Donor-Specific T Cell Senescence In Operationally Tolerant Liver Transplant Recipients
1Center for Transplantation Sciences, Massachusetts General Hospital, Boston, MA, 2Department of Gastroenterological and Transplantation Surgery, Hiroshima University, Hiroshima, Japan, 3Immune Tolerance Network, Bethesda, MD
Meeting: 2022 American Transplant Congress
Abstract number: 9025
Keywords: Immunosuppression, Liver transplantation, T cells, Tolerance
Topic: Basic Science » Basic Clinical Science » 17 - Biomarkers: Clinical Outcomes
Session Information
Session Name: Late Breaking: Basic / Translational
Session Type: Rapid Fire Oral Abstract
Date: Monday, June 6, 2022
Session Time: 3:30pm-5:00pm
Presentation Time: 4:00pm-4:10pm
Location: Hynes Room 313
*Purpose: Recent evidence indicates a correlation in liver transplant recipients between successful operational tolerance (OT) post immunosuppression withdrawal (ISW) with both recipient age and time post-transplant, suggesting the possibility that long-term exposure to high levels of donor antigen may induce T cell exhaustion or senescence. Using samples from the OPTIMAL ISW study (NCT02533180), an ITN sponsored multi-center trial, we explored potential mechanisms of OT using our novel alloreactive T cell detection assay (J Immunol Methods 2021).
*Methods: We examined MLRs pitting PBMC responders from 8 OPTIMAL patients (3 tolerant and 5 non-tolerant) against self, donor and 3rd party stimulators. Alloreactive T cells were detected by co-culturing rested recipient PBMCs with CFSE-labeled irradiated stimulators activated for 48h with multimeric CD40L and rIL-4. After 20h incubation, CD4 and CD8 alloreactive T cells were distinguished by CD69+CD154+ and CD69+CD137+, respectively. Senescence markers (CD57, KLRG1) were analyzed in patient samples from baseline, dose taper level 3 (33-50% baseline), 26 and 52-weeks post-ISW completion or failure. Samples were blinded until full analysis completion.
*Results: The percentage of donor-reactive CD4 and CD8 T cells was lower than that of 3rd party-reactive at baseline, perhaps suggesting an element of donor-specific deletion. The percentage of alloreactive Tregs (CD137+CD154-CD4+) did not correlate with successful OT. However, the ratio of %CD57+KLRG1hi in donor- vs. 3rd party-reactive CD8 T cells was significantly higher in Tol than non-Tol at baseline (mean 2.73 vs 1.15, p=0.020) and taper level 3 (3.97 vs 1.34, p=0.021). Kinetic analyses revealed relatively stable expression of CD57 and KLRG1 regardless of tolerance status over time.
*Conclusions: Our findings suggest that donor specific senescence may be a biomarker for operationally tolerant liver transplant recipients and may portend outcome in future ISW candidates. We speculate that the process of donor specific senescence contributes to development and maintenance of the tolerant state. Future work will explore mechanistic underpinnings of senescence in tolerant recipients and how senescence can be fostered to promote OT in patients not naturally inclined to its development.
To cite this abstract in AMA style:
Deng K, Tanimine N, Breeden C, Burrell B, Gaile G, Lee K, Matheson R, Qiang F, Rickert C, LeGuern C, Markmann J. Donor-Specific T Cell Senescence In Operationally Tolerant Liver Transplant Recipients [abstract]. Am J Transplant. 2022; 22 (suppl 3). https://atcmeetingabstracts.com/abstract/donor-specific-t-cell-senescence-in-operationally-tolerant-liver-transplant-recipients/. Accessed May 28, 2025.« Back to 2022 American Transplant Congress