Deciphering the mechanisms of intestinal stem cell elimination by allogeneic T cells in order to develop novel GVHD treatment approaches

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Graft-versus-host disease (GVHD) is a severe T cell-mediated complication of allogeneic hematopoietic stem cell/bone marrow transplantation (BMT), and damage to the gastrointestinal tract is the predominant contributor to acute GVHD-related morbidity and mortality. The immune system has the capability to regulate gastrointestinal recovery after GVHD-induced injury by release of cytokines. However, the direct interactions occurring between allogeneic T cells and recipient intestinal stem cell (ISC) compartment in GVHD are poorly understood. We hypothesize that ISCs will express death receptors that are involved in their immune-mediated elimination in GVHD. Given the high concordance between clinical acute GVHD and its experimental models, gastrointestinal GVHD represents an excellent experimental system to test immune-mediated regulation of the ISC compartment and develop novel approaches to reduce tissue damage in GVHD. In this project, we will use intestinal organoid cultures to measure in vivo GVHD and model intestinal alloreactivity in vitro. In order to elucidate the role of immune-mediated damage to the ISC compartment after BMT, we propose to test the following specific aims: (1) analyze viability, cell cycle progression, and apoptosis of ISCs post-BMT, (2) evaluate subtype and activation status of T cells exerting ISC damage, (3) examine cellular pathways regulating alloreactivity towards ISCs. This research project will contribute substantially to our understanding of mucosal immunology and may lead to the development of novel GVHD treatment approaches.