The role of tissue regeneration in graft-versus-host disease of the stomach

• Applicant: Professor Dr. Robert Zeiser
• Subject Area: Hematology, Oncology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 560868983

Allogeneic hematopoietic cell transplantation (allo-HCT) for the treatment of leukaemia and other hematological malignancies is increasingly performed worldwide. Acute graft-versus-host disease (aGVHD) accounts for 25% of deaths after allo-HCT and patients with steroid-refractory aGVHD have a dismal prognosis, with a mortality rate of 50% within three years after diagnosis. A major concern is the requirement for immunosuppression as it may reduce the graft-versus-leukaemia (GVL) activity in the patients. Therefore non-immunosupressive approaches are urgently needed. We could show that that targeting the Janus kinases 1 and 2 (JAK1 and 2) with ruxolitinib reduces aGVHD in mice and patients. We previously identified intestinal L cells as a target of aGVHD and observed that the decline of these cells and their tissue hormone Glucagon-like peptide 2 (GLP-2) caused a decrease in Paneth cells (PC) and intestinal stem cells (ISC). Conversely, GLP-2 substitution promoted intestinal repair mechanisms including Paneth cell and ISC recovery. Besides L cells, a number of other enteroendocrine cell types have been described, each defined by a distinct hormonal signature and intestinal location. These include G cells located in the stomach. The pathophysiology of stomach GVHD, the role of G cells and the contribution of frequently used medication in GVHD patients, as well as the impact of the microbiome on stomach GVHD are not well understood. Our preliminary data indicate a functional role for gastrin in stomach GVHD. To delineate the pathophysiology of graft-versus-host disease of the stomach our study has the objective to analyze the impact of gastrin, immunosuppressive agents, antibiotics and proton pump inhibitors on the gastric microbiome and stomach aGVHD. We plan to determine the regenerative potential of G cells and parietal cells during stomach GVHD and how regenerative therapy approaches impact the GVL effect. We will characterize the signalling in different stomach cells including parietal cells and G cells during GVHD and pentagastrin therapy. Ultimately we wish to clarify the role of gastrin in stomach GVHD of patients. Overall the study will help to understand gastric GVHD and to develop novel therapies against this complication after allo-HCT.

• DFG Programme: Research Grants