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. 2025 Apr 24.
doi: 10.1097/TP.0000000000005411. Online ahead of print.

Insights in Cellular and Molecular Signatures of the Small Intestinal Graft Posttransplantation: Successful, Recovered, and Rejected-A Case Series

Naomi Karmi  1 , Roy Oelen  2 , Emilia Bigaeva  1 , Sofie de Jong  1 , Jan Willem Haveman  3 , Frans van der Heide  1 , Marcela A Hermoso  1   4 , Monique G P van der Wijst  2 , Gursah Kats-Ugurlu  5 , Rinse K Weersma  1 , Eleonora A M Festen  1 , Werna T C Uniken Venema  1 , Gerard Dijkstra  1 ; TransplantLines Investigators
Collaborators, Affiliations

Insights in Cellular and Molecular Signatures of the Small Intestinal Graft Posttransplantation: Successful, Recovered, and Rejected-A Case Series

Naomi Karmi et al. Transplantation. .

Abstract

Background: Intestinal transplantation is the treatment for patients with irreversible intestinal failure and complications of parenteral nutrition. Five-year graft survival is only 56%, possibly due to an imbalance in immunosuppression, aiming to prevent rejection while maintaining protection against pathogens. Studying the graft's mucosal cell populations and regulation of donor and recipient cells posttransplantation offers a unique opportunity to address this (im)balance leading to rejection.

Methods: We performed single-cell mRNA sequencing of longitudinally sampled ileal graft biopsies from surgery up to 6 mo after transplantation, althrough the TransplantLines Biobank and Cohort Study to characterize the composition and function of donor and recipient cell populations.

Results: A rapid influx of recipient immune cells was observed in the rejected transplant. Induction therapy using anti-thymocyte globulin did not achieve complete T-cell depletion. Instead, during moderate rejection, apoptotic pathways in epithelial cells preceded pathology-defined severe rejection, indicating potential prognostic information in the transcriptomic profiles.

Conclusions: This first longitudinal cellular-molecular study of the total ileal graft mucosa and recipient cells within, shows a variable clinical course and response to medication, which align with heterogeneous signatures before intestinal transplantation rejection.

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Conflict of interest statement

E.A.M.F and W.T.C.U.V. were sponsored by a NVGE Gastrostart Grant. W.T.C.U.V., E.B., R.K.W., and E.A.M.F were sponsored by an unrestricted research grant from Takeda Pharmaceuticals. R.K.W. acted as a consultant for Takeda and received an unrestricted grant from Johnson and Johnson Pharmaceuticals and speaker fees from AbbVie, MSD, Olympus, and AstraZeneca. E.A.M.F. is supported by a ZonMW Clinical Fellowship grant (project 90719075). G.D. received speaker’s fees from Janssen-Cilag, Abbvie, Takeda, and Pfizer and received research grants from Royal DSM and Janssen-Cilag. G.K.-U. received awards from the University Medical Center Groningen Kanker Researchfonds and Owkin and a speakers fee from Diaceutics. M.G.P.v.d.W. is supported by an NWO Vidi grant (VI.Vidi.223.041). M.A.H. is supported by the Fondecyt/ANID (Chilean Agency for Research and Development) grant (1220702). The other authors declare no conflicts of interest.

References

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    1. Venick R. International Intestinal Transplant Registry: 2023 update. Available at https://intestinalregistry.org/images/registries/IITR%20Final%20Slides%2.... Accessed April 1, 2025.
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    1. He G, Kim OS, Thistlethwaite JR, et al. Differential effect of an anti-CD8 monoclonal antibody on rejection of murine intestine and cardiac allografts. Transplant Proc. 1999;31:1239–1241.
    1. He G, Hart J, Kim OS, et al. The role of CD8 and CD4 T cells in intestinal allograft rejection: a comparison of monoclonal antibody-treated and knockout mice. Transplantation. 1999;67:131–137.

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