| 1. |
- Magnusson, Maria K, 1972, et al.
(författare)
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A transductionally retargeted adenoviral vector for virotherapy of her2/neu-expressing prostate cancer
- 2012
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Ingår i: Human Gene Therapy. - : Mary Ann Liebert Inc. - 1043-0342 .- 1557-7422. ; 23, s. 70-82
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Tidskriftsartikel (refereegranskat)abstract
- The efficacy of adenovirus (Ad)-based gene therapy of solid tumors, such as prostate cancer, is limited. One of the many problems is that the virus infects many different cell types in the body, resulting in high toxicity, whereas the target cancer cells are often less prone to wild-type Ad infection. Our aim was to develop genetically de-and retargeted Ad vectors to reduce off-target effects and increase target infection for prostate cancer. We have previously reported an Ad5 vector specific for the cancer-associated receptor Her2/neu, created by inserting Her2/neu-reactive Affibody® molecules (ZH) into the HI loop of a coxsackievirus and adenovirus receptor binding-ablated fiber (Ad[ZH/1]). In addition to virus retargeting to Her2/neu, this virus was further modified from wild-type Ad by changing the RGD motif in the penton base to EGD and by substitution of the KKTK motif in the third shaft repeat to RKSK, resulting in the vector Ad[ZH/3]. The ZH-containing vectors could be produced to high titers and were specific for their target, resulting in efficient infection and killing of Her2/neu-positive androgen-dependent PC346C prostate cancer cells in vitro. Here we show that the oncolytic Ad[ZH/3] vector significantly prolonged survival time and reduced serum prostate-specific antigen levels in an orthotopic prostate tumor model in nude mice to the same extent as wild-type Ad5. Our results show that Her2/neu targeting using Ad-based vectors for prostate cancer is feasible and may serve as a basis for the development of gene therapy of human prostate cancer as well as other Her2/neu-expressing cancers. © 2012 Mary Ann Liebert, Inc.
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| 2. |
- Cardeno, A., et al.
(författare)
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The unsaponifiable fraction of extra virgin olive oil promotes apoptosis and attenuates activation and homing properties of T cells from patients with inflammatory bowel disease
- 2014
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Ingår i: Food Chemistry. - : Elsevier BV. - 0308-8146. ; 161, s. 353-360
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Tidskriftsartikel (refereegranskat)abstract
- The unsaponifiable fraction (UF) of extra virgin olive oil (EV00) possesses anti-inflammatory properties and exerts preventative effects in murine models of inflammatory bowel disease (IBD). The present study was designed to determine the in vitro effects of UF on blood and intestinal T cells from IBD patients and healthy subjects. The T cell phenotype was investigated by flow cytometry and cytokine secretion was determined by ELISA. The presence of UF of EVO0 promoted apoptosis and attenuated activation of intestinal and blood T cells isolated from IBD patients, decreasing the frequency of CD69(+) and CD25(+) T cells and, also, the secretion of IFN-gamma. Moreover, UF reduced the expression of the gut homing receptor integrin beta 7 on blood T cells from IBD patients. In conclusion, UF modulates the activity and the gut homing capacity of T cells, and might therefore be considered as a dietary complement with an anti-inflammatory role in IBD patients. (C) 2014 Published by Elsevier Ltd.
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| 3. |
- Dahlén, Rahil, et al.
(författare)
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Infliximab Inhibits Activation and Effector Functions of Peripheral Blood T Cells in vitro from Patients with Clinically Active Ulcerative Colitis
- 2013
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 0300-9475. ; 78:3, s. 275-284
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Tidskriftsartikel (refereegranskat)abstract
- Many patients with inflammatory bowel disease (IBD) are undergoing therapy with infliximab, an antibody specific for TNF. However, the exact mechanisms of action of infliximab are not completely understood. The aim of this study was to determine the in vitro effects of infliximab on blood T cells derived from anti-TNF therapy-naive ulcerative colitis (UC) patients with clinically active disease. Peripheral blood mononuclear cells were stimulated polyclonally or by antigen in the presence or absence of infliximab. The T cell phenotype was investigated by flow cytometry, cytokine secretion was determined by ELISA, and cell proliferation was determined by thymidine assay or CFSE dye. Presence of infliximab resulted in reduced expression of CD25 in CD4(+) and CD8(+) T cell populations and inhibited secretion of IFN-, IL-13, IL-17A, TNF as well as granzyme A. Infliximab also suppressed CD4(+) and CD8(+) T cell proliferation. These effects of infliximab were recorded both in T cells activated by polyclonal and antigen-specific stimulation. The effects of infliximab on T cell apoptosis and induction of FOXP3(+)CD4(+) T regulatory cells were ambiguous and depended on the originating cellular source and/or the stimulation mode and strength. In conclusion, infliximab is able to reduce T cell activation as measured by CD25, proliferation and cytokine secretion in vitro from UC patients with clinically active disease. These data suggest that suppression of T cell activity may be important for infliximab-mediated disease remission in patients with UC.
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| 4. |
- Granio, Ophélia, et al.
(författare)
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Adenovirus 5-fiber 35 chimeric vector mediates efficient apical correction of the CFTR defect in cystic fibrosis primary airway epithelia.
