Abstract:
:Recombinant poxviruses expressing immunomodulatory molecules together with specific antigens represent powerful vaccines for cancer immunotherapy. Recently, we and others have demonstrated, in vitro and in vivo, that coexpression of CD80 and CD86 costimulatory molecules enhances the immunogenic capacity of a recombinant vaccinia virus (rVV) encoding different tumor-associated antigens. To further investigate the capacity of these vectors to provide ligands for different costimulatory pathways relevant in the generation of T cell responses, we constructed a recombinant virus (rVV) expressing CD40 ligand or CD154 (CD154rVV). Upon binding the CD40 receptor expressed on antigen presenting cells (APC), this molecule, physiologically expressed on activated CD4+ T cells, increases their antigen presentation and immunostimulatory capacities. Therefore, we evaluated the effects of CD154rVV infection on APC activation and its consequences on T cell stimulation. CD154rVV infection of autologous fibroblasts, monocytes, or iDC promoted the expression of a number of cytokines, including GM-CSF, TNF-alpha, and IL-15 in iDC. Most importantly, IL-12 p40 gene expression and protein secretion were induced by CD154rVV but not by wild-type VV (WT VV) in either CD14+ cells or iDC, and these effects could be blocked by anti-CD40 monoclonal antibodies. Furthermore, phenotypic characterization of CD154rVV infected iDC revealed enhanced expression of CD83 and CD86 surface markers as compared with wild-type vaccinia virus infection. As expected, VV infection triggered cytokines gene expression in cultures including APC and T cells from VV immune donors. However, cytokine genes typically expressed by T cell receptor triggered T cells such as those encoding IL-2 and IFN-gamma, or T cell proliferation, were detectable to a significantly higher extent in CD154rVV infected cultures, as compared with WT VV. Activation of specific CD8+ T cells was then investigated using MART-1/Melan-A(27-35) epitope as the model of tumor-associated antigen (TAA). In the presence of CD154rVV activated APCs, significantly higher numbers of specific cytotoxic CD8+ T cells were detected, as compared with cultures performed in the presence of WT VV or in the absence of virus. Taken together, these data indicate that functional CD154 expression from rVV infected cells promotes APC activation, thereby enhancing antigen-specific T cell generation. Such a recombinant vector might help bypass the requirement for activated helper cells during CTL priming, thus qualifying as a potentially relevant vector in the generation of CD8+ T cell responses in cancer immunotherapy.
journal_name
Hum Gene Therjournal_title
Human gene therapyauthors
Feder-Mengus C,Schultz-Thater E,Oertli D,Marti WR,Heberer M,Spagnoli GC,Zajac Pdoi
10.1089/hum.2005.16.348keywords:
subject
Has Abstractpub_date
2005-03-01 00:00:00pages
348-60issue
3eissn
1043-0342issn
1557-7422journal_volume
16pub_type
杂志文章abstract::Human papillomavirus type 16 (HPV16) is associated with the development of anogenital cancers and their precursor lesions, intraepithelial neoplasia. Treatment strategies against HPV-induced intraepithelial neoplasia are not HPV specific and mostly consist of physical removal or ablation of lesions. We had previously ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2009.115
更新日期:2010-07-01 00:00:00
abstract::Naked plasmid DNA electrotransfer offers advantages over viral-based gene delivery, including being regulatory permissive, but factors influencing expression efficiency and cell fate impact on translational utility. This study compared co-expression of red and green fluorescence reporter plasmids with differing promot...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2018.062
更新日期:2019-02-01 00:00:00
abstract::Foamy virus (FV) vectors are a promising gene delivery system for use in hematopoietic stem cell gene therapy. Previous FV vector marking studies in the NOD/SCID xenotransplantation model used umbilical cord blood (UCB)-derived SCID repopulating cells (SRCs) that were assayed 5-10 weeks posttransplantation. We now rep...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340460732481
更新日期:2004-01-01 00:00:00
abstract::We reported that SNV-derived retroviral vectors, which display single-chain antibodies on the viral surface, enable cell type-specific gene delivery into various human cells. In particular, the SNV cell type-specific gene delivery vector system appears to be well suited to transduce genes into cells of the human hemat...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430349950016663
更新日期:1999-11-01 00:00:00
abstract::Approaches to alter the native tropism of adenoviruses (Ads) are beneficial to increase their efficacy and safety profile. Liver tropism is important with regard to potential clinical toxicity in humans. Ad5/3 chimeras in which the Ad5 knob is substituted by the Ad3 knob, such as Ad5/3luc1, have been recently shown to...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340460745829
更新日期:2004-05-01 00:00:00
