Human Glioma Immunobiology in Vitro: Implications for Immunogene Therapy

Parney, Ian F.; Farr-Jones, Maxine A.; Chang, Lung Ji; Petruk, Kenneth C.

doi:10.1097/00006123-200005000-00030

Cited by 82 publications

(49 citation statements)

References 54 publications

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“…Glioma-mediated immunosuppression and downregulation of the host immune response has been associated with the release of immunosuppressive factors by glioma cells, for example, transforming growth factor (TGF)-b1, b2, and b3. [32][33][34][35][36][37][38] In addition to TGF-b, other factors capable of inhibiting immune function 37 include the cytokines interleukin (IL)-6 and IL-10, [39][40][41][42][43][44][45] prostaglandin E, [46][47][48][49][50] and gangliosides. 51 TGF-b1 and IL-10 act by suppressing T cell function.…”

Section: Discussionmentioning

confidence: 99%

Downregulation of major histocompatibility complex antigens in invading glioma cells: stealth invasion of the brain

Zagzag

Salnikow

Chiriboga

et al. 2005

Laboratory Investigation

156

105

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Invasion into surrounding brain tissue is a fundamental feature of gliomas and the major reason for treatment failure. The process of brain invasion in gliomas is not well understood. Differences in gene expression and/or gene products between invading and noninvading glioma cells may identify potential targets for new therapies. To look for genes associated with glioma invasion, we first employed Affymetrix microarray Genechip s technology to identify genes differentially expressed in migrating glioma cells in vitro and in invading glioma cells in vivo using laser capture microdissection. We observed upregulation of a variety of genes, previously reported to be linked to glioma cell migration and invasion. Remarkably, major histocompatiblity complex (MHC) class I and II genes were significantly downregulated in migrating cells in vitro and in invading cells in vivo. Decreased MHC expression was confirmed in migrating glioma cells in vitro using RT-PCR and in invading glioma cells in vivo by immunohistochemical staining of human and murine glioblastomas for b2 microglobulin, a marker of MHC class I protein expression. To the best of our knowledge, this report is the first to describe the downregulation of MHC class I and II antigens in migrating and invading glioma cells, in vitro and in vivo, respectively. These results suggest that the very process of tumor invasion is associated with decreased expression of MHC antigens allowing glioma cells to invade the surrounding brain in a 'stealth'-like manner.

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Section: Discussionmentioning

confidence: 99%

Downregulation of major histocompatibility complex antigens in invading glioma cells: stealth invasion of the brain

Zagzag

Salnikow

Chiriboga

et al. 2005

Laboratory Investigation

156

105

View full text Add to dashboard Cite

show abstract

“…21 Finally, a factor(s) of a minimum weight of 49 kDa has recently been identified in the supernatant of glioblastoma cell cultures that not only suppresses T-cell responses but also alters the cytokine profiles of monocytederived antigen-presenting cells, 22 which, in turn, might also inhibit T-cell help for B cells which is needed for the production of antibodies against antigens expressed by gliomas. Thus, in addition to the development of specific peptide or whole-protein vaccines, immunotherapeutic approaches in astrocytomas must design strategies to overcome the immunosuppressive effects of the malignant cells at the tumor site that impair both immune recognition and effective effector mechanisms of the immune system against these tumors.…”

Section: Discussionmentioning

confidence: 99%

Analysis of the antibody repertoire of astrocytoma patients against antigens expressed by gliomas

