Modeling of T cell-mediated autoimmune pituitary disease using human induced pluripotent stem cell-originated organoid

Keitaro Kanie, Takeshi Ito, Genzo Iguchi, Ryusaku Matsumoto, Keiko Muguruma, Shin Urai, Shuichi Kitayama, Hironori Bando, Masaaki Yamamoto, Hidenori Fukuoka, Wataru Ogawa, Shin Kaneko and Yutaka Takahashi ()
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Keitaro Kanie: Kobe University Graduate School of Medicine
Takeshi Ito: Center for iPS Cell Research and Application (CiRA), Kyoto University
Genzo Iguchi: Kobe University
Ryusaku Matsumoto: CiRA, Kyoto University
Keiko Muguruma: Kansai Medical University
Shin Urai: Kobe University Graduate School of Medicine
Shuichi Kitayama: Center for iPS Cell Research and Application (CiRA), Kyoto University
Hironori Bando: Kobe University Hospital
Masaaki Yamamoto: Kobe University Hospital
Hidenori Fukuoka: Kobe University Hospital
Wataru Ogawa: Kobe University Graduate School of Medicine
Shin Kaneko: Center for iPS Cell Research and Application (CiRA), Kyoto University
Yutaka Takahashi: Kobe University Hospital

Nature Communications, 2025, vol. 16, issue 1, 1-14

Abstract: Abstract Anti-pituitary-specific transcription factor (PIT)−1 hypophysitis is an autoimmune disease characterized by hormone secretion impairment from PIT-1-expressing pituitary cells, accompanied by malignancies with ectopic PIT-1 expression. Cytotoxic T cells (CTL) targeting PIT-1-positive cells have been implicated in disease development, yet direct evidence is lacking. As human leukocyte antigen (HLA)-matching is required for modeling T cell-mediated autoimmune diseases, we employ induced pluripotent stem cells (iPSC) to generate pituitary organoids harboring the patients’ HLA haplotype and coculture the organoids with PIT-1-reactive CTLs isolated from the patients’ peripheral blood mononuclear cells. The coculture demonstrates specific CTL-mediated cytotoxicity against PIT-1-positive cells exclusively in autologous conditions, with this cytotoxicity inhibited by immunosuppressive agents such as dexamethasone and cyclosporin A. Multiple combinations of epitopes, CTLs, and HLA molecules are responsible for pathogenesis. These data demonstrate CTL-mediated autoimmunity in anti-PIT-1 hypophysitis and highlight the potential application of this strategy for other T cell-mediated autoimmune diseases.

Date: 2025
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DOI: 10.1038/s41467-025-63183-x

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