical protocol. PBSC harvesting was considered successful if at least 3×10(6) CD34+ cells/kg were collected. If three consecutive CD34+ tests were below 10/µL then PBSC harvesting was not performed. RESULTS: Patient characteristics were similar in both groups with no significant differences in age, diagnosis, previous chemotherapy, or chemotherapy mobilization regimen. No significant differences were observed between groups in median CD34+ cells mobilized and collected, or the number of G-CSF injections and leukaphereses required to obtain the minimal CD34+ cell count. Proportion of failures was also similar in both groups. CONCLUSION: Zarziois(®) comparable to Neupogen(®) for PBSC mobilization and collection after chemotherapy and so may provide a more cost-effective strategy.


Subject(s)
Granulocyte Colony-Stimulating Factor , Hematopoietic Stem Cell Mobilization/methods , Peripheral Blood Stem Cell Transplantation/methods , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols , Female , Filgrastim , Granulocyte Colony-Stimulating Factor/administration & dosage , Granulocyte Colony-Stimulating Factor/adverse effects , Granulocyte Colony-Stimulating Factor/pharmacokinetics , Hematologic Neoplasms/therapy , Hematopoietic Stem Cell Mobilization/standards , Humans , Injections, Subcutaneous , Leukapheresis/standards , Male , Middle Aged , Recombinant Proteins , Research Design , Transplantation, Autologous/methods , Treatment Outcome
9.
Immunotherapy ; 2(4): 481-96, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20636003

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.


Subject(s)
Hematopoietic Stem Cell Transplantation , Immunotherapy, Adoptive , T-Lymphocytes/immunology , Histocompatibility Testing , Humans , Immunotherapy, Adoptive/trends , T-Lymphocytes/cytology , T-Lymphocytes/transplantation
10.
Science ; 326(5954): 818-23, 2009 Nov 06.
Article in English | MEDLINE | ID: mdl-19892975

ABSTRACT

X-linked adrenoleukodystrophy (ALD) is a severe brain demyelinating disease in boys that is caused by a deficiency in ALD protein, an adenosine triphosphate-binding cassette transporter encoded by the ABCD1 gene. ALD progression can be halted by allogeneic hematopoietic cell transplantation (HCT). We initiated a gene therapy trial in two ALD patients for whom there were no matched donors. Autologous CD34+ cells were removed from the patients, genetically corrected ex vivo with a lentiviral vector encoding wild-type ABCD1, and then re-infused into the patients after they had received myeloablative treatment. Over a span of 24 to 30 months of follow-up, we detected polyclonal reconstitution, with 9 to 14% of granulocytes, monocytes, and T and B lymphocytes expressing the ALD protein. These results strongly suggest that hematopoietic stem cells were transduced in the patients. Beginning 14 to 16 months after infusion of the genetically corrected cells, progressive cerebral demyelination in the two patients stopped, a clinical outcome comparable to that achieved by allogeneic HCT. Thus, lentiviral-mediated gene therapy of hematopoietic stem cells can provide clinical benefits in ALD.


Subject(s)
ATP-Binding Cassette Transporters/genetics , Adrenoleukodystrophy/therapy , Genetic Therapy , Genetic Vectors , HIV-1/genetics , Hematopoietic Stem Cell Transplantation , Hematopoietic Stem Cells/physiology , ATP Binding Cassette Transporter, Subfamily D, Member 1 , Adrenoleukodystrophy/genetics , Adrenoleukodystrophy/pathology , Animals , Brain/pathology , Cell Differentiation , Cell Lineage , Child , Disease Progression , Fatty Acids/blood , Female , Gene Expression , Hematopoiesis , Hematopoietic Stem Cells/virology , Humans , Leukocytes, Mononuclear/metabolism , Male , Mice , Microglia/cytology , Microglia/metabolism , Myeloablative Agonists/therapeutic use , Transduction, Genetic , Transplantation Conditioning , Transplantation, Autologous , Virus Integration
11.
Curr Opin Immunol ; 21(5): 544-8, 2009 Oct.
Article in English | MEDLINE | ID: mdl-19766472

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.


