Allogeneic hematopoeitic stem cell transplantation (allo-HSCT) involves transplanting blood- or bone marrow- derived hematopoietic stem cells from a donor into a genetically non-identical recipient of the same species. The ability of allo-HSCT to cure hematopoietic disorders in humans is overshadowed by a highly morbid and lethal complication termed Graft-vs.-Host-Disease (GVHD) in which aberrantly activated donor T cells destroys host organs. Despite the plethora of research on GVHD, many of the factors and pathways that determine whether a patient will develop GVHD following allo-HSCT remain unclear. Since the gastrointestinal tract is a major target organ during GVHD, it is possible that pathways and mutations that contribute to other intestinal disorders also regulate GVHD. Additionally, commensal bacteria in the intestine are thought to contribute to disease. Atg16L1 is an autophagy gene associated with increased susceptibility of developing the inflammatory bowel disease (IBD) Crohn's disease. Although is it unclear why a gene associated with a cellular derivative pathway is associated with Crohn's disease, our lab has demonstrated an important role for Atg16L1 in the intestine. We found that mice with a mutation leading to decreased Atg16L1 protein levels develop Crohn's-like intestinal pathologies when exposed to a murine nor virus, and these pathologies were dependent on commensal bacteria. Based on the similarities between IBD and GVHD, we hypothesized that Atg16L1 mutant mice will allow us to investigate the contribution of commensal bacteria to GVHD as well. In collaboration with my co-mentor Dr. Marcel van den Brink, we have now found that Atg16L1 mutant mice display increased mortality compared with controls in a well-established murine model of GVHD. The goal of this proposal is to examine how host-commensal interactions in the context of Atg16L1 contribute to the pathogenesis of GVHD. Preliminary data indicates that treatment of these mice with antibiotics mitigates the observed lethality. In this fellowship proposal, I aim to 1) elucidae the extent to which GVHD morbidity and mortality in Atg16L1 mutant mice depends on the presence of commensal bacteria, 2) examine how the proportions of commensal bacteria shift following allo-HSCT, and 3) determine whether specific bacteria can positively or negatively influence the outcome of GVHD in mutant mice. Since mutation in Atg16L1 is common in humans and commensal bacteria can be targeted therapeutically, our results will have important implications for allo-HSCT procedures in humans. Additional, we hope to elucidate novel gene-commensal interactions that will lead to insight into intestinal bacteria and disease in general.
Graft-versus-host-disease (GVHD) is a common and often life-threatening complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), an otherwise curative treatment for patients with malignant and non-malignant hematopoietic diseases. We will use a well-established mouse model of allo- HSCT to examine how commensal bacteria in the intestine mediate GVHD in a genetically susceptible host.
|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|