A DNA vaccine expressing tyrosinase-related protein-2 induces T-cell-mediated protection against mouse glioblastoma

Insug, O; Blaszczyk-Thurin, Magdalena; Shen, Chunpang T; Ertl, Hildegund C. J.

doi:10.1038/sj.cgt.7700620

Cited by 28 publications

(5 citation statements)

References 48 publications

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“…In this study, we used intratumoral administration of G207 to vaccinate mice harboring a syngenic mouse glioma cell line, GL261, which is widely used for the study of immunotherapy against brain tumors [38][39][40][41]. We applied a modified SEREX method to the mouse glioma GL261 model in an attempt to identify molecular therapeutic targets for glioma.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of KIF23 suppresses glioma proliferation

et al. 2011

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To identify therapeutic molecular targets for glioma, we performed modified serological identification of antigens by recombinant complementary DNA (cDNA) expression cloning using sera from a mouse glioma model. Two clones, kinesin family member 23 (Kif23) and structural maintenance of chromosomes 4 (Smc4), were identified as antigens through immunological reaction with sera from mice harboring synergic GL261 mouse glioma and intratumoral inoculation with a mutant herpes simplex virus. The human Kif23 homolog KIF23 is a nuclear protein that localizes to the interzone of mitotic spindles, acting as a plus-end-directed motor enzyme that moves antiparallel microtubules in vitro. Expression analysis revealed a higher level of KIF23 expression in glioma tissues than in normal brain tissue. The introduction of small interfering RNA (siRNA) targeting KIF23 into two different glioma cell lines, U87MG and SF126, downregulated KIF23 expression, which significantly suppressed glioma cell proliferation in vitro. KIF23 siRNA-treated glioma cells exhibited larger cell bodies with two or more nuclei compared with control cells. In vivo analysis using mouse xenograft showed that KIF23 siRNA/DNA chimera-treated tumors were significantly smaller than tumors treated with control siRNA/DNA chimera. Taken together, our results indicate that downregulation of KIF23 decreases proliferation of glioma cells and that KIF23 may be a novel therapeutic target in malignant glioma.

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Section: Discussionmentioning

confidence: 99%

Downregulation of KIF23 suppresses glioma proliferation

et al. 2011

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“…The fact that solid tumours were observed at all argues in favour of an insufficient immune response merely delaying or retarding tumour growth. Others have reported long-term survival in a murine brain tumour model following DNA vaccination [12]. The effect of vaccination and reduced tumour growth on suvival time was not investigated in our model.…”

Section: Discussionmentioning

confidence: 95%

Incomplete tumour control following DNA vaccination against rat gliomas expressing a model antigen

et al. 2012

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BackgroundVaccination against tumour-associated antigens is one approach to elicit anti-tumour responses. We investigated the effect of polynucleotide (DNA) vaccination using a model antigen (E. coli lacZ) in a syngeneic gliosarcoma model (9L).MethodsFisher 344 rats were vaccinated thrice by intramuscular injection of a lacZ-encoding or a control plasmid in weekly intervals. One week after the last vaccination, lacZ-expressing 9L cells were implanted into the striatum.ResultsAfter 3 weeks, in lacZ-vaccinated animals the tumours were significantly smaller than in control-vaccinated animals. In cytotoxic T cell assays lysis rates of >50 % could only be observed in a few of the lacZ-vaccinated animals. This response was directed against lacZ-expressing and parental 9L cells but not against syngeneic MADB 106 adenocarcinoma cells. In Elispot assays interferon-γ production was observed upon stimulation with 9LlacZ and 9L wild-type but not MADB 106 cells. This response was higher for lacZ-immunized animals. All animals revealed dense infiltrates with CD8+ lymphocytes and, to a lesser extent, with NK cells. CD25-staining indicated cells possibly associated with the maintenance of peripheral tolerance to self-antigens. All tumours were densely infiltrated by microglia consisting mostly of ramified cells. Only focal accumulation of macrophage-like cells expressing ED1, a marker for phagocytic activity, was observed.ConclusionProphylactic DNA vaccination resulted in effective but incomplete suppression of brain tumour formation. Mechanisms other than cytotoxic T cell responses as measured in the generally used in vitro assays appear to play a role in tumour suppression.

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“…In some studies with DNA vaccines in knock-out mice, the simultaneous presence of CD4 + and CD8 + cells is necessary [40]–[42]. However, one study with a vaccine based on vaccinia virus showed requirement for CD4 + cells [43], while another with an adenovirus-based vaccine showed dependence on CD8 + cells [44].…”

Section: Discussionmentioning

confidence: 99%

CD4+ and CD8+ T Cells Can Act Separately in Tumour Rejection after Immunization with Murine Pneumotropic Virus Chimeric Her2/neu Virus-Like Particles

et al. 2010

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BackgroundImmunization with murine pneumotropic virus virus-like particles carrying Her2/neu (Her2MPtVLPs) prevents tumour outgrowth in mice when given prophylactically, and therapeutically if combined with the adjuvant CpG. We investigated which components of the immune system are involved in tumour rejection, and whether long-term immunological memory can be obtained.Methodology and ResultsDuring the effector phase in BALB/c mice, only depletion of CD4+ and CD8+ in combination, with or without NK cells, completely abrogated tumour protection. Depletion of single CD4+, CD8+ or NK cell populations only had minor effects. During the immunization/induction phase, combined depletion of CD4+ and CD8+ cells abolished protection, while depletion of each individual subset had no or negligible effect. When tumour rejection was studied in knock-out mice with a C57Bl/6 background, protection was lost in CD4−/−CD8−/− and CD4−/−, but not in CD8−/− mice. In contrast, when normal C57Bl/6 mice were depleted of different cell types, protection was lost irrespective of whether only CD4+, only CD8+, or CD4+ and CD8+ cells in combination were eradicated. No anti-Her2/neu antibodies were detected but a Her2/neu-specific IFNγ response was seen. Studies of long-term memory showed that BALB/c mice could be protected against tumour development when immunized together with CpG as long as ten weeks before challenge.ConclusionHer2MPtVLP immunization is efficient in stimulating several compartments of the immune system, and induces an efficient immune response including long-term memory. In addition, when depleting mice of isolated cellular compartments, tumour protection is not as efficiently abolished as when depleting several immune compartments together.

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A DNA vaccine expressing tyrosinase-related protein-2 induces T-cell-mediated protection against mouse glioblastoma

Cited by 28 publications

References 48 publications

Downregulation of KIF23 suppresses glioma proliferation

Downregulation of KIF23 suppresses glioma proliferation

Incomplete tumour control following DNA vaccination against rat gliomas expressing a model antigen

CD4+ and CD8+ T Cells Can Act Separately in Tumour Rejection after Immunization with Murine Pneumotropic Virus Chimeric Her2/neu Virus-Like Particles

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