Abstract:
:Previous studies have demonstrated that antigen-specific tolerance could be induced by lipopolysaccharide (LPS)-stimulated B cells retrovirally transduced with an immunoglobulin-antigen (or epitope-containing peptide) fusion construct. To investigate the mechanism of this gene therapy system, we now adapted this approach to immunotherapy of spontaneous diabetes in nonobese diabetic (NOD) mice, a T-cell-mediated autoimmune disease triggered, in part, by a pathogenic response to glutamate decarboxylase (GAD) 65. We demonstrate that LPS-stimulated splenocytes, retrovirally transfected with GAD-IgG fusion construct, induce a significant antigen-specific hyporesponsiveness at both cellular and humoral levels and reduce the incidence of diabetes in female NOD mice. Parallel with disease protection, we observed a prolonged increase of the numbers of CD4+CD25+ T cells in the periphery of GAD-IgG-treated mice, compared to those treated with a control IgG vector, both in the prediabetic period and persisting even 8 months after gene therapy. This increase appeared to be induced by the repeated stimulation of the antigen in the periphery instead of a result of differentiation of T-cell precursor in the thymus. Moreover, CD4+CD25+ T cells induced by GAD-IgG fusion construct were capable of suppressing the proliferative response of CD4+CD25- T cells in vitro; and ablation of the activity of CD4+CD25+ T cells by blocking antibody against CD25 could reverse GAD-specific T-cell hyporesponsiveness. These results suggested that CD4+CD25+ T-cell subset induced in GAD-IgG-treated NOD mice represented the regulatory or suppressive CD4+CD25+ T cells (Treg) and might play an important role in the induction and maintenance of tolerance in NOD mice. Furthermore, the numbers of splenic CD4+CD62L+ regulatory T cells in GAD-IgG-treated mice during the prediabetic period and serum TGF-beta levels in 34-38-week-old GAD-IgG-protected mice were also increased, compared to control IgG-treated ones. Therefore, we propose that the induction of tolerance and the prevention of diabetes incidence in NOD female mice induced by the GAD-IgG fusion construct may require CD4+ regulatory T cells, and the possible mediation of TGF-beta.
journal_name
Gene Therjournal_title
Gene therapyauthors
Song L,Wang J,Wang R,Yu M,Sun Y,Han G,Li Y,Qian J,Scott DW,Kang Y,Soukhareva N,Shen Bdoi
10.1038/sj.gt.3302327keywords:
subject
Has Abstractpub_date
2004-10-01 00:00:00pages
1487-96issue
20eissn
0969-7128issn
1476-5462pii
3302327journal_volume
11pub_type
杂志文章相关文献
GENE THERAPY文献大全abstract::Mucopolysaccharidosis type I (MPSI) is an autosomic recessive, lysosomal storage disorder due to the deficit of the enzyme α-L-iduronidase (IDUA). The disease accounts for a general impairment of tissue and organ functions, mainly including heart disease, corneal clouding, organomegaly, skeletal malformations and join...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/gt.2011.94
更新日期:2012-04-01 00:00:00
abstract::Advances in islet transplantation have encouraged efforts to create alternative insulin-secreting cells that overcome limitations associated with current therapies. We have recently demonstrated durable correction of murine and porcine diabetes by syngeneic and autologous implantation, respectively, of primary hepatoc...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/gt.2010.12
更新日期:2010-05-01 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::Foamy virus (FV) vectors are promising for hematopoietic stem cell (HSC) gene therapy but preclinical data on the clonal composition of FV vector-transduced human repopulating cells is needed. Human CD34(+) human cord blood cells were transduced with an FV vector encoding a methylguanine methyltransferase (MGMT)P140K ...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/gt.2015.20
更新日期:2015-07-01 00:00:00
abstract::Hepatic fibrosis is a common outcome of chronic liver diseases. In schistosomiasis, chronic parasite egg-induced granuloma formation can lead to fibrosis, which is immunologically characterized by the dominant Th2 response. Recently, it has been shown that gene therapy is an attractive approach for the treatment of he...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301524
更新日期:2001-09-01 00:00:00
abstract::Chimeric oligonucleotides have been used successfully to correct point and frameshift mutations in several cell types, as well as in animal and plant models. However, their application to primitive human blood cells has been limited. In this investigation, chimeric oligonucleotides designed to direct a site-specific n...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301610
更新日期:2002-01-01 00:00:00
abstract::We have designed new vectors for the construction of recombinant adenoviruses containing expression cassettes in the E1 and/or E3 regions. Using a versatile set of restriction enzymes, the cassettes are cloned into small bacterial vectors and subsequently introduced into large plasmids containing the adenoviral sequen...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301047
更新日期:2000-01-01 00:00:00
