학술논문
Post-transplant Inflammatory Bowel Disease Associated with Donor-Derived TIM-3 Deficiency
Document Type
Original Paper
Author
Baldrich, Adrian; Althaus, Dominic; Menter, Thomas; Hirsiger, Julia R.; Köppen, Julius; Hupfer, Robin; Juskevicius, Darius; Konantz, Martina; Bosch, Angela; Drexler, Beatrice; Gerull, Sabine; Ghosh, Adhideb; Meyer, Benedikt J.; Jauch, Annaise; Pini, Katia; Poletti, Fabio; Berkemeier, Caroline M.; Heijnen, Ingmar; Panne, Isabelle; Cavelti-Weder, Claudia; Niess, Jan Hendrik; Dixon, Karen; Daikeler, Thomas; Hartmann, Karin; Hess, Christoph; Halter, Jörg; Passweg, Jakob; Navarini, Alexander A.; Yamamoto, Hiroyuki; Berger, Christoph T.; Recher, Mike; Hruz, Petr
Source
Journal of Clinical Immunology: International Journal of Inborn Errors of Immunity and Related Diseases. 44(3)
Subject
Language
English
ISSN
0271-9142
1573-2592
1573-2592
Abstract
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.