Subject(s)
Graft vs Host Disease/immunology , Hematopoietic Stem Cell Transplantation , T-Lymphocytes/immunology , 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
12.
Blood ; 114(1): 211-8, 2009 Jul 02.
Article in English | MEDLINE | ID: mdl-19403888

ABSTRACT

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only curative treatment for Griscelli syndrome type 2, an inherited immune disorder causing fatal hemophagocytic lymphohistiocytosis (HLH). Optimal therapeutic modalities are not yet well known. We retrospectively analyzed the outcome for 10 patients who underwent HSCT in a single center between 1996 and 2008. Seven patients (70%) were cured of the primary immune defect (mean follow-up, 5.2 years; range, 0.8-12.0 years), 4 of them without neurologic sequelae. In the 3 deceased patients, death occurred within 110 days of HSCT and was probably due to adverse reaction to HSCT in 2 patients and to HLH relapse in one patient. One patient received 2 transplants because of graft failure. Clinical events included veno-occlusive disease (n = 5), acute (n = 7) or chronic (n = 1) graft-versus-host disease II-III, and Epstein-Barr virus-induced lymphoproliferative disease (n = 2). Of the 7 patients with neurologic involvement before HSCT, 4 survived and 2 presented sequelae. Furthermore, 1 patient lacking neurologic involvement before HSCT developed long-term sequelae. These results demonstrate the efficacy of HSCT in curing the immune disorder but also show that neurologic HLH before HSCT is a major factor, given the neurologic sequelae after otherwise successful HSCT. Additional studies are required to improve treatment.


Subject(s)
Hematopoietic Stem Cell Transplantation , Lymphohistiocytosis, Hemophagocytic/therapy , Brain/pathology , Child , Child, Preschool , Epstein-Barr Virus Infections/etiology , Female , Graft Survival , Graft vs Host Disease/etiology , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Infant , Infant, Newborn , Lymphohistiocytosis, Hemophagocytic/genetics , Lymphohistiocytosis, Hemophagocytic/immunology , Lymphohistiocytosis, Hemophagocytic/pathology , Lymphoproliferative Disorders/etiology , Magnetic Resonance Imaging , Male , Prognosis , Retrospective Studies , Survival Rate , Syndrome , Transplantation, Homologous
13.
Blood ; 113(17): 4114-24, 2009 Apr 23.
Article in English | MEDLINE | ID: mdl-19168787

ABSTRACT

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for severe combined immunodeficiency (SCID). Detailed assessment of the long-term outcome of HSCT, ie, the occurrence of clinical events and the quality and stability of immune reconstitution, is now required. We performed a single-center retrospective analysis of the long-term outcome of HSCT in 90-patient cohort followed for between 2 and 34 years (median, 14 years). Clinical events and immune reconstitution data were collected. Almost half the patients have experienced one or more significant clinical events, including persistent chronic graft-versus-host disease (GVHD), autoimmune and inflammatory manifestations, opportunistic and nonopportunistic infections, chronic human papilloma virus (HPV) infections, and a requirement for nutritional support. With the notable exception of severe HPV infection, these complications tend to become less common 15 years later after HSCT. A multivariate analysis showed that the occurrence of these events correlated with non-genoidentical donors, diagnosis of Artemis SCID, and quality of immune reconstitution. In most cases, HSCT enables long-term survival with infrequent sequelae. However, the occurrence of relatively late-onset complications is a concern that requires specific means of prevention and justifies careful patient follow-up.


Subject(s)
Hematopoietic Stem Cell Transplantation , Severe Combined Immunodeficiency/epidemiology , Severe Combined Immunodeficiency/surgery , Cohort Studies , Female , Follow-Up Studies , Humans , Infant , Male , Severe Combined Immunodeficiency/immunology , Severe Combined Immunodeficiency/psychology , Survival Rate , Time Factors , Treatment Outcome
14.
Immunol Res ; 44(1-3): 54-60, 2009.
Article in English | MEDLINE | ID: mdl-19034396

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.


Subject(s)
Hematopoietic Stem Cell Transplantation/adverse effects , Immunologic Deficiency Syndromes/etiology , Immunologic Deficiency Syndromes/therapy , Precursor Cells, T-Lymphoid/immunology , 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
15.
J Clin Invest ; 118(9): 3132-42, 2008 Sep.
Article in English | MEDLINE | ID: mdl-18688285

