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Production of immune-modulatory nonclassical molecules HLA-G and HLA-E by tumor infiltrating ameboid microglia/macrophages in glioblastomas: A role in innate immunity?

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Abstract

The possible role of immune-modulatory nonclassical molecules HLA-G and HLA-E in an anti-tumoral response and development of glioblastoma is not well characterized. In this study, we evaluated an expression of HLA-G and HLA-E by activated tumor infiltrating microglia/macrophages. We found production of HLA-G and HLA-E by tumor infiltrating activated microglia/macrophages in a majority of glioblastomas. We speculate that the expression of these molecules by activated microglia/CNS macrophages plays a role in the anti-tumoral immunity in the development of glioblastoma. Mechanisms of microglia–glioblastoma cell interactions with respect to the expression of these molecules deserves further study.

Introduction

The CNS has been traditionally considered an immunologicaly privileged site. Glioblastomas appear to benefit from this immunosuppressive milieu. Glioma cells themselves can interfere with anti-tumoral immune responses by expressing immune inhibitory cell surface molecules, such as HLA-G, or by releasing soluble immunosuppressants such as transforming growth factor (TGF)-beta (Friese et al., 2004). Microglia, a CNS type of plastic differentiated tissue macrophage, can under pathological conditions, both non-neoplastic and neoplastic, pursue a stereotypic activation process and become capable of phagocytosis, antigen presentation and cytokine secretion. The role of immune-modulatory nonclassical molecules HLA-G and HLA-E was originally thought to be restricted to participation in an induction of fetal semi-allograft tolerance during pregnancy. The role of HLA-G and HLA-E in anti-tumoral response/development of glioblastoma is not well characterized. Therefore, as a pilot study, we performed an immunohistochemical analysis of the expression of HLA-G and HLA-E by activated tumor infiltrating microglia/macrophages (aTIM/M).

Section snippets

Subjects

26 cases of glioblastoma were retrieved from the files of the Department of Pathology, University Hospital Brno, Czech Republic, EU. The scientific evaluation of the human specimens was approved by the University Hospital's Ethics Committee and have therefore been performed in accordance with the ethical standards laid down in an appropriate version of the 1964 Declaration of Helsinki. All patients gave their informed consent regarding potential inclusion of their biopsy samples into scientific

Pathological evaluation and results

Evaluation of the immunohistochemical staining and photographic documentation was performed on an Olympus BX45 microscope (Olympus Optical, Tokyo, Japan) equipped with 2×/0.08, 4×/0.13, 10×/0.30, 20×/0.50, 40×/0.75 and 60×/0.90 objective lenses and with an Olympus DP50 digital camera. Olympus Viewfinder Lite™ software was used to acquire and process images.

Sections from products of undesired pregnancies stained etravillous trophoblast for both HLA-G and HLA-E (Fig. 1 a–c). Of note, villous

Discussion

Under physiologic conditions, HLA-G and HLA-E were originaly thought to be specifically expressed only on extravillous trophoblast — fetal tissue in contact with maternal cells which lacks MHC class I antigens. This may indicate the physiological role of these “pregnancy-associated” molecules in the development of maternal tolerance to a semiallogeneic fetus (Kovats et al., 1990, King et al., 2000). This formerly presumed exclusive fetal tissue specificity has been subsequently considerably

Conclusions

The role of immune-modulatory nonclassical molecules HLA-G and HLA-E in anti-tumor response and development of glioblastoma is still not well characterized. These genes encoding the immunoregulatory mechanisms employed by the feto-placental unit could be of value in the CNS immune system. We speculate that up-regulation and expression of these immune-modulatory molecules by activated (ameboid) microglia/macrophages play a role in the anti-tumoral imunity in glioblastoma. Therefore, the role of

Acknowledgment

This study was supported by grants from the Ministry of Health of the Czech Republic, EU, No. IGA MZCR 9875-4 and IGA MZCR 9871-4.

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