Abstract:
:The insertion of suicide genes in donor T lymphocytes constitutes the basis of new approaches aiming at the treatment of the graft-versus-host disease (GVHD), a frequent complication in recipients of allogeneic haematopoietic grafts. In this study we investigated the impact that the ex vivo manipulation required for the retroviral transduction of T cells had on the functionality and differentiation of these cells. Compared to fresh T cells, samples that had been subjected to standard activation (1 microg/ml of both anti-CD3i and anti-CD28i MoAbs) followed by transduction with vectors encoding for the HSV-tk and tNGFR genes maintained the proliferative response to an allogeneic stimulus. These cells, however, had a significantly lower cytotoxic response to allogeneic cells compared to fresh samples. When the concentration of anti-CD3i was reduced to up to 1000-fold (1 ng/ml), similar T-cell transductions were obtained, while the cytotoxicity of the ex vivo manipulated samples was significantly recovered, when assessed either at 7 or 14 days of culture. In all instances, a similar functionality was observed in transduced samples not subjected to immunomagnetic cell sorting, compared to purified fractions enriched in NGFR(+) and NFGR(-) cells. The analysis of CD45RA and CCR7 markers in samples transduced under standard stimulatory conditions showed a differentiation of fresh CD8(+) CD45RA(+)/CCR7(+) naive cells to cells having a predominant central CD45RA(-)/CCR7(+) and effector CD45RA(-)/CCR7(-) memory phenotype. However, when samples were activated with low doses of anti-CD3i, a significant population of naive cells became apparent. Although activation with high doses of anti-CD3i/anti-CD28i resulted in a similar phenotype in both NGFR(+) and NFGR(-) populations, the naive population observed in samples activated with low concentrations of anti-CD3i was almost restricted to the NGFR(-) population. These results show that reducing the stimulation mediated by anti-CD3i in protocols of T-cell retroviral gene transfer significantly helps to preserve the cytotoxic capacity of these cells to allogeneic cells, without affecting the susceptibility of these cells to the retroviral vector. In addition, we observed that modulating the activation of transduced T cells implies the generation of changes in the differentiation of CD8(+) cells, although we could not establish a direct relationship between the CD45RA/CCR7 phenotype of these cells and their cytotoxic reactivity to an allogeneic stimulus.
journal_name
Gene Therjournal_title
Gene therapyauthors
Lamana ML,Bueren JA,Vicario JL,Balas Adoi
10.1038/sj.gt.3302188keywords:
subject
Has Abstractpub_date
2004-03-01 00:00:00pages
474-82issue
5eissn
0969-7128issn
1476-5462pii
3302188journal_volume
11pub_type
杂志文章相关文献
GENE THERAPY文献大全abstract::Gene targeting by single-stranded oligodeoxyribonucleotides (ssODNs) is a promising technique for introducing site-specific sequence alterations without affecting the genomic organization of the target locus. Here, we discuss the significant progress that has been made over the last 5 years in unraveling the mechanism...
journal_title:Gene therapy
pub_type: 杂志文章,评审
doi:10.1038/gt.2010.161
更新日期:2011-03-01 00:00:00
abstract::The recent surge of DNA sequence information resulting from the efforts of agencies interested in deciphering the human genetic code has facilitated technological developments that have been critical in the identification of genes associated with numerous disease pathologies. In addition, these efforts have opened the...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301740
更新日期:2002-06-01 00:00:00
abstract::Deficiency in acid alpha-D-glucosidase results in Pompe's disease. Modified single-stranded oligonucleotide (ODN) was designed to correct the acid alpha-D-glucosidase gene with a C1935 --> A (Asp --> Glu) point mutation which causes a complete loss of enzymatic activity for glycogen digestion in the lysosome. The ODN ...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3302096
更新日期:2003-10-01 00:00:00
abstract::Somatic gene transfer to the pulmonary endothelium may be a useful strategy for modifying the phenotype of endothelium and/or vascular smooth muscle in disorders such as primary pulmonary hypertension, ARDS or pulmonary metastatic disease. Adenoviral (Ad) vectors, although highly efficient in liver gene transfer, have...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301636
更新日期:2002-02-01 00:00:00
abstract::The development of lentiviral vectors that use Rev-independent mechanisms of nuclear export for their genomic RNA could facilitate the construction of novel anti-HIV vectors. We have improved the titers of Rev-independent lentiviral vectors having the SRV-1 CTE by mutating the major splice donor and acceptor sites pre...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301262
更新日期:2000-08-01 00:00:00
abstract::We report on long-term delivery of an interferon-gamma (IFN gamma) inhibitory protein by intramuscular (i.m.) gene therapy. IFN gamma is a cytokine that plays an important role in many inflammatory disorders, including autoimmune insulin-dependent diabetes mellitus (IDDM) in NOD mice and (in various strains) multiple ...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3300879
更新日期:1999-05-01 00:00:00
