Cytokines and molecular therapy最新文献_第3页

Recombinant adeno-associated virus (rAAV) vectors for somatic gene therapy: recent advances and potential clinical applications. 重组腺相关病毒(rAAV)载体用于体细胞基因治疗:最新进展和潜在的临床应用

Cytokines and molecular therapy Pub Date : 1996-06-01

M Hallek, C M Wendtner

{"title":"Recombinant adeno-associated virus (rAAV) vectors for somatic gene therapy: recent advances and potential clinical applications.","authors":"M Hallek, C M Wendtner","doi":"","DOIUrl":"","url":null,"abstract":"Adeno-associated virus (AAV) is a single-stranded DNA dependovirus of the family of Parvoviridae that has promising features as a vector for somatic gene therapy. Different recombinant (r) AAV vectors have been generated that seem to have some advantages compared with other vector systems, such as the transduction of terminally differentiated and non-dividing cells, the lack of any apparent pathogenicity, low immunogenicity, relatively high stability of transgene expression, and the potential of targeted integration. Recent improvements in rAAV packaging should allow the generation of sufficient quantities of rAAV for clinical trials. Preclinical studies with rAAV are currently being performed for the treatment of a variety of inherited monogenic defects, such as beta-thalassemia, sickle cell anemia. Fanconi anemia, chronic granulomatous disease, Gaucher disease, metachromatic leukodystrophy and cystic fibrosis, and of acquired diseases, such as HIV infection and non-Hodgkin lymphoma. The diversity of these studies indicates that rAAV might have a broad range of clinical applications. A first clinical trial with rAAV vectors has been started for cystic fibrosis. While several important issues, including safety, tissue tropism and methods to achieve site-specific integration, need further clarification, rAAV seems to have a sufficient number of advantages to be seriously considered as a future gene therapy vector.","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"2 2","pages":"69-79"},"PeriodicalIF":0.0,"publicationDate":"1996-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20314771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Towards endothelial-cell-directed cancer immunotherapy: in vitro expression of human recombinant cytokine genes by human and mouse primary endothelial cells. 内皮细胞导向肿瘤免疫治疗:人与小鼠原代内皮细胞体外表达重组细胞因子基因。

Cytokines and molecular therapy Pub Date : 1996-06-01

J O Ojeifo, N Su, U S Ryan, U N Verma, A Mazumder, J A Zwiebel

{"title":"Towards endothelial-cell-directed cancer immunotherapy: in vitro expression of human recombinant cytokine genes by human and mouse primary endothelial cells.","authors":"J O Ojeifo, N Su, U S Ryan, U N Verma, A Mazumder, J A Zwiebel","doi":"","DOIUrl":"","url":null,"abstract":"Recent studies have demonstrated the feasibility of cytokine gene transfer to enhance the antitumor activities of host immune cells. Endothelial cells forming the vascular supply of tumors may be useful vehicles for the delivery of cytokine molecules in order to effect tumor immunotherapy. In order to determine whether primary endothelial cells can express cytokine transgenes efficiently, we constructed two retroviral vectors containing a cDNA encoding either recombinant human interleukin-1 alpha (rhIL-1 alpha) or recombinant human interleukin-2 (rhIL-2), called LNCIL-1 alpha and LNCIL-2 respectively, and studied the expression of the two cytokines in vitro in non-immortalized endothelial cells. Human umbilical vein endothelial cells (HUVEC) transduced with LNCIL-1 alpha or LNCIL-2 secreted 1.8-33 ng/10(6) cells/24 h and 40-246.7 ng/10(6) cells/24 h of biological active rhIL-1 alpha and rhIL-2 respectively. Mouse microvascular endothelial cells (MMEC) transduced with LNCIL-1 alpha and LNCIL-2 secreted 1.5 ng/10(6) cells/24 h and 5.8-24.7 ng/10(6) of biologically active rhIL-1 alpha and rhIL-2 proteins respectively. Cocultivation of HUVEC/IL-2 and MMEC/IL-2 with normal human bone marrow cells generated potent cytotoxic activity against K562, Daudi and other cell targets in a 51Cr-release assay. While IL-2 transgene-expressing HUVEC and MMEC retained their normal morphology, rhIL-1 alpha transgene expression inhibited the growth and altered the morphology of both HUVEC and MMEC in culture. The cytokine-gene-transduced endothelial cells retained other endothelial cell features, including uptake of acetylated low-density lipoprotein (Ac-LDL) and expression of von Willebrand factor, and were euploid as shown by flow cytometry. These results demonstrate that endothelial cells, by sustaining the production of biologically active rhIL-2 at levels that are sufficient for the activation of potent cytotoxic lymphocyte activity, may be useful agents for cancer gene therapy.","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"2 2","pages":"89-101"},"PeriodicalIF":0.0,"publicationDate":"1996-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20314773","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Development of immunotherapy for the treatment of malignancies refractory to conventional therapies. 免疫疗法治疗常规疗法难治性恶性肿瘤的进展。

