The GI tract in Systemic Alloimmunity

About This Grant

ABSTRACT/PROJECT SUMMARY Acute Graft-versus-Host Disease (aGVHD) remains a critical barrier to clinical success after allogeneic hemato- poietic cell transplantation (allo-HCT) in patients with high-risk hematologic malignancies and non-malignant diseases. The current treatment options are limited and rely heavily on non-specific immunosuppression with high-dose glucocorticoids, which is only partially effective while increasing infection risk and potentially abating the protective Graft-versus-Leukemia (GVL) effect. Emerging evidence highlights the gastrointestinal (GI) tract as a pivotal driver of systemic alloimmunity, but the exact biological pathways involved in the interface between the GI tract and the immune system are incompletely understood, which impedes the development of novel targeted anti-aGVHD approaches. This proposal seeks to investigate the mechanisms of GI-driven T cell repro- gramming during aGVHD to identify novel therapeutic targets. We hypothesize that GI-derived T cells mediate systemic aGVHD-induced immunopathology while being dispensable for the GVL effect, which we will test in the three Specific Aims. Aim 1 will examine how GI-driven reprogramming impacts donor T cell pathogenicity. We will use photoconvertible Dendra2 donor mice to trace, profile, and functionally characterize GI-reprogrammed T cells as they traffic to distal organs during multiorgan aGVHD. Aim 2 will evaluate genetic (Itgb7-mutant T cells) and pharmacologic (anti-MadCAM-1 antibodies) strategies to block T cell trafficking to the GI tract, thereby mitigating extra-GI immunopathology in skin/esophageal aGVHD model induced by transplantation of OVA-spe- cific OT-I T cells to B6-K14.OVA recipient mice with keratinocyte-restricted OVA expression. Aim 3 will employ allo-HCT models in which aGVHD and GVL are mediated by distinct T cell subsets to determine whether GI- driven reprogramming affects the cytotoxic function of tumor-specific T cells in vivo. This project will provide foundational insights into tissue-specific immune regulation and inform the development of precision therapies to control aGVHD while preserving GVL. These findings promise broader relevance to T cell-mediated alloim- mune and autoimmune diseases, paving the way for clinical translation.