abstract::Cancer cachexia, characterized by anorexia, weight loss and progressive tissue wasting, has been postulated to be mediated by various cytokines. However, the precise mechanism of cachexia induction is not fully explained. We have developed synthetic double-stranded oligodeoxynucleotides (ODN) as 'decoy' cis-elements t...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3300819
更新日期:1999-01-01 00:00:00
abstract::Autonomous parvoviruses are small, single strand DNA viruses which preferentially replicate in transformed and tumor cells, causing cell death by expression of the cytotoxic nonstructural protein, NS1. Several parvoviruses of the rodent group, including LuIII, efficiently infect human transformed cell lines. The poten...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3300832
更新日期:1999-03-01 00:00:00
abstract::Lentivirus can be engineered to be a highly potent vector for gene therapy applications. However, generation of clinical grade vectors in enough quantities for therapeutic use is still troublesome and limits the preclinical and clinical experiments. As a first step to solve this unmet need we recently introduced a bac...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/gt.2010.162
更新日期:2011-06-01 00:00:00
abstract::Different lipids and cationic polymers were tested in vitro for their ability to transfect rabbit aortic smooth muscle cells and human endothelial cells with lacZ marker gene. Toxicity of the complexes was evaluated with MTT assay. Selected plasmid-polymer complexes with different charge ratios were then tested for in...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3300800
更新日期:1999-01-01 00:00:00
abstract::More than one hundred different mutations in the gene encoding rhodopsin are associated with a group of retinal degenerations including retinitis pigmentosa, congenital stationary night blindness and retinitis punctata albescens. Given this large heterogeneity of mutations, it would be ideal to develop mutation-indepe...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3302512
更新日期:2005-08-01 00:00:00
abstract::Adeno-associated virus (AAV) gene therapy constitutes a powerful tool for the treatment of neurodegenerative diseases. While AAVs are generally administered systemically to newborns in preclinical studies of neurological disorders, in adults the maturity of the blood-brain barrier (BBB) must be considered when selecti...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/gt.2017.18
更新日期:2017-05-01 00:00:00
abstract::The prognosis of pancreatic adenocarcinoma is poor and current treatment ineffective. A novel treatment strategy is described here using a mouse model system for pancreatic cancer. Cells that have been genetically modified to express the cytochrome P450 2B1 enzyme are encapsulated in cellulose sulphate and implanted i...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3300671
更新日期:1998-08-01 00:00:00
abstract::Radiosensitization of human gastrointestinal tumors by 5-fluorouracil (5-FU) has been studied in vitro and clinically in human cancer therapy trials. The bacterial enzyme cytosine deaminase (CD) converts the nontoxic prodrug 5-fluorocytosine (5-FC) into 5-FU. Human colon cancer cells stably expressing CD have been sho...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301196
更新日期:2000-06-01 00:00:00
abstract::Oligonucleotides (ODNs) show great promise in their ability to specifically inhibit single gene expression but must cross the cell membrane, escape the endosomal vesicle, and possibly traverse the nuclear membrane to arrive at their intracellular target molecules. In an attempt to improve the delivery of phosphodieste...
journal_title:Gene therapy
pub_type: 杂志文章
doi:
更新日期:1996-04-01 00:00:00
abstract::The role of gap junctional intercellular communication (GJIC) in bystander killing with herpes simplex virus thymidine kinase (HSV-TK) and ganciclovir (GCV) was evaluated in U251 cells expressing a dominant-negative connexin 43 cDNA (DN14), and in HeLa cells, reportedly devoid of connexin protein. These cell lines bot...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3302487
更新日期:2005-07-01 00:00:00
abstract::Phase 1 clinical trials of liposome-mediated gene therapy for cystic fibrosis have been completed and in all cases the expression level achieved has been low and transient. Clearly, improvements in the efficiency of gene transfer are required. It is now being recognised that delivery of high doses of DNA/liposomes to ...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301097
更新日期:2000-03-01 00:00:00
abstract::Soluble receptors to vascular endothelial growth factor (VEGF) can inhibit its angiogenic effect. Since angiogenesis is involved in wound repair, we hypothesized that adenovirus-mediated gene transfer of a soluble form of VEGF receptor 2 (Flk-1) would attenuate wound healing in mice. C57Bl/6J and genetically diabetic ...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3302162
更新日期:2004-02-01 00:00:00
abstract::Aptamers are oligonucleotides evolved in vitro or in nature to bind target ligands with high affinity and specificity. They are emerging as powerful tools in the fields of therapeutics, drug development, target validation and diagnostics. Aptamers are attractive alternatives to antibody- and small-molecule-based thera...
