Human Glioma-derived Interleukin-10 Inhibits Antitumor Immune Responses In Vitro

Hishii, Makoto; Nitta, Taizo; Ishida, Hiroshi; Ebato, Michimasa; Kurosu, Akihiro; Yagita, Hideo; Satô, Kiyoshi; Okumura, Ko

doi:10.1227/00006123-199512000-00016

Cited by 142 publications

(46 citation statements)

References 27 publications

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“…In the case of experimental autoimmune encephalomyelitis (EAE), these CD11c+ cells exhibit a maturational phenotype similar to immature BM-derived DC or splenic DCs, and were unable to prime naïve T cells, and in some cases inhibited T-cell proliferation. 1 Gliomas in the brain may also attract and then functionally subvert APC function via tumor-associated factors such as IL-10, TGF-b2 and Fas-L. 2,[34][35][36] Our experiments using adoptively transferred EGFP-DCs demonstrated that few DCs remained within the i.c. tumor lesion by day 5 following Ad-LacZ injection.…”

Section: Glioma Gene Therapy With Ifn-a and Dcsmentioning

confidence: 99%

Sequential delivery of interferon-α gene and DCs to intracranial gliomas promotes an effective antitumor response

et al. 2004

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Effective presentation of tumor antigens by dendritic cells (DCs) is considered to be essential for the induction of antitumor T-cell responses. Apoptotic and necrotic tumors have been noted to be a robust antigen source for DCs. Because glioma cells undergo apoptosis after transfection with the type I interferon (IFN) gene and type I IFNs promote the stimulatory activity of DCs, we hypothesized that transfection of glioma cells with type I IFN genes and provision of DCs would promote particularly effective antitumor activity by both facilitating apoptosis of glioma cells and the presentation of the glioma antigens, thereby inducing specific immune responses against glioma cells. We have previously reported the proof of this hypothesis in vitro and in a subcutaneous tumor model. Here we report an extension of this approach in intracranial (i.c.) gliomas using adenoviral IFN-a (Ad-IFN-a) vector. Mice bearing day-5 i.c. GL261 glioma received sequential intratumoral (i.t.) delivery of Ad-IFN-a and bone marrow-derived syngeneic DCs. This treatment prolonged survival in that nine of 17 animals survived long term (460 days versus 0 of 10 control animals). Specific CTL activity was demonstrated following this regimen in the cervical lymph nodes, and the therapeutic efficacy was dependent upon CD8+ cells. Furthermore, these animals were protected against subsequent rechallenge with GL261 gliomas. DCs injected i.t. survived in the tumor and migrated into cervical lymph node. In vitro migration assays revealed the ability of DCs to migrate toward the tumor, suggesting that i.t. injected DCs migrate through the glioma. Taken together, this combination of gene therapy and cellular immunotherapy may be an effective future strategy for treating human gliomas.

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Section: Glioma Gene Therapy With Ifn-a and Dcsmentioning

confidence: 99%

Sequential delivery of interferon-α gene and DCs to intracranial gliomas promotes an effective antitumor response

et al. 2004

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“…IL-10 liberated by gliomas has also been shown to reduce the antigen presenting capacity of monocytes by down modulating MHC Class II expression, thus hindering antigen stimulated proliferation of T cells. 39 IL-10 mediated suppression of human T cell proliferation could be overcome with exogenous IL-2. 29 Our observation also showed that with exogenous IL-2 application in glioma-induced conditions, significant increase (p < 0.001) in the PTK activity was observed in cytosolic and membrane fraction of lymphocytes and in the membrane fraction of microglia membrane.…”

Section: Discussionmentioning

confidence: 99%

Differential regulation of the protein tyrosine kinase activity followingiInterleukin-2 (IL-2), Interferron gamma (IFN?) and SRBC administration in brain tumor induced conditions: SRBC acting as a dual potentiator in regulating the cytokine profile

Bhattacharjee

Sarkar²,

Dutta³

et al. 2004

Cancer Biology & Therapy

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Protein tyrosine kinases (PTKs) act as an important class of signal transducer in cytokine mediated signaling. Defects in phosphorylation of tyrosine residues of intracellular substrates of the immunocytes are a noted phenomenon in glioma induced immune suppression. Administration of BRMs like Interleukin2 (IL-2), Interferon γ (IFN-γ) and SRBC in glioma induced experimental models, improved their survival status by immune potentiation. It was shown that SRBC exerts the maximum anti-tumor immune boosting by augmenting the functional status of the two immunocytes-microglia and lymphocytes when compared with IL-2 and IFN-γ. The present study focuses on the differential modulation of the protein tyrosine kinase activity in lymphocytes and microglia following the administration of the 3 BRMs. Our findings indicate that PTKs actively transduce signals on administration of exogenous IL-2. But exogenous IFN-γ administration fails to elicit the enzyme activity. With SRBC administration, a differential PTK activity modulation was observed in the two immunocytes. SRBC not only shifted the cytokine profile to Th 1 subset of lymphocytes but also simultaneously upregulated the expression of the activation marker IL-2Rα/CD25 thereby resulting in auto-activation of the hosts immunocytes.

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“…44,45 Secretion of interleukin 10 (IL-10), a Th2 type cytokine, correlates with a poor prognosis for human astrocytic tumors. 46 IL-10 downregulates expression of MHC class II determinants by monocytes and inhibits IFN-g and TNF-a production. 47,48 It also drives immune responses toward the Th2 pathway and prevents stimulation of Th1 type immune responses needed for activation of cytolytic T cells.…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2003

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A mouse glioblastoma cell line, termed GL261, was shown to express high levels of proteins involved in melanin biosynthesis such as the tyrosinase-related protein-2 (TRP-2), which is commonly overexpressed in melanoma cells. Mice injected with GL261 cells developed a CD8 + T-cell response to TRP-2 and a DNA vaccine expressing human (h)TRP-2 induced CD8 + T cells that recognized TRP-2 expressed by GL261 cells indicating that this melanoma-associated antigen may be suited for active immunotherapy of glioblastoma. Mice vaccinated with a DNA vaccine expressing TRP-2 were partially protected against subcutaneous, intravenous, or intracerebral challenge with the glioblastoma cells. Vaccine-induced protection against intracerebral challenge required both CD4 + and CD8 + T cells. Vaccine efficacy was enhanced upon addition of IL-12 as a genetic adjuvant. These results indicate that this well-defined melanoma-associated antigen can induce an adaptive immune response, which limits the intracerebral progression of a glioblastoma.

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Human Glioma-derived Interleukin-10 Inhibits Antitumor Immune Responses In Vitro

Cited by 142 publications

References 27 publications

Sequential delivery of interferon-α gene and DCs to intracranial gliomas promotes an effective antitumor response

Sequential delivery of interferon-α gene and DCs to intracranial gliomas promotes an effective antitumor response

Differential regulation of the protein tyrosine kinase activity followingiInterleukin-2 (IL-2), Interferron gamma (IFN?) and SRBC administration in brain tumor induced conditions: SRBC acting as a dual potentiator in regulating the cytokine profile

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

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