Insight into the regulation by second messenger molecules of the permeability of the blood‐brain barrier

Despite progress in brain tumor therapy, the prognosis of malignant glioma patients remains dismal. Among the new treatments currently being investigated, immunotherapy is theoretically very attractive since it offers the potential for high tumor-specific cytotoxicity. Increasing numbers of reports demonstrate that systemic immunotherapy using dendritic cells is capable of inducing an antiglioma response. Therefore, dendritic cell-based immunotherapy could be a new treatment modality for patients with glioma. In this chapter, we will discuss the implications of these findings for glioma therapy, reviewing current literature on dendritic cell-based glioma immunotherapy. We will overview the role of dendritic cells in immunobiology, the central nervous system and tumor immunology, before outlining dendritic cell therapy results in clinical trials and future directions. Dendritic cell-based immunotherapy strategies appear promising as an approach to successfully induce an antitumor immune response in patients with glioma, where it seems to be safe and without major side effects. The development of methods for manipulating dendritic cells for the purpose of vaccination will enhance the clinical usefulness of these cells for biotherapy. Its efficacy should be further determined in randomized, controlled clinical trials.

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Chemically, mechanically, and hyperosmolarity-induced calcium responses of rat cortical capillary endothelial cells in culture

Paemeleire¹,

Hemptinne²,

Leybaert³

1999

Experimental Brain Research

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The purpose of the present work was to characterize calcium responses of brain-capillary endothelial cells (BCEC), the cells forming the blood-brain barrier, to chemical, hyperosmolar and mechanical stimulation. Confluent BCEC cultures were grown from capillary fragments isolated from rat cerebral cortex. Intracellular free calcium ([Ca2+]i) was measured using fura-2 and digital imaging. Our experiments show large endothelial calcium responses to substance P and ATP, up to a peak value of approximately 1000 and 600 nM, respectively, and these responses were observed in 2/3 of the cells. Calcium responses to bradykinin, histamine, and hyperosmolar sucrose or mannitol were smaller, attaining a peak in the range 180-340 nM, and were observed in a smaller fraction of the cells. No calcium responses were observed to high-potassium, L-glutamate, serotonin, carbachol, noradrenaline, and nitric-oxide donors. Consecutive superfusion of the cultures with ATP, bradykinin, and histamine showed that cells with a certain response pattern were spatially grouped; the response pattern itself varied widely between experiments. Mechanical stimulation of a single cell caused a calcium response in the stimulated cell in primary cultures and triggered an intercellularly propagating calcium wave in passaged cultures. Given the important effect of endothelial [Ca2+]i on blood-brain barrier permeability and transport, we conclude that substance P and ATP are potential modulators of blood-brain barrier function. Hyperosmolarity-induced blood-brain barrier opening is probably not mediated through endothelial [Ca2+]i.

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Insight into the regulation by second messenger molecules of the permeability of the blood‐brain barrier

Cited by 12 publications

References 69 publications

Structure and Pathology of the Blood–Brain Barrier

Structure and Pathology of the Blood–Brain Barrier

Dendritic Cell Vaccines

Chemically, mechanically, and hyperosmolarity-induced calcium responses of rat cortical capillary endothelial cells in culture

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