Cytokines and molecular therapy Pub Date : 1996-03-01

S Kim, G P Haas, G G Hillman

引用次数: 0

Construction and characterization of a selectable multidrug resistance-glucocerebrosidase fusion gene. 选择性多药耐药-葡萄糖脑苷酶融合基因的构建与表征。

Cytokines and molecular therapy Pub Date : 1996-03-01

J M Aran, U A Germann, M M Gottesman, I Pastan

{"title":"Construction and characterization of a selectable multidrug resistance-glucocerebrosidase fusion gene.","authors":"J M Aran, U A Germann, M M Gottesman, I Pastan","doi":"","DOIUrl":"","url":null,"abstract":"Gene fusions can be employed to ensure concomitant expression of two different proteins under the same transcriptional control elements. We have synthesized a retroviral expression vector (pHaMG1) containing a human multidrug resistance (MDR1)-glucocerebrosidase (GC) chimeric gene inserted between the long terminal repeats of the Harvey murine sarcoma virus. When introduced into psi-CRE mouse fibroblasts, pHaMG1 conferred the drug-selectable multidrug resistance phenotype, and drug-resistant clones produced active human GC of about 60 kDa. Percoll gradient fractionation of homogenates prepared from transfectants confirmed correct targeting of P-glycoprotein to the plasma membrane and of GC to lysosomes. Although this construction was designed as a translational fusion of the MDR1 gene product, P-glycoprotein, and human GC, no evidence for a fusion protein was found in transfected cells, and an analysis of the RNAs transcribed from the integrated pHaMG1 retroviral vector suggests that either P-glycoprotein and GC are translated from one mRNA and rapidly processed into two proteins or they are translated separately from different mRNAs. These results reveal the feasibility of using fusion genes, which are smaller than alternative constructions with two promoters or with an internal ribosome entry site, for coexpression of selectable and nonselectable cDNAs in retroviral vectors.","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"2 1","pages":"47-57"},"PeriodicalIF":0.0,"publicationDate":"1996-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20312809","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

AK-5 tumor-induced modulation of host immune function: upregulation of Th-1-type cytokine response mediates early tumor regression. AK-5肿瘤诱导的宿主免疫功能调节:th -1型细胞因子反应上调介导肿瘤早期消退

Cytokines and molecular therapy Pub Date : 1996-03-01

A Khar, S Kausalya, M A Kamal

{"title":"AK-5 tumor-induced modulation of host immune function: upregulation of Th-1-type cytokine response mediates early tumor regression.","authors":"A Khar, S Kausalya, M A Kamal","doi":"","DOIUrl":"","url":null,"abstract":"AK-5, a rat histiocytoma, grows as ascites and undergoes spontaneous regression upon subcutaneous transplantation. Earlier studies from this laboratory have demonstrated that immunogenic rejection of AK-5 tumor is mediated through ADCC involving CD8+ NK cells and anti-AK-5 antibody. Upon subcutaneous transplantation, 55-60% of animals initiated tumor regression between 12-15 days after tumor transplantation (early rejectors), while 40-45% did not evoke regression up to 20-25 days (late rejectors). In order to delineate this differential response among syngeneic animals to the same tumor, we have evaluated the cytokine profiles in circulation of both early and late rejecting animals. Our results show that an increase in IL-2, IFN-gamma, IL-4, IL-12 and TNF-alpha contributed to early regression, suggesting a predominantly Th-1 type of cytokine function being evoked against AK-5 tumor. Hosts with lower circulating levels of these cytokines showed delayed tumor regression. In addition, administration of anti-IL-4/anti-IL-4 + anti-IL-10 lead to a decreased antibody response to AK-5 surface antigens in vivo. Neutralization of IFN-gamma in tumor-bearing animals resulted in inhibition of NK-cell-mediated cytotoxicity against AK-5 cells and delayed the regression process. The present study suggests that early regression of AK-5 tumor depends primarily on the higher levels of circulating Th-1-type cytokines; however, the role of IL-4 and anti-AK-5 antibody in tumor regression cannot be ruled out.","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"2 1","pages":"39-46"},"PeriodicalIF":0.0,"publicationDate":"1996-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20312808","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Influence of Epstein-Barr virus latent gene expression on the apoptosis-inducing effects of cortisone and 2-chlorodeoxyadenosine (2-CDA) in B-cell lines. eb病毒潜伏基因表达对可的松和2-氯脱氧腺苷(2-CDA)诱导b细胞株凋亡的影响。