Schmits

Cochlovius

Treitz

et al. 2001

Intl Journal of Cancer

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The molecular characterization of antigens preferentially or exclusively expressed by astrocytomas and recognized by the autologous immune system are a prerequisite for the development of specific vaccines. To identify such antigens, we screened 5 cDNA expression libraries derived from astrocytomas and other gliomas for reactivity with high-titered IgG antibodies in the sera of astrocytoma patients using SEREX, the serologic identification of antigens by recombinant cDNA expression cloning. Autologous and allogeneic SEREX analysis of >5 ؋ 10 6 clones with the sera of 18 astrocytoma patients revealed 10 antigens: the differentiation antigen glial fibrillary acidic protein (GFAP), Bax-inhibitor 1 (which was overexpressed in all glioma samples tested), 3 other molecules involved in the regulation of gene expression and proliferation (the nm23-H2-encoded nucleoside diphosphate kinase B, the Ran binding protein-2 and a DNA binding protein encoded by the son gene), SP40,40 (a complement inhibitory molecule), the chaperonin TCP-1, calnexin and 2 new gene products. No immune responses were detected against the "shared tumor" or "cancer testis antigens" that are regularly expressed in gliomas. Antibody responses in astrocytoma patients against antigens expressed by gliomas were rare and, with the exception of Bax-inhibitor 1 and the product of the son gene, were also found in apparently healthy controls. We conclude that although astrocytomas express a broad spectrum of antigens, they elicit antibody responses only rarely, most likely because of their intrinsic immunosuppressive effects.

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“…18 Tumor regression by immunotherapy is largely dependent on apoptotic killing of the neoplastic cells. 19,20 As previous histological evidences indicated the glioma regression by apoptosis in T11TS treated animals, 3 the exploration of T11TS as an apoptosis inducer is evident. The phosphatidylserine exposure on the cell membrane and fragmentation of nuclear DNA exposed in cytoplasm are the hallmark of apoptosis.…”

Section: Introductionmentioning

confidence: 85%

CD2-SLFA3/T11TS interaction facilitates immune activation and glioma regression by apoptosis

Sarkar¹,

Ghosh²,

Mukherjee³

et al. 2004

Cancer Biology & Therapy

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Objective: Exogenous application of T11TS/SLFA3 in glioma model had shown the regression of tumor load through immunopotentiation. The mechanistic module of this interaction on immunological synapse formation and resulting effect in glioma regression is searched for delineating immunotherapeutic efficacy of T11TS.Methods: After purification of T11TS/SLFA3 from sheep erythrocytes the glycoprotein was characterized by SDS-PAGE analysis and glycoprotein staining. The modulatory effect of T11TS application on glioma animals were studied by CD2 and MHC class II expression on peripheral lymphocytes, PMN, macrophages and intracranial microglia by flowcytometric analysis. Finally apoptotic killing of brain cells were studied through annevin-V expression and measuring fragmented cytoplasmic DNA by ELISA.Results: Compared to healthy normal counter-parts the CD2 receptor downregulation by ENU treatment in lymphocytes and PMN were upregulated with three consecutive doses of T11TS. Splenic antigen presenting macrophages and intracranial mocroglia had shown CD2 and MHC class II modulation simultaneously in their different subtypes. These receptor studies revealed significant boosting of the immune competent cells most effectively in second dose of T11TS whereas the third dose had some regulatory effect. Sharp increase of apoptosis in brain cells was found by phosphatidylserine externalization and presence of fragmented DNA in cytoplasm with application of T11TS in consecutive doses as a result of immune potentiation.Conclusion: Receptor studies revealed modulation of CD2 and MHC class II, two important constituents of immunological synapse successfully help to form the TCR-p-MHC complex and provide required co-stimulation for activation. Potentiated immune effector machinery was then directed to abrogate glioma by apoptosis signifying T11TS as an immunotherapeutic probe.

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Human Glioma Immunobiology in Vitro: Implications for Immunogene Therapy

Cited by 82 publications

References 54 publications

Downregulation of major histocompatibility complex antigens in invading glioma cells: stealth invasion of the brain

Downregulation of major histocompatibility complex antigens in invading glioma cells: stealth invasion of the brain

Analysis of the antibody repertoire of astrocytoma patients against antigens expressed by gliomas

CD2-SLFA3/T11TS interaction facilitates immune activation and glioma regression by apoptosis

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