Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is used to treat a variety of malignant and non-malignant disorders, and involves the transfer of stem cells from the bone marrow, blood, or umbilical cord from a non-identical donor. The widespread application of this procedure is limited by the high rate of graft-versus-host disease (GVHD), a life-threatening condition that is mediated by alloreactive T cells from the transplant. Improving the procedure is dependent on identifying the mechanisms that contribute to this damaging T cell reactivity. We previously demonstrated in a preclinical mouse model of allo-HSCT that the autophagy protein ATG16L1 is essential for preventing intestinal inflammation and GVHD. Autophagy is a process by which cytosolic material is delivered to the lysosome for degradation, and is involved in maintaining cellular and tissue homeostasis. Additionally, a common polymorphism in ATG16L1 leading to a coding change (T300A) is associated with susceptibility to inflammatory bowel disease (IBD) and transplant-related mortality in allo-HSCT patients. Given the high prevalence of the T300A variant and the challenges associated with treating intestinal GVHD, addressing the mechanism by which ATG16L1 and autophagy protect against intestinal damage is a research priority. During the previous funding period, we made significant progress by demonstrating that ATG16L1 prevents necroptosis in intestinal epithelial cells (IECs) following allo-HSCT. Necroptosis is a form of programmed necrosis that has received attention as a therapeutic target for limiting the tissue damage observed in a range of inflammatory diseases. Our findings suggest that the intersection between autophagy and necroptosis can be targeted to treat GVHD, especially in high risk patients such as individuals harboring the ATG16L1T300A variant. However, the molecular basis for the interaction between ATG16L1 and necroptosis is obscure, and the upstream signals that trigger the adverse signaling events require examination. Thus, we lack detailed mechanistic understanding of the inflammatory process that is necessary to apply such strategies to allo-HSCT recipients. The goal of this proposal is to how ATG16L1 and autophagy integrate IEC-intrinsic and -extrinsic signals to block necroptosis following allo-HSCT, and determine how the T300A variant disrupts this protective function. We anticipate this knowledge will yield significant insight into GVHD pathogenesis and inform intervention strategies for improving allo-HSCT outcome.

Public Health Relevance

Allogeneic hematopoietic stem cell transplantations can cure a range of disorders including certain types of cancer, but can also cause intestinal graft-versus-host disease (GVHD), a frequently lethal complication in transplant recipients. In this proposal, we will use a preclinical animal model and advanced 3D culture techniques to examine how the autophagy gene ATG16L1 promotes the viability of intestinal epithelial cells to protect against GVHD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL123340-06
Application #
9915940
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Welniak, Lisbeth A
Project Start
2015-09-01
Project End
2023-05-31
Budget Start
2020-06-01
Budget End
2021-05-31
Support Year
6
Fiscal Year
2020
Total Cost
Indirect Cost
Name
New York University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
Martin, Patricia K; Marchiando, Amanda; Xu, Ruliang et al. (2018) Autophagy proteins suppress protective type I interferon signalling in response to the murine gut microbiota. Nat Microbiol 3:1131-1141
Cadwell, Ken; Debnath, Jayanta (2018) Beyond self-eating: The control of nonautophagic functions and signaling pathways by autophagy-related proteins. J Cell Biol 217:813-822
Neil, Jessica A; Cadwell, Ken (2018) The Intestinal Virome and Immunity. J Immunol 201:1615-1624
Wong, Serre-Yu; Cadwell, Ken (2018) There was collusion: Microbes in inflammatory bowel disease. PLoS Pathog 14:e1007215
Velardi, Enrico; Tsai, Jennifer J; Radtke, Stefan et al. (2018) Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury. Nat Med 24:239-246
Wong, Serre-Yu; Coffre, Maryaline; Ramanan, Deepshika et al. (2018) B Cell Defects Observed in Nod2 Knockout Mice Are a Consequence of a Dock2 Mutation Frequently Found in Inbred Strains. J Immunol 201:1442-1451
Wilen, Craig B; Lee, Sanghyun; Hsieh, Leon L et al. (2018) Tropism for tuft cells determines immune promotion of norovirus pathogenesis. Science 360:204-208
DeFilipp, Zachariah; Peled, Jonathan U; Li, Shuli et al. (2018) Third-party fecal microbiota transplantation following allo-HCT reconstitutes microbiome diversity. Blood Adv 2:745-753
Matsuzawa-Ishimoto, Yu; Shono, Yusuke; Gomez, Luis E et al. (2017) Autophagy protein ATG16L1 prevents necroptosis in the intestinal epithelium. J Exp Med 214:3687-3705
Staffas, Anna; Burgos da Silva, Marina; van den Brink, Marcel R M (2017) The intestinal microbiota in allogeneic hematopoietic cell transplant and graft-versus-host disease. Blood 129:927-933

Showing the most recent 10 out of 17 publications