Yukio Takeshita

Lerner Research Institute, Cleveland, Ohio, United States

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Publications (4)25.03 Total impact

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    ABSTRACT: In vitro blood-brain barrier (BBB) models can be useful for understanding leukocyte-endothelial interactions at this unique vascular-tissue interface. Desirable features of such a model include shear stress, non-transformed cells and co-cultures of brain microvascular endothelial cells with astrocytes. Recovery of transmigrated leukocytes for further analysis is also appealing.
    Journal of Neuroscience Methods 05/2014; · 2.11 Impact Factor
  • Yukio Takeshita, Richard M Ransohoff
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    ABSTRACT: The blood-brain barrier (BBB) is the brain-specific capillary barrier that is critical for preventing toxic substances from entering the central nervous system (CNS). In contrast to vessels of peripheral organs, the BBB limits the exchange of inflammatory cells and mediators under physiological and pathological conditions. Clarifying these limitations and the role of chemokines in regulating the BBB would provide new insights into neuroprotective strategies in neuroinflammatory diseases. Because there is a paucity of in vitro BBB models, however, some mechanistic aspects of transmigration across the BBB still remain largely unknown. In this review, we summarize current knowledge of BBB cellular components, the multistep process of inflammatory cells crossing the BBB, functions of CNS-derived chemokines, and in vitro BBB models for transmigration, with a particular focus on new and recent findings.
    Immunological Reviews 07/2012; 248(1):228-39. · 12.16 Impact Factor
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    ABSTRACT: The accumulation of inflammatory cells in the brain parenchyma is a critical step in the pathogenesis of neuroinflammatory diseases such as multiple sclerosis (MS). Chemokines and adhesion molecules orchestrate leukocyte transmigration across the blood-brain barrier (BBB), but the dynamics of chemokine receptor expression during leukocyte transmigration are unclear. We describe an in vitro BBB model system using human brain microvascular endothelial cells that incorporates shear forces mimicking blood flow to elucidate how chemokine receptor expression is modulated during leukocyte transmigration. In the presence of the chemokine CXCL12, we examined modulation of its receptor CXCR4 on human T cells, B cells, and monocytes transmigrating across the BBB under flow conditions. CXCL12 stimulated transmigration of CD4(+) and CD8(+) T cells, CD19(+) B cells, and CD14(+) monocytes. Transmigration was blocked by CXCR4-neutralizing antibodies. Unexpectedly, CXCL12 selectively down-regulated CXCR4 on transmigrating monocytes, but not T cells. Monocytes underwent preferential CXCL12-mediated adhesion to the BBB in vitro compared with lymphocytes. These findings provide new insights into leukocyte-endothelial interactions at the BBB under conditions mimicking blood flow and suggest that in vitro BBB models may be useful for identifying chemokine receptors that could be modulated therapeutically to reduce neuroinflammation in diseases such as MS.
    Science translational medicine 02/2012; 4(119):119ra14. · 10.76 Impact Factor
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    ABSTRACT: A 46-year-old man experienced numbness and muscle weakness in the distal portions of both hands, which progressed over following three months. Neurological examination showed mild muscle weakness only in distal arms, hypoflexia or areflexia, and hypesthesia in glove and stocking distribution. Motor conduction study revealed markedly prolonged distal latency and abnormal temporal dispersion. Sensory nerve potentials were reduced or could not be recorded. Histopathlogical findings of the sural nerve showed several nerve fibers with thinning myelin sheath and mild reduction of myelinated fibers. These results suggested the diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Two weeks after intravenous immunoglobulin therapy, neurological deficits rapidly improved and electrophysiological abnormalities were also ameliorated. Thereafter, there was no clinical deterioration for two years without further treatment. Our patient suggested that immunomodulating treatment is needed for stopping the initial progression of neurological deficits, but maintenance therapy is not always necessary for keeping the remitting state in distal variant of CIDP.
    Rinsho shinkeigaku = Clinical neurology 07/2011; 51(7):478-82.