ABSTRACT

Previously, several individuals with X-linked SCID (SCID-X1) were treated by gene therapy to restore the missing IL-2 receptor gamma (IL2RG) gene to CD34+ BM precursor cells using gammaretroviral vectors. While 9 of 10 patients were successfully treated, 4 of the 9 developed T cell leukemia 31-68 months after gene therapy. In 2 of these cases, blast cells contained activating vector insertions near the LIM domain-only 2 (LMO2) proto-oncogene. Here, we report data on the 2 most recent adverse events, which occurred in patients 7 and 10. In patient 10, blast cells contained an integrated vector near LMO2 and a second integrated vector near the proto-oncogene BMI1. In patient 7, blast cells contained an integrated vector near a third proto-oncogene,CCND2. Additional genetic abnormalities in the patients' blast cells included chromosomal translocations, gain-of-function mutations activating NOTCH1, and copy number changes, including deletion of tumor suppressor gene CDKN2A, 6q interstitial losses, and SIL-TAL1 rearrangement. These findings functionally specify a genetic network that controls growth in T cell progenitors. Chemotherapy led to sustained remission in 3 of the 4 cases of T cell leukemia, but failed in the fourth. Successful chemotherapy was associated with restoration of polyclonal transduced T cell populations. As a result, the treated patients continued to benefit from therapeutic gene transfer.


Subject(s)
Chromosomes, Human, X , Genetic Therapy/adverse effects , Genetic Therapy/methods , Leukemia, T-Cell/etiology , Severe Combined Immunodeficiency/therapy , Adaptor Proteins, Signal Transducing , Antineoplastic Agents/pharmacology , Chromosome Aberrations , Cyclin D2 , Cyclins/genetics , DNA-Binding Proteins/genetics , Gammaretrovirus/metabolism , Humans , Infant , Janus Kinase 3/genetics , LIM Domain Proteins , Leukemia, T-Cell/complications , Leukemia, T-Cell/therapy , Metalloproteins/genetics , Models, Biological , Mutation , Proto-Oncogene Mas , Proto-Oncogene Proteins , Receptors, Interleukin-2/genetics , Severe Combined Immunodeficiency/complications
16.
Mod Pathol ; 21(7): 837-46, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18487998

ABSTRACT

Critical leg ischemia is associated with a high risk of amputation when revascularization is not possible. Cell therapy based on bone marrow-derived mononuclear cells or with peripheral mononuclear cells, collected after stimulation with G-CSF has been used in an attempt to stimulate angiogenesis. Although several studies have raised the hope that such cell therapy may be effective in critical leg ischemia, no direct demonstration of angiogenesis induced by bone marrow-derived mononuclear cell/peripheral mononuclear cell injection has been reported in man. The aim of this study was to identify and to evaluate the extent of the angiogenic process associated with cell therapy in critical leg ischemia in man. To address this question, this pathological study was conducted in patients enrolled in the OPTIPEC clinical trial (Optimization of Progenitor Endothelial Cells in the Treatment of Critical leg ischemia), an interventional cell therapy study in critical leg ischemia. Amputation specimens from these patients were submitted to a standardized dissection protocol. In three patients, an active angiogenesis was observed in the distal part of the ischemic limb but not in the gastrocnemius muscle, the site of bone marrow cell injection. All the newly formed vessels were positive for endothelial cell markers (CD31, CD34, von Willebrand factor) and negative for markers of lymphatic vessels (podoplanin). Immunohistochemical staining for Ki-67 and c-kit showed extensive endothelial cell proliferation within the new vessels. Bone marrow-derived mononuclear cell therapy in patients with critical leg ischemia induces an active, substained angiogenesis in the ischemic and distal parts of the treated limb, although this may not prevent amputation in some patients with very severe ischemia.


Subject(s)
Bone Marrow Transplantation , Ischemia/therapy , Leg/blood supply , Leukocytes, Mononuclear/transplantation , Neovascularization, Physiologic , Aged , Aged, 80 and over , Amputation, Surgical , Antigens, CD34/metabolism , Biomarkers/metabolism , Blood Vessels/metabolism , Cell Proliferation , Endothelium, Vascular/cytology , Granulocyte Colony-Stimulating Factor/therapeutic use , Hematopoietic Stem Cell Mobilization , Humans , Ischemia/etiology , Male , Middle Aged , Platelet Endothelial Cell Adhesion Molecule-1/metabolism , Treatment Outcome , von Willebrand Factor/metabolism
17.
Transplantation ; 85(6): 911-5, 2008 Mar 27.
Article in English | MEDLINE | ID: mdl-18360276

