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Post-transplant Inflammatory Bowel Disease Associated with Donor-Derived TIM-3 Deficiency.

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Baldrich, Adrian 
Althaus, Dominic 
Menter, Thomas 
Hirsiger, Julia R 
Köppen, Julius 


Inflammatory bowel disease (IBD) occurring following allogeneic stem cell transplantation (aSCT) is a very rare condition. The underlying pathogenesis needs to be better defined. There is currently no systematic effort to exclude loss- or gain-of-function mutations in immune-related genes in stem cell donors. This is despite the fact that more than 100 inborn errors of immunity may cause or contribute to IBD. 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 the patient's serum, and in vitro-activated patient-derived T cells expressed reduced TIM-3 levels. In contrast, T cell-intrinsic CD25 expression and production of inflammatory cytokines were preserved. TIM-3 expression was barely detectable in the immune cells of the patient's intestinal mucosa, while being detected unambiguously in the inflamed and non-inflamed colon from unrelated individuals. In conclusion, we report the first case of acquired, "transplanted" insufficiency of the regulatory TIM-3 checkpoint linked to post-aSCT IBD.


Acknowledgements: We thank the patient for his continuing support of this study. We thank the clinical staff for detailed and provident clinical care.

Funder: University of Basel


HAVCR2, Inborn errors of immunity, TIM-3, immune checkpoint, inflammatory bowel disease, stem cell transplantation, Humans, Cytokines, Hepatitis A Virus Cellular Receptor 2, Inflammatory Bowel Diseases, Intestinal Mucosa, Stem Cell Transplantation

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J Clin Immunol

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Springer Science and Business Media LLC
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (310030_192652, PP00P3_181038)