abstract::Bone morphogenetic protein (BMP) adenoviral vectors for the induction of osteogenesis are being developed for the treatment of bone pathology. However, it is still unknown which BMP adenoviral vector has the highest potential to stimulate bone formation in vivo. In this study, the osteogenic activities of recombinant ...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3302075
更新日期:2003-09-01 00:00:00
abstract::Urothelial bladder cancer is the most common malignancy of the urinary tract. Although most cases are initially diagnosed as non-muscle-invasive, more than 80% of patients will develop recurrent or metastatic tumors. No effective therapy exists currently for late-stage metastatic tumors. By intravesical application, l...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/gt.2016.18
更新日期:2016-05-01 00:00:00
abstract::Attempts have been made to use various forms of cellular vectors to deliver therapeutic genes to diseased tissues like malignant tumours. However, this approach has proved problematic due to the poor uptake of these vectors by the target tissue. We have devised a novel way of using magnetic nanoparticles (MNPs) to enh...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/gt.2008.57
更新日期:2008-06-01 00:00:00
abstract::The clinical efficacy and safety as well as the application range of gene therapy will be broadened by developing systems capable of finely modulating the expression of therapeutic genes. Transgene regulation will be crucial for maintaining appropriate levels of a gene product within the therapeutic range, thus preven...
journal_title:Gene therapy
pub_type: 杂志文章,评审
doi:10.1038/sj.gt.3302251
更新日期:2004-04-01 00:00:00
abstract::Recently, there has been an increasing level of interest in electroporation for gene delivery due to the site-specific nature of the delivery, as well as the high efficiency of the method. Electroporation involves the application of a pulsed electric field to cells to enhance cell permeability, resulting in the transi...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301733
更新日期:2002-08-01 00:00:00
abstract::We have previously shown that recombinant Sendai virus (SeV) vector, derived from murine parainfluenza virus, is one of the most efficient vectors for airway gene transfer. We have also shown that SeV-mediated transfection on second administration, although reduced by 60% when compared with levels achieved after a sin...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/gt.2010.131
更新日期:2011-02-01 00:00:00
abstract::Gene transfer technology has opened novel treatment avenues toward the treatment of damaged musculoskeletal tissues, and may be particularly beneficial to articular cartilage. There is no natural repair mechanism to heal damaged or diseased cartilage. Existing pharmacologic, surgical and cell based treatments may offe...
journal_title:Gene therapy
pub_type: 杂志文章,评审
doi:10.1038/sj.gt.3302201
更新日期:2004-02-01 00:00:00
abstract::T-cell dysfunction is thought to be central to the immunodeficiency state seen in patients with the Wiskott-Aldrich syndrome (WAS). Aspects of the WAS phenotype have been corrected in other cell types on introduction of the normal WAS protein (WASP), but the potential for correction of the T-cell defects has not been ...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301950
更新日期:2003-05-01 00:00:00
abstract::Inhibition of virus replication by means of RNA interference has been reported for several important human pathogens, including human immunodeficiency virus type 1 (HIV-1). RNA interference against these pathogens has been accomplished by introduction of virus-specific synthetic small interfering RNAs (siRNAs) or DNA ...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3302786
更新日期:2006-10-01 00:00:00
abstract::Prostate cancer is the most common cancer in men of the western world. To date, no effective treatment exists for metastatic prostate cancer and consequently, there is an urgent need to develop new and improved therapeutics. In recent years, the therapeutic potential of RNA interference (RNAi) has been extensively exp...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/gt.2015.50
更新日期:2015-10-01 00:00:00
abstract::Apo(a) is a very atherogenic plasma protein without apparent function, which is highly expressed in humans. The variation in plasma Lp(a) concentration among individuals is considerable. Approximately 10-15% of the white population exhibit plasma Lp(a) concentrations above the atherogenic cut-off value of approximatel...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301434
更新日期:2001-03-01 00:00:00
abstract::Cytomegalovirus (CMV) promoter is often present in recombinant adenovirus vectors (AdVs) suitable for gene therapy, ensuring high levels of transgene production in a wide range of hosts. Despite this characteristic, the presence of the AdV genome in target cells and tissues typically lasts longer than transgene produc...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301296
更新日期:2000-10-01 00:00:00
abstract::Retroviral vectors are being used increasingly in clinical gene therapy protocols but low transduction frequencies are presenting a significant obstacle to progress. In this paper we report a simple method to enhance the efficiency of ex vivo retroviral gene transfer. Calcium chloride is added to the vector stock and ...
