An intestinal organoid-based platform that recreates susceptibility to T-cell-mediated tissue injury
- 24 June 2020
- journal article
- research article
- Published by American Society of Hematology in Blood
- Vol. 135 (26), 2388-2401
- https://doi.org/10.1182/blood.2019004116
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 in- dividuals 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. (Blood. 2020;135(26):2388-2401)This publication has 73 references indexed in Scilit:
- Low Paneth cell numbers at onset of gastrointestinal graft-versus-host disease identify patients at high risk for nonrelapse mortalityBlood, 2013
- Apoptosis, necrosis and necroptosis: cell death regulation in the intestinal epitheliumGut, 2012
- DAI/ZBP1/DLM-1 Complexes with RIP3 to Mediate Virus-Induced Programmed Necrosis that Is Targeted by Murine Cytomegalovirus vIRACell Host & Microbe, 2012
- Type I-IFNs control GVHD and GVL responses after transplantationBlood, 2011
- Genetics and pathogenesis of inflammatory bowel diseaseNature, 2011
- Virus-Plus-Susceptibility Gene Interaction Determines Crohn's Disease Gene Atg16L1 Phenotypes in IntestineCell, 2010
- A key role for autophagy and the autophagy gene Atg16l1 in mouse and human intestinal Paneth cellsNature, 2008
- Recombinant human soluble tumor necrosis factor receptor fusion protein as treatment for steroid refractory graft‐versus‐host disease following allogeneic hematopoietic stem cell transplantationAmerican Journal of Hematology, 2006
- Pilot Trial on the Use of Etanercept and Methylprednisolone as Primary Treatment for Acute Graft-versus-Host DiseaseTransplantation and Cellular Therapy, 2005
- In situ detection of fragmented dna (tunel assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: A cautionary noteHepatology, 1995