abstract::Umbilical cord blood (CB) from the early gestational human fetus is recognized as a rich source of hematopoietic stem cells. To examine the value of fetal CB for gene therapy of inborn immunohematopoietic disorders, we tested the feasibility of genetic modification of CD34(+) cells from CB at weeks 24 to 34 of pregnan...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340150504000
更新日期:2001-03-01 00:00:00
abstract::The immune response against human immunodeficiency virus type-1 (HIV-1) is believed to play a role in controlling the early stages of disease progression. The cellular immune response, in particular cytotoxic T lymphocyte (CTL) activity, may be important for eliminating virally infected cells in HIV-1-infected individ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1994.5.7-853
更新日期:1994-07-01 00:00:00
abstract::PhD-trained biomedical scientists are moving into an increasingly diverse variety of careers within the sciences. However, graduate and postdoctoral training programs have historically focused on academic career preparation, and have not sufficiently prepared trainees for transitioning into other scientific careers. A...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2016.154
更新日期:2016-11-01 00:00:00
abstract::The immunogenicity of adenovirus vectors remains a major obstacle to their safe and efficacious use for gene therapy. In order to identify T-cell epitopes directly from adenoviruses, four viral protein sequences were screened for the well-characterized 9-mer HLA-A2 binding motif. Peripheral blood mononuclear cells (PB...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/104303402320138952
更新日期:2002-07-01 00:00:00
abstract::Cell therapies are treatments in which stem or progenitor cells are stimulated to differentiate into specialized cells able to home to and repair damaged tissues. After their discovery, endothelial progenitor cells (EPCs) stimulated worldwide interest as possible vehicles to perform autologous cell therapy of tumors. ...
journal_title:Human gene therapy
pub_type: 杂志文章,评审
doi:10.1089/hum.2016.066
更新日期:2016-10-01 00:00:00
abstract::Therapeutic levels of expression of the beta-globin gene have been difficult to achieve with conventional retroviral vectors without the inclusion of DNase I-hypersensitive site (HS2, HS3, and HS4) enhancer elements. We generated recombinant adeno-associated viral (AAV) vectors carrying an antisickling human beta-glob...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2007.173
更新日期:2008-04-01 00:00:00
abstract::Combining chemotherapy and immunotherapy is problematic because chemotherapy can ablate the immune responses initiated by modulators of the immune system. We hypothesized that protection of immunocompetent cells from the toxic effects of chemotherapy, using drug resistance gene therapy strategies, would allow the comb...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2006.17.798
更新日期:2006-08-01 00:00:00
abstract::The central nervous system (CNS) is a predominant site of involvement in several lysosomal storage diseases (LSDs); and for many patients, these diseases are diagnosed only after the onset of symptoms related to the progressive accumulation of macromolecules within lysosomes. The mucopolysaccharidosis type VII (MPS VI...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340050015707
更新日期:2000-03-01 00:00:00
abstract::With the aim of developing new gene transfer tools for treating CF with gene therapy, we have synthesized a novel family of molecules named cationic phosphonolipids. The most efficient among them were selected by in vitro screening to compare their activities in vivo in mouse lungs. We used a reporter gene whose activ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1998.9.16-2309
更新日期:1998-11-01 00:00:00
abstract::Gene-modified lymphocytes have a potential role in the therapy of cancer, infectious diseases, and genetic disorders of the immune system. Current gene therapy protocols involving gene transfer into lymphocytes utilize retroviruses with amphotropic envelope proteins. However, transduction efficiencies in lymphocytes u...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1996.7.12-1415
更新日期:1996-08-01 00:00:00
abstract::Bone marrow mesenchymal stem cells (BMSCs) represent an important source of cells for tissue repair. The tropism of these cells to the sites of injury and tumors has been well established. Their tumor-homing properties make BMSCs good candidates as antitumor agent delivery vehicles. In this study, we showed that BMSCs...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2010.116
更新日期:2011-04-01 00:00:00
abstract::Gene delivery via murine-based recombinant retroviral vectors is currently widely used in gene therapy clinical trials. The vectors are engineered to be replication defective by replacing the structural and nonstructural genes of a cloned infectious retrovirus with a therapeutic gene of interest. The retroviral partic...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1997.8.10-1231
更新日期:1997-07-01 00:00:00
abstract::Lentiviral vectors are efficient gene delivery vehicles for therapeutic and research applications. In contrast to oncoretroviral vectors, they are able to infect most nonproliferating cells. In the liver, induction of cell proliferation dramatically improved hepatocyte transduction using all types of retroviral vector...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2011.227
