Current Issue : April - June Volume : 2014 Issue Number : 2 Articles : 6 Articles
Background: Cancer is both a systemic and a genetic disease. The pathogenesis of cancer might be related to\r\ndampened immunity. Host immunity recognizes nascent malignant cells ââ?¬â?? a process referred to as immune\r\nsurveillance. Augmenting immune surveillance and suppressing immune escape are crucial in tumor\r\nimmunotherapy.\r\nMethods: A recombinant plasmid capable of co-expressing granulocyte-macrophage colony- stimulating factor\r\n(GM-SCF), interleukin-21 (IL-21), and retinoic acid early transcription factor-1 (Rae-1) was constructed, and its effects\r\ndetermined in a mouse model of subcutaneous liver cancer. Serum specimens were assayed for IL-2 and INF-? by\r\nELISA. Liver cancer specimens were isolated for Rae-1 expression by RT-PCR and Western blot, and splenocytes were\r\nanalyzed by flow cytometry.\r\nResults: The recombinant plasmid inhibited the growth of liver cancer and prolonged survival of tumor-loaded\r\nmice. Activation of host immunity might have contributed to this effect by promoting increased numbers and\r\ncytotoxicity of natural killer (NK) cells and cytotoxic T lymphocytes (CTL) following expression of GM-SCF, IL-21, and\r\nRae-1. By contrast, the frequency of regulatory T cells was decreased, Consequently, activated CTL and NK cells\r\nenhanced their secretion of INF-?, which promoted cytotoxicity of NK cells and CTL. Moreover, active CTL showed\r\ndramatic secretion of IL-2, which stimulates CTL. The recombinant expression plasmid also augmented Rae-1\r\nexpression by liver cancer cells. Rae-1 receptor expressing CTL and NK cells removed liver cancer.\r\nConclusions: The recombinant expression plasmid inhibited liver cancer by a mechanism that involved activation\r\nof cell-mediated immunity and Rae-1 in liver cancer....
Background: Inflammatory bowel disease (IBD) is characterized by disturbance of pro-inflammatory cytokines and\r\nanti-inflammatory cytokines. Previous studies have demonstrated the effect of anti-inflammatory cytokines, such as\r\ninterleukin-10 (IL-10) or IL-4 on IBD, but their data were controversial. This study further investigated the effect of\r\nIL-4 (IL-4), IL-10 and their combination on treatment of trinitrobenzenesulfonic acid (TNBS)-induced murine colitis.\r\nMethods: pcDNA3.0 carrying murine IL-4 or IL-10 cDNA was encapsulated with LipofectAMINE 2000 and intraperitoneally\r\ninjected into mice with TNBS-induced colitis. The levels of intestinal IL-4 and IL-10 mRNA were confirmed by\r\nquantitative-RT-PCR. Inflamed tissues were assessed by histology and expression of interferon (IFN)-?, tumor necrosis\r\nfactor (TNF)-a and IL-6.\r\nResults: The data confirmed that IL-4 or IL-10 over-expression was successfully induced in murine colon tissues after\r\nintraperitoneal injection. Injections of IL-4 or IL-10 significantly inhibited TNBS-induced colon tissue damage, disease\r\nactivity index (DAI) and body weight loss compared to the control mice. Furthermore, expression of IFN-?, TNF-a and\r\nIL-6 was markedly blocked by injections of IL-4 or IL-10 plasmid. However, there was less therapeutic effect in mice\r\ninjected with the combination of IL-4 and IL-10.\r\nConclusions: These data suggest that intraperitoneal injection of IL-4 or IL-10 plasmid was a potential strategy in control\r\nof TNBS-induced murine colitis, but their combination had less effect....
Background: The human umbilical cord mesenchymal stem cells (hUCMSCs) have the ability to migrate into\r\ntumors and therefore have been considered as an alternative source of mesenchymal progenitors for the therapy\r\nof malignant diseases. The present study was aimed to investigate effect of hUCMSCs as vehicles for a constant\r\nsource of transgenic interleukin-21 (IL-21) on ovarian cancer in vivo.\r\nMethods: The hUCMSCs were engineered to express IL-21 via lentiviral vector- designated ââ?¬Ë?hUCMSCs-LV-IL-21ââ?¬â?¢, and\r\nthen were transplanted into SKOV3 ovarian cancer xenograft-bearing nude mice. The therapeutic efficacy and\r\nmechanisms of this procedure on ovarian cancer was evaluated.\r\nResults: The isolated hUCMSCs were induced to differentiate efficiently into osteoblast and adipocyte lineages in vitro.\r\nThe expressed IL-21 in the supernatant from hUCMSCs-LV-IL-21 obviously stimulated splenocyteââ?¬â?¢s proliferation. The\r\nhUCMSCs-LV-IL-21 significantly reduced SKOV3 ovarian cancer burden in mice indicated by tumor sizes compared with\r\ncontrol mice. The expressed IL-21 not only regulated the levels of IFN-? and TNF-a in the mouse serum but also\r\nincreased the expression of NKG2D and MIC A molecules in the tumor tissues. The down regulation of Ã?Ÿ-catenin and\r\ncyclin-D1 in the tumor tissues may refer to the inhibition of SKOV3 ovarian cancer growth in mice. In addition, hUCMSCs\r\ndid not form gross or histological teratomas up to 60 days posttransplantation in murine lung, liver, stomach and spleen.\r\nConclusion: These results clearly indicate a safety and usability of hUCMSCs-LV- IL-21 in ovarian cancer gene therapy,\r\nsuggesting the strategy may be a promising new method for clinical treatment of ovarian cancer....