ABSTRACT

Immunopathology of acute graft-versus-host disease (aGVHD) involves secretion of proinflammatory cytokines with subsequent expression of danger signals by injured host tissues. This explanation, however, does not explain the cluster of aGVHD target organs (skin, gut, and liver). NKG2D ligands (MICA/B and ULBP1-3 proteins) are stress-induced molecules that act as danger signals to alert NK and alphabeta or gammadelta CD8 T cells through engagement of the activating NKG2D receptor. We observed a strong and reversible induction of MICA/B expression in skin and liver sections during aGVHD. Tumor necrosis factor-alpha and gamma-radiation up-regulated expression of MICA/B and ULBP proteins in vitro on skin and intestine epithelial cell lines and ex vivo in normal skin explants. This NKG2D-ligand induction was regulated by a complex interplay between NFkB and JNK activation pathways. Our data suggest that NKG2D ligand induction might participate in the amplification loop that leads to tissue damage during aGVHD.


Subject(s)
Gamma Rays , Graft vs Host Disease/pathology , Intercellular Signaling Peptides and Proteins/biosynthesis , Intercellular Signaling Peptides and Proteins/radiation effects , Tumor Necrosis Factor-alpha/pharmacology , Acute Disease , Biopsy , Cell Line , Epithelial Cells/physiology , Epithelial Cells/radiation effects , GPI-Linked Proteins , Graft vs Host Disease/metabolism , Humans , Skin/cytology , Skin/radiation effects
18.
J Exp Med ; 204(13): 3085-93, 2007 Dec 24.
Article in English | MEDLINE | ID: mdl-18070935

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.


Subject(s)
Stem Cells/metabolism , Thymus Extracts/metabolism , Thymus Gland/metabolism , 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
19.
Transfusion ; 47(10): 1851-7, 2007 Oct.
Article in English | MEDLINE | ID: mdl-17880611

ABSTRACT

BACKGROUND: Quantification of peripheral blood (PB) CD34+ cells is commonly used to plan peripheral blood progenitor cell (PBPC) collection but is time-consuming. Sysmex has developed a hematology analyzer that can quickly identify a population of immature hematopoietic cells (HPCs) according to cell size, cell density, and differential lysis resistance, which may indicate the presence of PBPCs in PB. This prospective study has evaluated the potential of such method to predict the PBPC mobilization. STUDY DESIGN AND METHODS: A total of 141 patients underwent PBPC mobilization. PB HPCs and PB CD34+ cells were simultaneously quantified with a hematology analyzer (SE2100, Sysmex) and flow cytometry, respectively. The number of blood volumes processed was then based on PB CD34+ cell concentration. RESULTS: The optimal PB HPC level able to predict a minimal level of 10 x 10(6) PB CD34+ cells per L was 5 x 10(6) per L with positive and negative predictive values of 0.93 and 0.36 percent, respectively. For this cutoff point, sensitivity and specificity were 0.81 and 0.65, respectively. The median number of blood volumes processed according to the PB CD34+ cell count allowed us to perform only one apheresis procedure for a majority of patients. CONCLUSION: PB HPC quantification is very useful to quickly determine the initiation of PBPC apheresis especially for patients with higher concentrations. For patients exhibiting a lower HPC count (<5 x 10(6)/L), other parameters such as a CD34 test may be needed. Such a policy associated with a length of apheresis adapted to the richness in the PB CD34+ cells allows for optimizing the organization of centers with an improvement in patient comfort and economical savings.


Subject(s)
Antigens, CD34/blood , Blood Component Removal/methods , Hematopoietic Stem Cell Mobilization/methods , Hematopoietic Stem Cells/cytology , Adult , Aged , Algorithms , Antigens, CD/blood , Humans , Leukemia/blood , Leukemia/therapy , Lymphoma/blood , Lymphoma/therapy , Middle Aged , Neoplasms/blood , Neoplasms/therapy , Sensitivity and Specificity
20.
C R Biol ; 330(6-7): 538-42, 2007.
Article in French | MEDLINE | ID: mdl-17631450

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.


Subject(s)
Hematologic Diseases/genetics , Hematologic Diseases/therapy , Hematopoiesis/physiology , Hematopoietic System/physiology , Stem Cell Transplantation , Animals , Graft Rejection/physiopathology , HLA Antigens/immunology , HLA Antigens/physiology , History, 20th Century , Humans , Immunologic Deficiency Syndromes/therapy , Stem Cell Transplantation/history
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