- 2010
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Ingår i: Human gene therapy. - : Mary Ann Liebert Inc. - 1557-7422 .- 1043-0342. ; 21:3, s. 251-269
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Tidskriftsartikel (refereegranskat)abstract
- In vivo gene transfer to the human respiratory tract using Adenovirus serotype 5 (Ad5) vectors has revealed their limitations related to inefficient gene transfer, host antiviral response and innate adenoviral toxicity. In the present work, we compared the cytotoxicity and efficiency of Ad5 and a chimeric Ad5F35 vector with respect to CFTR gene transfer to cystic fibrosis (CF) and non-CF human airway epithelial cells. We found that high doses of Ad5 vector had an adverse effect on the function of exogenous and endogenous CFTR. Results obtained with Ad5 capsid mutants suggested that the RGD motifs on the penton base capsomers were responsible for the negative effect on the CFTR function. This negative interference was not a result of a lower level of biosynthesis and/or altered cellular trafficking of the CFTR protein, but rather from an indirect mechanism of functional blockage of CFTR, related to the RGD-integrin-mediated endocytic pathway of Ad5. No negative interference with CFTR was observed for Ad5F35, an Ad5-based vector pseudotyped with fibers from Ad35, a serotype which uses another cell entry pathway. In vitro, Ad5F35 vector expressing the GFP-tagged CFTR (Ad5F35-GFP-CFTR) showed a 30-fold higher efficiency of transduction and chloride channel correction in CFTR-deficient cells, compared to Ad5GFP-CFTR. Ex vivo, Ad5F35-GFP-CFTR had the capacity to transduce efficiently reconstituted airway epithelia from CF patients (CF-HAE) via the apical surface, restored the chloride channel function at relatively low vector doses, and showed a relatively stable expression of GFP-CFTR for several weeks.
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| 5. |
- Magnusson, Maria K, 1972, et al.
(författare)
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CD25 and TNF receptor II reflect early primary response to infliximab therapy in patients with ulcerative colitis
- 2013
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Ingår i: United European Gastroenterology Journal. - : Wiley. - 2050-6406 .- 2050-6414. ; 1:6, s. 467-476
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Tidskriftsartikel (refereegranskat)abstract
- Background Although infliximab treatment is an option for patients with ulcerative colitis (UC), not all patients do respond to therapy, and cellular mechanisms leading to therapy response are incompletely known. Objective The objective of this article is to determine early effects of infliximab therapy on T cells in the blood of UC patients and if effects differed in therapy responders and nonresponders. Methods: Blood samples were obtained before and two weeks post-treatment start from 34 anti-tumor necrosis factor (TNF) therapy-naïve UC patients undergoing infliximab therapy. Response to therapy was evaluated prior to the fourth treatment dose. Expression of T cell surface markers and levels of soluble receptors and cytokines in serum were determined. Results At baseline, there were no differences in cellular, biochemical or clinical parameters between therapy responders and nonresponders. Infliximab therapy reduced frequencies of CD25+ T cells and increased frequencies of annexin V+ T cells in patients responding to infliximab, but not in nonresponding patients, two weeks after therapy start. Only therapy responders had decreased serum levels of sCD25 and sTNFRII two weeks after treatment start. In contrast, clinical parameters did not reflect therapy outcome already two weeks after therapy start. Conclusion Soluble and membrane-bound T cell receptors may be early indicators of infliximab therapy response in UC, which can be of clinical importance for the decision when to continue or to stop the treatment.
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| 6. |
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| 7. |
- Wenzel, Ulf Alexander, 1975, et al.
(författare)
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Spontaneous colitis in Muc2-deficient mice reflects clinical and cellular features of active ulcerative colitis.
- 2014
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 9:6
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Tidskriftsartikel (refereegranskat)abstract
- The colonic mucus layer plays a critical role in intestinal homeostasis by limiting contact between luminal bacteria and the mucosal immune system. A defective mucus barrier in animal models allows bacterial contact with the intestinal epithelium and results in spontaneous colitis. A defective mucus barrier is also a key feature of active ulcerative colitis (UC). Alterations in the immune compartment due to intestinal bacterial breach in mice lacking the colon mucus barrier have not been characterized and correlated to active UC.
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| 8. |
- Wising, Catharina, 1973, et al.
(författare)
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Toxic activity of the CdtB component of Haemophilus ducreyi cytolethal distending toxin expressed from an adenovirus 5 vector
- 2010
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Ingår i: APMIS. - : Wiley. - 1600-0463 .- 0903-4641. ; 118:2, s. 143-149
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Tidskriftsartikel (refereegranskat)abstract
- The Haemophilus ducreyi cytolethal distending toxin (HdCDT) catalytic subunit CdtB has DNase-like activity and mediates DNA damage after its delivery into target cells. We constructed a replication-deficient adenovirus type 5 (Ad5) vector expressing CdtB and investigated the toxic properties of this vector on HeLa cells. Ad5CdtB caused loss of cell viability, morphologic changes, and cell cycle arrest, findings similar to HdCDT intoxication. This confirmed that CdtB is responsible for the toxicity of the holotoxin when expressed in cells following transduction by an adenoviral vector, and indicated a possible potential of this novel strategy in studies of activity of intracellular products and in gene therapy of cancer.
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