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. Autophagy, a cellular process by which cytosolic material is delivered to the lysosome for degradation, is receiving increasing attention as a pathway that contributes to a balanced immune response. Additionally, a highly common polymorphism in the autophagy gene Atg16L1 is associated with inflammatory bowel disease (IBD), suggesting a role for this gene and pathway in inflammatory conditions. To test the role of Atg16L1 in GVHD, we performed an allo-HSCT using Atg16L1 mutant recipient mice and found that deficiency in this gene significantly increased lethality and disease following the transplant This enhanced GVHD is associated with increased donor-derived T cell proliferation and intestinal barrier disruption, most likely due to an unexpected role of Atg16L1 in suppressing dendritic cell hyperactivation. Moreover, preliminary data indicates that the IBD risk polymorphism of Atg16L1 is associated with a higher incidence of transplant-related mortality in humans, thus supporting our observations in a preclinical mouse model. In this proposal, we will further define the role of Atg16L1 and autophagy during allo-HSCT and elucidate mechanism. We will identify the factors that contribute to enhanced GVHD, examine graft-versus-tumor reactions, and understand how Atg16L1 suppresses dendritic cell hyperactivity. We anticipate that these results will yield significant insight into allo-HSCT as well as reveal processes that ae fundamental to inflammatory disease.

Public Health Relevance

Bone marrow transplantation can cure certain types of blood disorders and cancer, but can also lead to graft- versus-host disease (GVHD), a frequently lethal complication in transplant recipients. In this proposal, we will use well-established mouse models of the transplantation procedure to examine a unique mechanism by which the autophagy gene Atg16L1 protects against GVHD.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Cancer Immunopathology and Immunotherapy Study Section (CII)
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Welniak, Lisbeth A
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New York University
Schools of Medicine
New York
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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
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
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

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