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

   


Authors: Matsuzawa-Ishimoto, Y.; Hine, A.; Shono, Y.; Rudensky, E.; Lazrak, A.; Yeung, F.; Neil, J. A.; Yao, X.; Chen, Y. H.; Heaney, T.; Schuster, S. L.; Zwack, E. E.; Axelrad, J. E.; Hudesman, D.; Tsai, J. J.; Nichols, K.; Dewan, M. Z.; Cammer, M.; Beal, A.; Hoffman, S.; Geddes, B.; Bertin, J.; Liu, C.; Torres, V. J.; Loke, P.; van den Brink, M. R. M.; Cadwell, K.
Article Title: An intestinal organoid-based platform that recreates susceptibility to T-cell-mediated tissue injury
Abstract: 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.
Journal Title: Blood
Volume: 135
Issue: 26
ISSN: 0006-4971
Publisher: American Society of Hematology  
Date Published: 2020-06-25
Start Page: 2388
End Page: 2401
Language: English
DOI: 10.1182/blood.2019004116
PUBMED: 32232483
PROVIDER: scopus
PMCID: PMC7317146
DOI/URL:

https://www.scopus.com/inward/record.uri?eid=2-s2.0-85087098824&doi=10.1182%2fblood.2019004116&partnerID=40&md5=ba3ed7c252a1290abc563245dc6fc6a0
Notes: Article -- Export Date: 3 August 2020 -- Source: Scopus
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MSK Authors
  1. Marcel R M Van Den Brink
    616 Van Den Brink
  2. Jennifer Tsai
    52 Tsai
  3. Yusuke Shono
    39 Shono
  4. Amina Lazrak
    21 Lazrak
  5. Katherine Blessing Nichols
    11 Nichols
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