Objectives: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a common therapeutic modality for a number of malignant diseases. The most common complication of an allo-HSCT is Graft versus host disease (GVHD) that results in significant target organ damage that can result in death. It is caused by cells fro the graft initiating an immune response against the host tissues. Inflammatory bowel disease (IBD) and GHVD resemble each other in their pathology, genetics, and treatment. Several genetic factors have been associated with IBD have also been identified as risk factors for treatment-induced mortality after an allo- HSCT. One of these risk factors, Atg16L1, a gene important for autophagy, has been shown to be critical for IBD development and may influence mortality in patients after an allo-HSCT. Mice that are hypomrophic (HM) for Atg16L1, along with infection with a murine norovirus (MNV) display IBD-like pathologies. Norovirus infection, the most common cause of gastroenteritis worldwide, has been shown to be a complication for GVHD. Our data demonstrates that Atg16L1HM recipients have increased GVHD compared to wild type controls, and that this is dependent on commensal bacteria. We have also found that the small intestines is particularly affected by H&E sections and increased T cell infiltration in the intraepithelial cells. Our preliminary data using 454 sequencing in untransplanted Atg16L1HM mice indicate a preponderance of Clostradales, a Firmicutes that has recently been shown to worsen GVHD. This proposal aims to delineate the mechanism by which Atg16L1 mediates increased GVHD and to determine if norovirus infection exacerbates GVHD in a wild type as well as an Atg16L1-deficient setting.
Specific Aims : The goal of this project is to study the hypothesis that 1) Atg16L1HM with GVHD have severe target organ damage, particularly in their intestinal tissue, and that commensal bacteria may be mediating this effect 2) Determine whether the hematopoietic or non-hematopoietic compartment contributes to this phenotype, and whether this is dependent on commensal bacteria, and 3) To study the hypothesis that MNV may worsen GVHD in the WT and/or Atg16L1HM setting. Study Design: We will perform allo-HSCT using a complete mismatch using Atg16L1HM as recipients and assessing GVHD morbidity and mortality using established methods. To study the role of Atg16L1 in the hematopoietic compartment we will perform BM chimeras using Atg16L1HM as donors and recipients in order to study the effect of having Atg16L1 mutation in the hematopoietic as well as epithelial compartment and assessing for GVHD morbidly and mortality as well as DC activation and proliferation. We will also assess target organ damage and lymphocytic infiltration via Flow Cytometry and histology of various GVHD target organ tissues (spleen, thymus, liver, skin, small intestines and colon). We will also assess whether exacerbated GVHD is dependent on commensal bacteria by performing these experiments in germ-free Atg16L1HM mice. We will also study the role of the microbiota in Atg16L1HM after allo-HSCT to determine if a particular commensal is affected. Finally, in order to study MNV infection in the GVHD setting we will perform allo-HSCT and infect mice WT and Atg16L1HM mice with MNV and follow the mice for survival and morbidity.

Public Health Relevance

Complications from a bone marrow transplant (a common way to treat leukemia) include Graft-versus-host-Disease, which is life-threatening. This proposal addresses how genetic and environmental factors predispose certain individuals to deadly Graft- versus-Host-disease, and provides solutions for how to reduce lethality. !

National Institute of Health (NIH)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Welniak, Lisbeth A
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New York University
Schools of Medicine
New York
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Hubbard-Lucey, Vanessa M; Shono, Yusuke; Maurer, Katie et al. (2014) Autophagy gene Atg16L1 prevents lethal T cell alloreactivity mediated by dendritic cells. Immunity 41:579-91
Marchiando, Amanda M; Ramanan, Deepshika; Ding, Yi et al. (2013) A deficiency in the autophagy gene Atg16L1 enhances resistance to enteric bacterial infection. Cell Host Microbe 14:216-24