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

Abstract

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.

Bax Inhibitor-1 Is Overexpressed in Prostate Cancer and Its Specific Down-Regulation by RNA Interference Leads to Cell Death in Human Prostate Carcinoma Cells

“…This finding was supported by a large-scale DNA microarray analysis on primary breast tumors from 117 young patients, showing that BI-1 (TEGT) expression is up-regulated in breast cancer and co-regulates with the expression of the estrogen receptor-␣ gene. 14 Furthermore, Schmitts and co-workers 15 reported that BI-1 expression was between 5 and 10 times stronger in 16 glioma samples tested compared with normal brain and other normal tissues. Finally, microarray analyses of the expression levels of more than 8900 different human genes in a set of normal and malignant prostate tissues revealed that BI-1 (TEGT) is highly and specifically expressed in malignant samples.…”

Characterization of BAX inhibitor-1 as a novel leukemia-associated antigen

“…13 Furthermore, BI-1 is highly expressed in tumor cells such as human prostate cancer, human breast cancer, human brain tumor, or large cell lymphoma. 12,[14][15][16]30 In addition, in this work, we found BI-1 to be expressed in primary AML-blasts and -cell lines. Consistent with these findings, small-interfering RNAmediated inhibition of BI-1 expression in different prostate carcinoma cell lines led to caspase-3 activation and spontaneous apotosis.…”

“…11 BI-1 gene expression is accentuated not only in tissues with low apoptotic activity, such as the epithelium of the developing lung, but also in several human malignant tumors, such as prostate carcinoma, breast carcinoma, and brain tumors. [12][13][14][15] Grzmil et al 16 were able to increase spontaneous apoptosis rates in prostate carcinoma cell lines by suppressing BI-1 expression using specific small-interfering RNA. Lee et al 17 presented evidence that BI-1 regulates generation of reactive oxygen species in the context of endoplasmic reticulum stress and thus inhibits apoptotic cell death.…”

Bax Inhibitor 1 in apoptosis and disease

“…Levels of BI-1 expression differ in different human cancers-while breast, glioma, prostate, uterine and ovarian cancers show two and above fold upregulation (Schmits et al, 2002;del Carmen Garcia Molina Wolgien et al, 2005;Grzmil et al, 2006), stomach, colon, kidney, lung and rectal cancers exhibit twofold downregulation of BI-1 (Grzmil et al, 2006). It is unknown whether these changes are relevant to the cancerous state or are simply a reflection of different levels of BI-1 in these tissues during development (for example, BI-1 expression is inhibited during lung development and was found to be downregulated in lung cancer).…”