02188nas a2200349   4500000000100000000000100001008004100002260001500043653002400058653003500082653002300117653002800140100001800168700001600186700001700202700002200219700001900241700001400260700002100274700001900295700002100314700002100335700001700356700001600373700002100389245012300410856005500533300000900588490000700597520122000604022001401824       2025                            d  c2025-08-2510aAutoimmune Diseases10aExperimental models of disease10aPituitary diseases10aStem-cell biotechnology1 aKeitaro Kanie1 aTakeshi Ito1 aGenzo Iguchi1 aRyusaku Matsumoto1 aKeiko Muguruma1 aShin Urai1 aShuichi Kitayama1 aHironori Bando1 aMasaaki Yamamoto1 aHidenori Fukuoka1 aWataru Ogawa1 aShin Kaneko1 aYutaka Takahashi00aModeling of T cell-mediated autoimmune pituitary disease using human induced pluripotent stem cell-originated organoid  uhttps://www.nature.com/articles/s41467-025-63183-x  a79000 v163 aAnti-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.  a2041-1723