Background: Self-complementary adeno-associated virus (scAAV) vectors have become a desirable vector for\r\ntherapeutic gene transfer due to their ability to produce greater levels of transgene than single-stranded AAV\r\n(ssAAV). However, recent reports have suggested that scAAV vectors are more immunogenic than ssAAV. In this\r\nstudy, we investigated the effects of a self-complementary genome during gene therapy with a therapeutic protein,\r\nhuman factor IX (hF.IX).\r\nMethods: Hemophilia B mice were injected intramuscularly with ss or scAAV1 vectors expressing hF.IX. The\r\noutcome of gene transfer was assessed, including transgene expression as well as antibody and CD8+ T cell\r\nresponses to hF.IX.\r\nResults: Self-complementary AAV1 vectors induced similar antibody responses (which eliminated systemic hF.IX\r\nexpression) but stronger CD8+ T cell responses to hF.IX relative to ssAAV1 in mice with F9 gene deletion. As a\r\nresult, hF.IX-expressing muscle fibers were effectively eliminated in scAAV-treated mice. In contrast, mice with F9\r\nnonsense mutation (late stop codon) lacked antibody or T cell responses, thus showing long-term expression\r\nregardless of the vector genome.\r\nConclusions: The nature of the AAV genome can impact the CD8+ T cell response to the therapeutic transgene\r\nproduct. In mice with endogenous hF.IX expression, however, this enhanced immunogenicity did not break\r\ntolerance to hF.IX, suggesting that the underlying mutation is a more important risk factor for transgene-specific\r\nimmunity than the molecular form of the AAV genome....
Until the late 1990s, aerosol therapy consisted of beta2-adrenergic agonists, anti-cholinergics, steroidal and\r\nnon-steroidal agents, mucolytics and antibiotics that were used to treat patients with asthma, COPD and cystic\r\nfibrosis. Since then, inhalation therapy has matured to include drugs that: (1) are designed to treat diseases outside\r\nthe lung and whose target is the systemic circulation (systemic drug delivery); (2) deliver nucleic acids that lead to\r\npermanent expression of a gene construct, or protein coding sequence, in a population of cells (gene therapy); and\r\n(3) provide needle-free immunization against disease (aerosolized vaccination). During the evolution of these\r\nadvanced applications, it was also necessary to develop new devices that provided increased dosing efficiency and\r\nless loss during delivery. This review will present an update on the success of each of these new applications and\r\ntheir devices. The early promise of aerosolized systemic drug delivery and its outlook for future success will be\r\nhighlighted. In addition, the challenges to aerosolized gene therapy and the need for appropriate gene vectors will\r\nbe discussed. Finally, progress in the development of aerosolized vaccination will be presented. The continued\r\nexpansion of the role of aerosol therapy in the future will depend on: (1) improving the bioavailability of\r\nsystemically delivered drugs; (2) developing gene therapy vectors that can efficiently penetrate the mucus barrier\r\nand cell membrane, navigate the cell cytoplasm and efficiently transfer DNA material to the cell nucleus;\r\n(3) improving delivery of gene vectors and vaccines to infants; and (4) developing formulations that are safe for\r\nacute and chronic administrations....
Background: Non-invasive imaging of the biodistribution of novel therapeutics including gene therapy vectors in\r\nanimal models is essential.\r\nMethods: This study assessed the utility of high-frequency ultrasound (HF-US) combined with biofluoresence\r\nimaging (BFI) to determine the longitudinal impact of a Herpesvirus saimiri amplicon on human colorectal cancer\r\nxenograft growth.\r\nResults: HF-US imaging of xenografts resulted in an accurate and informative xenograft volume in a longitudinal\r\nstudy. The volumes correlated better with final ex vivo volume than mechanical callipers (R2 = 0.7993, p = 0.0002 vs.\r\nR2 = 0.7867, p = 0.0014). HF-US showed that the amplicon caused lobe formation. BFI demonstrated retention and\r\nexpression of the amplicon in the xenografts and quantitation of the fluorescence levels also correlated with\r\ntumour volumes.\r\nConclusions: The use of multi-modal imaging provided useful and enhanced insights into the behaviour of gene\r\ntherapy vectors in vivo in real-time. These relatively inexpensive technologies are easy to incorporate into\r\npre-clinical studies....
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