journal_title:Gene therapy
pub_type: 杂志文章,评审
doi:10.1038/sj.gt.3302900
更新日期:2007-02-01 00:00:00
abstract::Lentiviral vectors pseudotyped with the baculovirus envelope protein GP64 transduce primary cultures of human airway epithelia (HAE) at their apical surface. Our goal in this study was to harness a directed evolution approach to develop a novel envelope glycoprotein with increased transduction properties for HAE. Usin...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/gt.2017.78
更新日期:2017-10-01 00:00:00
abstract::Cationic lipid-based delivery systems such as lipoplexes or stabilized plasmid-lipid particles (SPLP) represent a safer alternative to viral systems for gene therapy applications. We studied the impact of cell cycle status on the efficiency of transfection of human ovarian carcinoma tumor cells using two cationic-lipi...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3300837
更新日期:1999-03-01 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::The accessibility of adipose tissue and its ability to secrete various bioactive molecules suggest that adipose cells may be attractive targets for gene therapy applications. Here, we report the use of highly defective herpes simplex virus (HSV) vectors as suitable gene transfer agents for adipose cells in culture and...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3302359
更新日期:2005-01-01 00:00:00
abstract::Gyrate atrophy (GA) of the choroid and retina is an autosomal recessive chorioretinal degeneration, caused by deficiency of the mitochondrial matrix enzyme ornithine-delta-aminotransferase (OAT). This deficiency results in the accumulation of ornithine in the body fluids and leads to hyperornithinemia. Although the cl...
journal_title:Gene therapy
pub_type: 杂志文章
doi:
更新日期:1995-01-01 00:00:00
abstract::The potential of gene therapy for treatment of lung disease remains unrealised. Early model systems often resulted in promising efficiency of gene transfer, only to prove irreproducible in the clinic. While problems such as induction of host immune responses and duration of expression also need to be addressed, it is ...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301146
更新日期:2000-04-01 00:00:00
abstract::Mesenchymal stem cells (MSC) are a group of clonogenic cells present among the bone marrow stroma and capable of multilineage differentiation into mesoderm-type cells such as osteoblasts, adipocytes and chondrocytes. Due to their ease of isolation and their differentiation potential, MSC are being introduced into clin...
journal_title:Gene therapy
pub_type: 杂志文章,评审
doi:10.1038/sj.gt.3303067
更新日期:2008-01-01 00:00:00
abstract::Efficient gene delivery is a critical obstacle for gene therapy that must be overcome. Until current limits of gene delivery technology are solved, identification of systems with bystander effects is highly desirable. As an anticancer agent, radioactive iodine (131)I has minimal toxicity. The physical characteristics ...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3302758
更新日期:2006-07-01 00:00:00
abstract::This study uses a novel approach to gene therapy in which plasmid DNA is targeted to the pancreas in vivo using ultrasound-targeted microbubble destruction (UTMD) to achieve islet regeneration. Intravenous microbubbles carrying plasmids are destroyed within the pancreatic microcirculation by ultrasound, achieving loca...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/gt.2010.85
更新日期:2010-11-01 00:00:00
abstract::We have shown that various forms of oligonucleotides, chimeric RNA-DNA oligonucleotide (RDO) and single-stranded oligodeoxynucleotide (ODN), are capable of chromosomal gene alterations in mammalian cells. Using two ODNs we corrected an inactivating mutation in the tyrosinase gene and introduced an activating mutation ...
journal_title:Gene therapy
pub_type: 杂志文章
doi:10.1038/sj.gt.3301862
更新日期:2002-12-01 00:00:00