Post-transplant inflammatory bowel disease associated with donor-derived TIM-3 deficiency

Abstract

Abstract Purpose Inflammatory bowel disease (IBD) occurring following allogenic stem cell transplantation (aSCT) is a very rare condition. The underlying pathogenesis is poorly defined. There is currently no systematic effort to exclude loss- or gain-of-function mutations in immune-related genes in stemcell donors. Methods Whole exome sequencing of hematopoietic cell-intrinsic, donor-derived vs. skin-derived germline DNA was performed in an index patient with post-aSCT IBD. Expression of the immune checkpoint protein TIM-3 and T cell-edrived cytokines/chemokines was assessed in in vitro activated patient-derived T cells by flow-cytometry and by performing immune-histology on sections from inflamed vs. non-inflamed intestinal tissue. Results We have molecularly characterized a patient who developed fulminant inflammatory bowel disease following aSCT with stable 100% donor-derived hematopoiesis. A pathogenic c.A291G; p.I97M HAVCR2 mutation encoding the immune checkpoint protein TIM-3 was identified in the patient’s blood-derived DNA, while being absent in DNA derived from the skin. TIM-3 expression was much decreased in in vitro activated patient-derived T cells, while effector cytokines and Foxp3 expression were preserved. TIM-3 expression was barely detectable in the patient’s intestinal mucosa, while being detected unambiguously in inflamed and non-inflamed colon from unrelated individuals. Conclusion We report the first case of acquired, ‘transplanted’ insufficiency of the regulatory TIM-3 checkpoint linked to post-aSCT IBD.