An intestinal organoid-based platform that recreates susceptibility to T-cell-mediated tissue injury.

Autor:	Matsuzawa-Ishimoto Y; Kimmel Center for Biology and Medicine at the Skirball Institute.; Department of Microbiology, and., Hine A; Department of Microbiology, and.; Division of Gastroenterology and Hepatology, Department of Medicine, New York University Grossman School of Medicine, New York, NY., Shono Y; Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY., Rudensky E; Kimmel Center for Biology and Medicine at the Skirball Institute.; Sackler Institute of Graduate Biomedical Sciences., Lazrak A; Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY., Yeung F; Kimmel Center for Biology and Medicine at the Skirball Institute.; Sackler Institute of Graduate Biomedical Sciences., Neil JA; Kimmel Center for Biology and Medicine at the Skirball Institute.; Department of Microbiology, and., Yao X; Kimmel Center for Biology and Medicine at the Skirball Institute.; Department of Microbiology, and., Chen YH; Kimmel Center for Biology and Medicine at the Skirball Institute.; Department of Microbiology, and., Heaney T; Kimmel Center for Biology and Medicine at the Skirball Institute., Schuster SL; Kimmel Center for Biology and Medicine at the Skirball Institute., Zwack EE; Department of Microbiology, and., Axelrad JE; Division of Gastroenterology and Hepatology, Department of Medicine, New York University Grossman School of Medicine, New York, NY., Hudesman D; Division of Gastroenterology and Hepatology, Department of Medicine, New York University Grossman School of Medicine, New York, NY., Tsai JJ; Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY., Nichols K; Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY., Dewan MZ; Histopathology Core, Office of Collaborative Science, and., Cammer M; Microscopy Core, Office of Collaborative Science, New York University Grossman School of Medicine, New York, NY., Beal A; Innate Immunity Research Unit, GlaxoSmithKline, Collegeville, PA., Hoffman S; Innate Immunity Research Unit, GlaxoSmithKline, Collegeville, PA., Geddes B; Innate Immunity Research Unit, GlaxoSmithKline, Collegeville, PA., Bertin J; Innate Immunity Research Unit, GlaxoSmithKline, Collegeville, PA., Liu C; Department of Pathology and Laboratory Medicine, Rutgers New Jersey Medical School and Rutgers Robert Wood Johnson Medical School, Newark, NJ., Torres VJ; Department of Microbiology, and., Loke P; Department of Microbiology, and., van den Brink MRM; Department of Immunology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY.; Weil Medical College of Cornell University, New York, NY; and.; Adult BMT Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY., Cadwell K; Kimmel Center for Biology and Medicine at the Skirball Institute.; Department of Microbiology, and.; Division of Gastroenterology and Hepatology, Department of Medicine, New York University Grossman School of Medicine, New York, NY.
Jazyk:	angličtina
Zdroj:	Blood [Blood] 2020 Jun 25; Vol. 135 (26), pp. 2388-2401.
DOI:	10.1182/blood.2019004116
Abstrakt:	A goal in precision medicine is to use patient-derived material to predict disease course and intervention outcomes. Here, we use mechanistic observations in a preclinical animal model to design an ex vivo platform that recreates genetic susceptibility to T-cell-mediated damage. Intestinal graft-versus-host disease (GVHD) is a life-threatening complication of allogeneic hematopoietic cell transplantation. We found that intestinal GVHD in mice deficient in Atg16L1, an autophagy gene that is polymorphic in humans, is reversed by inhibiting necroptosis. We further show that cocultured allogeneic T cells kill Atg16L1-mutant intestinal organoids from mice, which was associated with an aberrant epithelial interferon signature. Using this information, we demonstrate that pharmacologically inhibiting necroptosis or interferon signaling protects human organoids derived from individuals harboring a common ATG16L1 variant from allogeneic T-cell attack. Our study provides a roadmap for applying findings in animal models to individualized therapy that targets affected tissues. (© 2020 by The American Society of Hematology.)
Databáze:	MEDLINE
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