Cytokines and molecular therapy Pub Date : 1996-03-01

A Röth, P Pfaff, W Lange, J Finke

{"title":"Influence of Epstein-Barr virus latent gene expression on the apoptosis-inducing effects of cortisone and 2-chlorodeoxyadenosine (2-CDA) in B-cell lines.","authors":"A Röth, P Pfaff, W Lange, J Finke","doi":"","DOIUrl":"","url":null,"abstract":"Burkitt's lymphoma (BL) cell lines are heterogenous with regard to phenotype, growth characteristics, Epstein-Barr virus (EBV) latent gene and BCL-2 expression. Previously we have demonstrated that transfection with the EBV genes LMP or EBNA-2 upregulates BCL-2 in B-cell lines. In order to test the functional relevance of these findings, cell lines were examined with regard to their sensitivity towards different apoptosis-inducing agents. BL cell lines transfected with LMP expressed high levels of BCL-2, and were compared with the parental cell line expressing little or no BCL-2. We also studied EBV immortalized lymphoblastoid cell lines (LCL) with high BCL-2 expression and strong resistance towards low serum concentrations. Hydrocortisone (HC) and 2-chlorodeoxyadenosine (2-CDA) were used alone or in different combinations. Cell growth and apoptosis were studied morphologically and by determination of viability and DNA fragmentation. BL cell lines showed different sensitivity towards HC-induced apoptosis, and sensitive cell lines became more resistant towards HC after infection with EBV or transfection with LMP and subsequent upregulation of BCL-2 expression. BL cell lines and LCL were relatively insensitive towards 2-CDA-induced apoptosis, and high concentrations of 2-CDA were necessary, independently of the levels of BCL-2 expression. In contrast to low-grade non-Hodgkin's lymphomas, 2-CDA does not appear to be a valuable drug for the treatment of Burkitt's lymphoma. LMP expression provides resistance towards hydrocortisone-induced apoptosis in vitro, possible through upregulation of BCL-2.","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"2 1","pages":"21-8"},"PeriodicalIF":0.0,"publicationDate":"1996-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20312806","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Role of interleukin-1 beta converting enzyme (ICE) in leukemia. 白细胞介素1 β转换酶(ICE)在白血病中的作用。

Cytokines and molecular therapy Pub Date : 1996-03-01

Z Estrov, M Talpaz

{"title":"Role of interleukin-1 beta converting enzyme (ICE) in leukemia.","authors":"Z Estrov, M Talpaz","doi":"","DOIUrl":"","url":null,"abstract":"Interleukin (IL)-1 is a proinflammatory cytokine that plays a pivotal role in driving the in vitro proliferation of leukemic cells through autocrine or paracrine pathways. Both IL-1 genes, IL-1 alpha and the prominent IL-1 beta, produce 31 kDa proteins. Whereas the precursor (pro) 31 kDa form of IL-1 alpha is biologically active, pro-IL-1 beta is inactive unless cleaved to its mature form by a cytoplasmic cysteine protease termed IL-1 beta converting enzyme (ICE). Although ICE was first thought to be a unique enzyme with a single biologic activity, several investigators have demonstrated that ICE shares sequence homology with the protein product of ced-3, the gene for cell death of the nematode Caenorhabditis elegans, and can induce apoptosis in different cellular systems. However, recent data indicate that ICE is a member of an increasingly recognized family of ICE-related molecules whose other members, such as CPP32, do not cleave pro-IL-1 beta but rather are effective inducers of apoptotic cell death. We recently investigated the effect of ICE inhibition on acute myelogenous leukemia (AML) colony growth. We found that inhibition of ICE reduced the production of mature IL-1 beta and suppressed the proliferation of AML colony-forming units, confirming the central role of IL-1 beta in AML progenitor proliferation. These data suggest that the primary role of ICE in AML cells is cleavage of pro-IL-1 beta rather than induction of apoptosis and that the antileukemic activity of specific ICE inhibitors warrants further exploitation.","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"2 1","pages":"1-11"},"PeriodicalIF":0.0,"publicationDate":"1996-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20312804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Control of stroma-dependent hematopoiesis by basic fibroblast growth factor: stromal phenotypic plasticity and modified myelopoietic functions. 碱性成纤维细胞生长因子对基质依赖性造血的控制:基质表型可塑性和骨髓功能的改变。

