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1.
Figure 3

Figure 3. MV-GFP-HAA-IL-13 entry is interleukin-13 receptor α2 (IL-13Rα2) dependent. From: Interleukin-13 Displaying Retargeted Oncolytic Measles Virus Strains Have Significant Activity Against Gliomas With Improved Specificity.

Pre-exposure of IL-13Rα2 expressing U87 cells to IL-13 (30 ng/ml) precludes infection (a) and decreases replication of the MV-GFP-HAA-IL-13 virus by 3½ logs (b). In contrast, pre-exposure of U87 cells to lower concentrations of IL-13 (1 ng/ml) or different cytokines such as IL-2 or IL-4 had no affect on viral infection or replication, indicating specificity of viral entry in IL-13Rα2-expressing tumor cells. Similarly, preincubation with an IL-13Ra2 antibody blocks infection with MV-GFP-HAA-IL-13 (c). GFP, green fluorescent protein.

Cory Allen, et al. Mol Ther. ;16(9):1556-1564.
2.
Figure 5

Figure 5. MV-GFP-HAA-IL-13 has significant antitumor activity in vivo. From: Interleukin-13 Displaying Retargeted Oncolytic Measles Virus Strains Have Significant Activity Against Gliomas With Improved Specificity.

(a) Antitumor effect of measles virus strain displaying interleukin-13 (IL-13) in the orthotopic animal model glioblastoma multiforme 12 (GBM12) that overexpresses interleukin-13 (IL-13) receptor α2. The MV-GFP-HAA-IL-13 retargeted strain had significant antitumor activity which is comparable to the unmodified strain MV-GFP, resulting in significant propagation of survival in MV-GFP-HAA-IL-13-treated animals (P < 0.0001) as compared with ultraviolet (UV)-inactivated virus. (b) Treatment induced cytopathic effect with syncytia formation observed in GBM12 xenografts treated with the MV-GFP-HAA-IL-13 virus.

Cory Allen, et al. Mol Ther. ;16(9):1556-1564.
3.
Figure 1

Figure 1. Construction of MV-GFP-HAA-IL-13. From: Interleukin-13 Displaying Retargeted Oncolytic Measles Virus Strains Have Significant Activity Against Gliomas With Improved Specificity.

(a) Schematic representation of the interleukin-13 (IL-13) receptor α2-retargeted virus. The hemagglutinin (H) protein contains both CD46 and signaling lymphocyte activation molecule–ablating mutations (Y481A and R533A, respectively). IL-13 is displayed on the C-terminus of H protein. The virus also contains the gene encoding green fluorescent protein (GFP) in position 1. (b) Expression levels of viral H protein were determined by western immunoblotting. The retargeted virus expresses chimeric H protein with higher molecular weight (84 kd as compared with 75 kd for the unmodified H protein). Expression levels of IL-13 in viral preparations were determined by western immunoblotting. In contrast to the unmodified virus MV-GFP, the MV-GFP-HAA-IL-13 virus expresses IL-13. (d) Comparable replication of the MV-GFP HAA-IL-13 virus to the unmodified MV-GFP virus was demonstrated in Vero-αHis cells.

Cory Allen, et al. Mol Ther. ;16(9):1556-1564.
4.
Figure 6

Figure 6. Lack of MV-GFP-HAA-IL-13 toxicity in a susceptible transgenic mouse model. From: Interleukin-13 Displaying Retargeted Oncolytic Measles Virus Strains Have Significant Activity Against Gliomas With Improved Specificity.

(a) Survival of Ifnarko CD46 mice after central nervous system administration of MV-GFP or MV-GFP-HAA-IL-13. In contrast to the lethal neurotoxicity observed by day 7 in four of five MV-GFP-treated mice, mice treated with the interleukin-13 (IL-13) displaying retargeted measles virus strain survived without toxicity. (b) Viral recovery from brains of MV-GFP-treated mice on Vero-αHis cell overlays as demonstrated by syncytia formation (I), expressing green fluorescence protein II. (c) Histopathological examination of the brains of MV-GFP-treated Ifnarko CD46 Ge mice demonstrated inflammation at the injection site (I), meningitis (II), and ventriculitis (III) with syncytia formation (close-up view). In contrast, the brains of MV-GFP-HAA-IL-13 mice have normal appearance on histopathological examination (IV).

Cory Allen, et al. Mol Ther. ;16(9):1556-1564.
5.
Figure 2

Figure 2. MV-GFP-HAA-IL-13 infectivity in vitro. From: Interleukin-13 Displaying Retargeted Oncolytic Measles Virus Strains Have Significant Activity Against Gliomas With Improved Specificity.

(a) The MV-GFP-HAA-IL-13 retargeted strain has comparable infectivity to the unmodified MV-GFP virus in glioma lines expressing intermediate or high levels of the interleukin-13 (IL-13) receptor α2 (IL-13Rα2) (GBM12, U251, U87), but not in glioma lines expressing low receptor levels (U118, GBM8) as demonstrated by expression of the green fluorescent protein and syncytia formation after viral infection (multiplicity of infection 1). (b) Cytopathic effect in glioma lines after infection with MV-GFP-HAA-IL-13 and MV-GFP was quantitated by trypan blue exclusion assays at multiple time points. There was comparable cytotoxicity between the IL-13 displaying and the unmodified virus in tumor cell lines expressing intermediate or high level of the IL-13Rα2 receptor (GBM12, U251, U87, GBM10, GBM38). Representative data on day 7 are shown. GBM, glioblastoma multiforme.

Cory Allen, et al. Mol Ther. ;16(9):1556-1564.
6.
Figure 4

Figure 4. Lack of MV-GFP-HAA-IL-13 cytopathic effect in normal (nontumor) cells. From: Interleukin-13 Displaying Retargeted Oncolytic Measles Virus Strains Have Significant Activity Against Gliomas With Improved Specificity.

(a) Western immunoblotting of lysates derived from normal human astrocytes and fibroblasts shows lack of expression of the interleukin-13 (IL-13) receptor α2 (IL-13Rα2). U87 cells expressing high levels of IL-13Rα2 and U118 cells (low expressors) were used as controls. (b) In contrast to infection with MV-GFP, treatment of normal human astrocytes and fibroblasts with MV-GFP-HAA-IL-13 virus did not cause infection or fusion [multiplicity of infection (MOI) 1.0, 72 hours after infection). (c) Cell viability of normal human astrocytes and fibroblasts in response to infection with MV-GFP-HAA-IL-13 and MV-GFP was determined by trypan blue exclusion assays and presented as percentage of uninfected cells. In contrast to MV-GFP, the IL-13 displaying retargeted strain had no significant cytopathic effect (MOI 1.0). (d) Western immunoblotting for the measles virus nucleocapsid N protein was performed in cell lysates derived from primary glioblastoma multiforme lines, normal human astrocytes, and fibroblasts 48 hours after viral infection with either MV-GFP or MV-GFP-HAA-IL-13 (MOI 1.0). In contrast to MV-GFP infection, there was no expression of measles virus N protein after treatment of normal human astrocytes and fibroblasts with the IL-13 displaying retargeted strain, thus indicating lack of infection. In contrast, in the IL-13Rα2-positive line U87 there is abundant N protein expression after infection with the retargeted strain. GFP, green fluorescent protein.

Cory Allen, et al. Mol Ther. ;16(9):1556-1564.

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