Abstract: SA-OR50
Immune Cell Transcriptome in Living-Donor Kidney Transplant Patients Tolerized With Allogeneic Hematopoietic Stem Cell Transplantation Therapy
Session Information
- Transplantation: Clinical Outcomes and Biomarkers
November 05, 2022 | Location: W240, Orange County Convention Center‚ West Building
Abstract Time: 05:51 PM - 06:00 PM
Category: Transplantation
- 2002 Transplantation: Clinical
Authors
- McDaniels, Jennifer M., University of Maryland Baltimore, Baltimore, Maryland, United States
- Shetty, Amol C., University of Maryland Baltimore, Baltimore, Maryland, United States
- Rousselle, Thomas, University of Maryland Baltimore, Baltimore, Maryland, United States
- Leventhal, Joseph, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Ildstad, Suzanne, Talaris Therapeutics Inc, Louisville, Kentucky, United States
- Mas, Valeria R., University of Maryland Baltimore, Baltimore, Maryland, United States
Background
Long-term outcomes in living donor kidney transplant (LDKT) patients are suboptimal due to lifelong chronic immunosuppression complications. FREEDOM-1 is a randomized, controlled, open-label Phase 3 study of FCR001 in adult LDKT patients. The mechanisms underlying immune tolerance after HSCT are poorly understood. This study deciphered the immune landscape associated with tolerance at single cell resolution.
Methods
Peripheral blood mononuclear cells (PBMCs) from 4 LDKT patients (3 in the FCR001 group and 1 with standard of care (SOC) immunosuppression) were studied at 4 timepoints (T0-, T1-, T3-, and T6-month(s)). Cross-sectional and longitudinal evaluations were done. Analysis was done using CellRanger software and visualized with UMAP. DEGs (FDR≤0.05) identified enriched GO terms and pathways.
Results
Unsupervised PBMCs clustering (>100,000 cells) identified 17 unique cell clusters, including monocytes, natural killer (NK) and T cell subclusters (Fig 1A). At T6, FCR was characterized by decreased NK1, T helper, and T memory cells, while CD14+ monocytes, NK2, and T proliferating cell clusters were increased compared to SOC. A mixed immune cluster was increased in FCR (Fig 1B) and characterized by PD-L1 checkpoint and T cell receptor signaling pathways. There was a higher proportion of cells in S phase from FCR, indicating early alterations in transcriptional activity (Fig 1C). High heterogeneity in NK clusters was observed; NK1 was reduced in FCR (Fig 1D). DEGs showed that NK1 cells were less transcriptionally active in FCR at T6 (Fig 1E).
Conclusion
This study represents the first longitudinal evaluation of PBMCs from LDKT patients underlying mechanisms of tolerance at single cell resolution. Unique patterns of immune cell types, cell states, and transcriptional activity were identified with NK cell subclusters playing a critical role.
Funding
- Commercial Support –