A novel coculture system for assessing respiratory sensitizing potential by IL-4 in T cells

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Izuru Mizoguchi
Yasuhiro Katahira
Shinya Inoue
Eri Sakamoto
Aruma Watanabe
Yuma Furusaka
Atsushi Irie
Satoru Senju
Yasuharu Nishimura
Shusaku Mizukami
Kenji Hirayama
Sou Nakamura
Koji Eto
Hideaki Hasegawa
Takayuki Yoshimoto

Abstract

Although several in vitro assays that predict the sensitizing potential of chemicals have been developed, none can distinguish between chemical respiratory and skin sensitizers. Recently, we established a new three-dimensional dendritic cell (DC) coculture system consisting of a human airway epithelial cell line, immature DCs derived from human peripheral monocytes, and a human lung fibroblast cell line. In this coculture system, compared to typical skin sensitizers, typical respiratory sensitizers showed enhanced mRNA expression in DCs of the key costimulatory molecule OX40 ligand (OX40L), which is important for T helper 2 (Th2) cell differentiation. Herein, we established a new two-step DC/T cell coculture system by adding peripheral allogeneic naive CD4+ T cells to the DCs stimulated in the DC coculture system. In this DC/T cell coculture system, typical respiratory sensitizers but not skin sensitizers enhanced mRNA expression of the predominant Th2 marker interleukin-4 (IL-4) and its transcription factor GATA-binding protein 3. To improve the versatility, in place of peripheral monocytes, monocyte-derived proliferating cells called CD14-ML were also used in the DC coculture system. Similar to peripheral monocytes, enhanced mRNA expression of OX40L was observed by typical respiratory sensitizers compared to skin sensitizers. When these cell lines were applied to the DC/T cell coculture system with peripheral allogeneic naive CD4+ T cells, typical respiratory sensitizers but not skin sensitizers enhanced the mRNA expression of IL-4. Thus, this DC/T cell coculture system might be useful for discriminating between respiratory and skin sensitizers by differential mRNA upregulation of IL-4 in T cells.

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Mizoguchi, I., Katahira, Y., Inoue, S., Sakamoto, E. ., Watanabe, A., Furusaka, Y., Irie, A., Senju, S., Nishimura, Y., Mizukami, S., Hirayama, K., Nakamura, S., Eto, K., Hasegawa, H. . and Yoshimoto, T. (2022) “A novel coculture system for assessing respiratory sensitizing potential by IL-4 in T cells”, ALTEX - Alternatives to animal experimentation. doi: 10.14573/altex.2111181.
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