更新日期:2013-02-01 00:00:00
abstract::Lentiviral vectors hold great promise for the genetic correction of various inherited diseases. However, lentiviral vector biology is still not completely understood and warrants the precise decoding of molecular mechanisms underlying integration and post-translational modification. This study investigated a series of...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2017.162
更新日期:2017-10-01 00:00:00
abstract::Diabetes mellitus derives from either insulin deficiency (type I) or resistance (type II). Homozygous mutations in the insulin receptor (IR) gene cause the rare leprechaunism and Rabson-Mendenhall syndromes, severe forms of hyperinsulinemic insulin resistance for which no therapy is currently available. Systems have b...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2004.15.1101
更新日期:2004-11-01 00:00:00
abstract::Williams-Beuren syndrome (WBS) and supravalvular aortic stenosis (SVAS) are genetic syndromes marked by the propensity to develop severe vascular stenoses. Vascular lesions in both syndromes are caused by haploinsufficiency of the elastin gene. We used these distinct genetic syndromes as models to evaluate the feasibi...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2011.201
更新日期:2012-11-01 00:00:00
abstract::Hepatic stellate cells (HSCs) are the primary cell type responsible for liver fibrogenesis. Transforming growth factor beta 1 (TGF-β1) and platelet-derived growth factor (PDGF) are key profibrotic cytokines that regulate HSC activation and proliferation with functional convergence. Dual RNA interference against their ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2018.047
更新日期:2019-02-01 00:00:00
abstract::Lung disease associated with disorders such as cystic fibrosis (CF) may be amenable to somatic gene therapy in which there is delivery of the normal gene directly to the respiratory epithelium using E1a- adenovirus (Ad) type 2- or 5-based vectors. For safety reasons, the Ad vectors are rendered replication deficient b...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1994.5.9-1105
更新日期:1994-09-01 00:00:00
abstract::The in vitro genetic manipulation of dendritic cells (DCs) for the expression of foreign proteins or peptides will assist in the development of immunotherapeutic approaches to treat cancer, immunological disorders, and/or infectious diseases. Reports have shown the expansion and differentiation of CD34(+) progenitor c...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340050207975
更新日期:2000-12-10 00:00:00
abstract::Targeted therapy produces objective responses in bladder cancer patients, although the responses can be short. Meanwhile, response rates to immune therapy are lower, but the effects are more durable. Based on these findings, it was hypothesized that urothelial carcinoma associated 1 (UCA1)-targeted therapy could syner...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2018.048
更新日期:2018-12-01 00:00:00
abstract::Recombinant adeno-associated virus serotype 2 (rAAV2)-based human gene therapy for cystic fibrosis has progressed through a series of preclinical studies and phase I and II clinical trials. This agent has shown an encouraging safety profile, consistent levels of DNA transfer, and positive evidence of short-term clinic...
journal_title:Human gene therapy
pub_type: 临床试验,杂志文章
doi:10.1089/hum.2005.16.921
更新日期:2005-08-01 00:00:00
abstract::Successful gene therapy approaches for metachromatic leukodystrophy (MLD), based either on hematopoietic stem/progenitor cells (HSPCs) or direct central nervous system (CNS) gene transfer, highlighted a requirement for high levels of arylsulfatase A (ARSA) expression to achieve correction of disease manifestations in ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2007.048
更新日期:2007-09-01 00:00:00
abstract::Human immunodeficiency virus (HIV) infection represents one of the most challenging systems for gene therapy. Thanks to the extended knowledge of the molecular biology of the HIV life cycle, many different strategies have been developed including transdominant modifications of HIV proteins, RNA decoys, antisense RNA, ...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.1998.9.5-621
更新日期:1998-03-20 00:00:00
abstract::Clinical applications of gene therapy require advances in gene delivery systems. Although numerous clinical trials are already underway, the ultimate success of gene therapies will depend on gene transfer vectors that facilitate the expression of a specific gene at therapeutic levels in the desired cell populations wi...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/10430340360535751
更新日期:2003-02-10 00:00:00
abstract::Retinal ganglion cells (RGCs) play a key role in the pathogenesis and development of glaucoma. The present study aims to investigate the underlying mechanism of long noncoding RNA growth arrest-specific transcript 5 (GAS5) in glaucoma development through regulating the apoptosis of RGCs. Rat models of chronic glaucoma...
journal_title:Human gene therapy
pub_type: 杂志文章
doi:10.1089/hum.2019.056
更新日期:2019-12-01 00:00:00