Neuropeptide Y Receptor Signaling in Gut GVHD: Targeting Y1/Y2 Pathways for Immune Modulation

Acute graft-versus-host disease (aGVHD) of the gastrointestinal (GI) tract is a major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (allo-HCT). Severe gut aGVHD is often refractory to standard immunosuppression, highlighting a critical need for novel therapeutic strategies that target the specific pathology of the inflamed gut microenvironment. The neuro-immune axis is an emerging frontier in gut inflammation, but its role in aGVHD is unknown. Neuropeptide Y (NPY), a key mediator of neuro-immune crosstalk, signals through NPY1R and NPY2R to modulate immunity. While NPY is pro-inflammatory in models of colitis, its function in the allo-immune setting of aGVHD has not been investigated. Our preliminary data provide the first link: using bulk RNA-sequencing of intestinal tissue from murine aGVHD models, we discovered a selective and robust upregulation of Npy1r and Npy2r exclusively in mice conditioned with irradiation, a regimen associated with severe gut pathology. This finding suggests that radiation-induced injury activates pathogenic NPY signaling that amplifies gut inflammation. We hypothesize that NPY signaling via the Y1 and Y2 receptors is a critical, previously unrecognized driver of intestinal aGVHD, and that pharmacologic blockade of these receptors will ameliorate disease. To test this, we will pursue two specific aims. Aim 1 will use a combination of multiplex immunofluorescence, flow cytometry, and qPCR to create the first comprehensive spatial and cellular map of the NPY-Y1/Y2 axis in the gut during experimental aGVHD. This will identify the key cell types and locations where NPY signaling is active. Aim 2 will establish the therapeutic efficacy of targeting this pathway. We will test whether systemic administration of selective NPY1R and NPY2R antagonists, alone or in combination, can improve survival and reduce disease severity in a clinically relevant, radiation-based murine aGVHD model. The mechanisms of action will be interrogated through detailed histologic, cytokine, and immune cell profiling. aGVHD’s neuro-immune crosstalk and radiation-specific NPY regulation require an intact system that in vitro or in silico methods cannot replicate. Ethical constraints preclude serial human tissue access and interventional proof-of-concept at this R03 stage. Murine models provide the only viable means to validate this axis. This project is significant as it investigates a completely novel pathway in GVHD biology. Successful completion will provide the first proof-of-concept for NPY receptor antagonism as a non-immunosuppressive therapeutic strategy for gut aGVHD. The findings will lay the essential groundwork for future R01-funded studies and the potential clinical translation of a new class of drugs to treat this devastating disease. Project Number: 1R03CA313441-01 | Fiscal Year: 2026 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Ran Reshef | Institution: COLUMBIA UNIVERSITY HEALTH SCIENCES, NEW YORK, NY | Award Amount: $164,500 | Activity Code: R03 | Study Section: Immunobiology of Transplantation and Alloimmunity Study Section[ITA] View on NIH RePORTER: https://reporter.nih.gov/project-details/11359654