Yoshiaki Takashima

Oxidized low density lipoprotein caused CNS neuron cell death.

Death induced by oxidized low density lipoproteins (oxLDL) to embryonic CNS neuronal and neuroblastoma cells was investigated. Cell damage and viability were evaluated by LDH leakage and the MTT method, respectively. Dose- and time-dependent degeneration of neurons occurred after oxLDL (1-100 microg/ml) treatment but was absent after native low density lipoproteins (LDL). This degeneration was mediated, in part, by apoptosis because increased TUNEL and Hoechst dye-positive staining was observed. These effects occurred in the absence of microglia. However, DNA degradation was not detected. The cytotoxicity was attenuated by pre-treatment with antioxidants. These results suggest that oxidation by oxLDL may be important in neurocytotoxicity in the brain.

Distribution of IL-31 and its receptor expressing cells in skin of atopic dermatitis

BACKGROUND To understand the clinical segments of IL-31 signaling blockade therapy in pruritus of atopic dermatitis (AD), direct detection of the target proteins in the diseased tissues will provide crucial information. There is a lack of direct evidence concerning the cellular origin of IL-31 in AD skins, and data on the expression of IL-31RA in AD are inconsistent. Also, there is no available information regarding IL-31RA protein expression in human dorsal root ganglia (DRG), which mediates the sensation of itch and is the long-suspected source of the protein. OBJECTIVE We sought to obtain direct evidence concerning the distribution of IL-31- and IL-31RA-protein expressing cells and their characteristics in AD skin samples and in human DRG. METHODS IL-31 was detected immunohistochemically in AD skins, and representative sections were double stained with IL-31 and several immune-markers. IL-31RA was stained immunohistochemically in AD skins and normal human DRG, and representative AD skins were double stained with IL-31RA and PGP9.5 (a nerve marker). RESULTS IL-31-positive cells were observed as mononuclear infiltrating cells and as CD11b co-expressing cells in severe AD samples. As for IL-31RA, positive reactions were detected in keratinocytes and nerve fibers in the dermis of AD and in the neurons of normal DRG. CONCLUSION The detection of IL-31 in infiltrating cells of severe AD skin and of IL-31RA in nerve fibers of AD dermis and normal DRG indicates IL-31 signaling may be a contributing factor in the persistence and exacerbation of AD skin lesions.

Cynomolgus monkey model of interleukin-31-induced scratching depicts blockade of human interleukin-31 receptor A by a humanized monoclonal antibody

Scratching is an important factor exacerbating skin lesions through the so‐called itch‐scratch cycle in atopic dermatitis (AD). In mice, interleukin (IL)‐31 and its receptor IL‐31 receptor A (IL‐31RA) are known to play a critical role in pruritus and the pathogenesis of AD; however, study of their precise roles in primates is hindered by the low sequence homologies between primates and mice and the lack of direct evidence of itch sensation by IL‐31 in primates. We showed that administration of cynomolgus IL‐31 induces transient scratching behaviour in cynomolgus monkeys and by that were able to establish a monkey model of scratching. We then showed that a single subcutaneous injection of 1 mg/kg nemolizumab, a humanized anti‐human IL‐31RA monoclonal antibody that also neutralizes cynomolgus IL‐31 signalling and shows a good pharmacokinetic profile in cynomolgus monkeys, suppressed the IL‐31‐induced scratching for about 2 months. These results suggest that the IL‐31 axis and IL‐31RA axis play as critical a role in the induction of scratching in primates as in mice and that the blockade of IL‐31 signalling by an anti‐human IL‐31RA antibody is a promising therapeutic approach for treatment of AD. Nemolizumab is currently under investigation in clinical trials.