journal_title:Gene therapy
pub_type: 杂志文章
doi:
更新日期:1995-09-01 00:00:00
abstract::Gene therapy is thought to be a promising method for the treatment of various diseases. One gene therapy strategy involves the manipulations on a process of formation of new vessels, commonly defined as angiogenesis. Angiogenic and antiangiogenic gene therapy is a new therapeutic approach to the treatment of cardiovas...
journal_title:Gene therapy
pub_type: 杂志文章,评审
doi:10.1038/sj.gt.3302621
更新日期:2005-10-01 00:00:00
abstract::This study examines the clinical relevance of tissue engineering integrating gene therapy and polymer science to bone regeneration. Bilateral maxillary defects (3 x 1.2 cm(2)) in 20 miniature swine were bridged with a bioresorbable internal splint. Constructs were created using ex vivo adenovirus bone morphogenetic pr...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3302106
更新日期:2003-11-01 00:00:00
abstract::We introduce an injectable system for the formation of a biodegradable DNA-containing implant that releases DNA over a 2-month period to provide a robust and prolonged gene expression at the site. Sustained delivery of the appropriate plasmid DNA resulted in sustained expression of luciferase, the persistent appearanc...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301786
更新日期:2002-09-01 00:00:00
abstract::Radioiodide concentrating activity in the thyroid, mediated by human Na+/I- symporter (hNIS), provides a mechanism for effective radioiodide treatment for patients who have invasive, recurrent, and metastatic thyroid cancers after total thyroidectomy. In an attempt to develop hNIS gene transfer for radioiodide therapy...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301170
更新日期:2000-05-01 00:00:00
abstract::Fibrodysplasia ossificans progressiva (FOP) is an autosomal dominant congenital disorder characterized by progressive heterotopic bone formation. Currently, no definitive treatment exists for FOP. The activin receptor type IA / activin-like kinase 2 (ACVR1/ALK2) gene has been identified as the responsible gene for FOP...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/gt.2011.193
更新日期:2012-07-01 00:00:00
abstract::The production of high-titer recombinant adeno-associated virus (rAAV) vector is essential for treatment of genetic diseases affecting the retina and choroid, where anatomical constraints may limit injectable volumes. Problematically, cytotoxicity arising from overexpression of the transgene during vector production f...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/gt.2017.50
更新日期:2017-08-01 00:00:00
abstract::Microwave (MW) energy consists of electric and magnetic fields and is able to penetrate deep into biological materials. We investigated the effect of MW (2450 MHz) irradiation on gene delivery in cultured mouse myoblasts and observed enhanced transgene expression. This effect is, however, highly variable and criticall...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/gt.2008.144
更新日期:2009-01-01 00:00:00
abstract::For the development of human immunodeficiency virus type 1 (HIV-1) vaccines, traditional approaches inducing virus-neutralizing antibodies have so far failed. Thus the effort is now focused on elicitation of cellular immunity. We are currently testing in clinical trials in the United Kingdom and East Africa a T-cell v...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3302241
更新日期:2004-07-01 00:00:00
abstract::RNA interference (RNAi) is an evolutionarily conserved process by which plants and animals protect their genomes utilizing small, double-stranded RNAs to degrade target RNAs in a sequence-specific manner. Post-transcriptional gene silencing by these moieties can lead to degradation of both cellular and viral RNAs. It ...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3302339
更新日期:2004-12-01 00:00:00
abstract::Adenovirus vectors have great potential in cancer gene therapy. Targeting of cancer-testis (CT) antigens, which are specifically presented at the surface of tumor cells by human leukocyte antigen (HLA) class I molecules, is an attractive option. In this study, a single-chain T-cell receptor (scTCR) directed against th...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/gt.2008.26
更新日期:2008-07-01 00:00:00
abstract::Recombinant adeno-associated virus (rAAV) vectors are attractive candidates for the treatment of inherited and acquired retinal disease. Although rAAV vectors are well characterized in rodent models, a prerequisite to their clinical application in human patients is the thorough evaluation of their efficacy and safety ...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301990
更新日期:2003-08-01 00:00:00