Cytokines and molecular therapy Pub Date : 1996-03-01

D Sternberg, A Peled, E Shezen, O Abramsky, W Jiang, F Bertolero, D Zipori

{"title":"Control of stroma-dependent hematopoiesis by basic fibroblast growth factor: stromal phenotypic plasticity and modified myelopoietic functions.","authors":"D Sternberg, A Peled, E Shezen, O Abramsky, W Jiang, F Bertolero, D Zipori","doi":"","DOIUrl":"","url":null,"abstract":"It has been suggested that basic fibroblast growth factor (bFGF) affects hematopoietic cells directly and that it may also act indirectly by modulating stromal cell functions. We tested the response of phenotypically and functionally distinct stromal cell clones to this cytokine. We studied cell phenotype, the composition and organization of cytoskeleton and extracellular matrix, the ability to repopulate 'wounded areas', the expression of cytokine genes, and the capacity of the stroma to support long-term hematopoiesis in vitro. Although the impact of bFGF on cell growth was small, it induced a prominent morphological change in three stromal cell types that we tested. We analyzed the molecular basis for this change: bFGF modified the protein expression of alpha-smooth muscle actin (alpha-SMA), tropomyosin, alpha-tubulin, fibronectin and paxillin in a distinct manner characteristic of each of the stromal cell types. Immunofluorescence analysis of these proteins revealed profound changes in the cytoskeleton and extracellular matrix (ECM) networks accompanied by increased ability of the 14F1.1 stromal cells to scatter in in vitro 'wounded' areas. Furthermore, although only limited changes were monitored in the expression of cytokine genes, the ability of the stromal cells to support hematopoiesis was markedly modified. Thus bFGF profoundly changes the cellular organization of stromal cells, their adhesion and their motility properties. These changes are associated with modified capacity to support hematopoiesis in culture.","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"2 1","pages":"29-38"},"PeriodicalIF":0.0,"publicationDate":"1996-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20312807","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Antigen incorporation into liposomes results in the enhancement of IL-4 and IgG1 secretion: evidence for preferential expansion of Th-2 cells. 抗原掺入脂质体导致IL-4和IgG1分泌增强:Th-2细胞优先扩增的证据。

Cytokines and molecular therapy Pub Date : 1996-03-01

J N Agrewala, M Owais, C M Gupta, G C Mishra

引用次数: 0

Deficient cell cycle control in myeloid cells of patients with newly diagnosed chronic myeloid leukemia. 新诊断的慢性髓性白血病患者髓系细胞的细胞周期控制能力不足。

Cytokines and molecular therapy Pub Date : 1995-12-01

R Schwab, C Peschel, D Desprès, G Derigs, T Fischer, C Huber, W E Aulitzky

{"title":"Deficient cell cycle control in myeloid cells of patients with newly diagnosed chronic myeloid leukemia.","authors":"R Schwab, C Peschel, D Desprès, G Derigs, T Fischer, C Huber, W E Aulitzky","doi":"","DOIUrl":"","url":null,"abstract":"Cell cycle control subsequent to gamma irradiation or growth factor starvation has been studied in immative hematopoietic cells of 19 previously untreated chronic myeloid leukemia (CML) patients in chronic phase compared with 18 normal controls. CD34-positive cells were cultured for seven days in the presence of optimal concentrations of appropriate growth factors. At day 7 of culture both S-phase fraction and differentiation were identical in normal and leukemic cells. In normal cells the proportion of S-phase cells was reduced by irradiation with 500 rad from 40 +/- 3% to 16 +/- 2%. In contrast, in CML cells a reduction of S-phase cells from 35 +/- 2% to 25 +/- 3% was observed. Moreover, irradiated CML cells arrested at a smaller number of cells in G2. Similarly, a significantly higher proportion of CML cells remained in S phase after withdrawal of growth factors. Semiquantitative PCR of p21 (waf1/cip1) induction by gamma irradiation provided no evidence for a major functional deficiency of p53 response to irradiation in these cells. Our results demonstrate an abnormal cell cycle arrest in chronic-phase CML cells both after gamma irradiation and after growth factor removal. This observation might have important implications for understanding the pathogenesis of both hyperplasia of chronic phase and the development of blast crisis in CML. The molecular mechanisms underlying these abnormalities in bcr-abl-positive cells remain to be clarified.","PeriodicalId":79484,"journal":{"name":"Cytokines and molecular therapy","volume":"1 4","pages":"281-8"},"PeriodicalIF":0.0,"publicationDate":"1995-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"20313543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0