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Cellular and cytokine responses of the human central nervous system to intracranial administration of tumor necrosis factor α for the treatment of malignant gliomas

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Abstract

To elucidate the role of tumor necrosis factor α (TNFα) as a biological response modifier, we studied cellular and cytokine responses of the central nervous system to TNFα administered intracranially in a phase I clinical trial for patients with malignant gliomas. Six patients received injections of TNFα (1.25×103−10×103 U/injection) into the tumor cavities, and regional fluids (RF) and lumbar cerebrospinal fluids (CF) were serially sampled before and after the injections. Recruitment of neutrophils occurred, mostly peaking 8 h after TNFα injection, and fewer numbers of CD4+ T cells and monocytes/macrophages migrated, subsequently peaking at 24 h. The CF leukocytosis persisted for 48 h and was associated with an increased level of neutrophil chemotactic activity in the CF. This neutrophil chemotactic activity was attributed to interleukin-8 (IL-8) by HPLC. The level of IL-6 activity in the CF and RF consistently increased; beginning 2 h after TNFα injection and reaching the maximum between 8 h and 12 h. It returned to the basal level within 48 h. IL-1β was detected in the CF of three patients, its level peaking at 8 h. Prostaglandin E2 also increased after injection of TNFα, peaking between 4 h and 12 h and then gradually decreasing. Transforming growth factor γ was found in all cases tested and one patient showed a significant change after TNFα injection. IL-2 activity, interferon α (INFα) activity, IFNβ, and granulocyte/macrophage-colony-stimulating factor were not detected in the CF or RF. In conclusion, TNFα is biologically effective in inducing migration of immune cells and generating multiple cytokine responses in the human central nervous system.

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Authors and Affiliations

  1. Department of Neurosurgery, Hokkaido University School of Medicine, North-15, West-7, Kita-Ku, 060, Sapporo, Japan

    Mitsuhiro Tada, Yutaka Sawamura, Shirou Sakuma, Toshimitsu Aida & Hiroshi Abe

  2. Department of Antibiotics, National Institute of Health, Tokyo, Japan

    Kazuo Suzuki

  3. Pharmaceutical Laboratory of Mochida Pharmaceutical Co. Ltd., Fujieda, Japan

    Hidemi Ohta

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  1. Mitsuhiro Tada
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  2. Yutaka Sawamura
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  3. Shirou Sakuma
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  7. Hiroshi Abe
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Tada, M., Sawamura, Y., Sakuma, S. et al. Cellular and cytokine responses of the human central nervous system to intracranial administration of tumor necrosis factor α for the treatment of malignant gliomas. Cancer Immunol Immunother 36, 251–259 (1993). https://doi.org/10.1007/BF01740907

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