Abstract: SA-OR48
A Regimen of Nonmyeloablative Conditioning and CD8+/TCR- Facilitating Cells Tips the Balance Towards Immune Downregulation and Away From Cytopathic Activity in Kidney Allograft Recipients
Session Information
- Transplantation: Clinical Outcomes and Biomarkers
November 05, 2022 | Location: W240, Orange County Convention Center‚ West Building
Abstract Time: 05:33 PM - 05:42 PM
Category: Transplantation
- 2002 Transplantation: Clinical
Authors
- Lee, John Richard, Weill Cornell Medicine, New York, New York, United States
- Leventhal, Joseph, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
- Li, Carol Y., Weill Cornell Medicine, New York, New York, United States
- Ildstad, Suzanne, Talaris Therapeutics, Inc., Louisville, Kentucky, United States
- Suthanthiran, Manikkam, Weill Cornell Medicine, New York, New York, United States
Background
We tested the hypothesis that tolerance induced with a regimen of nonmyeloablative conditioning and CD8+/TCR- facilitating cells (FCR001) is associated with immune down regulation and away from cytopathic activity.
Methods
Blinded to clinical status and biopsy diagnosis, the Laboratory quantified urinary cell mRNA levels in 28 urines from 14 FCR001-tolerant patients with durable chimerism and off immunosuppression per protocol(FCR DC off IS); 23 urines from 12 FCR001-tolerant patients with DC and on immunosuppression per protocol(FCR DC on IS); 43 biopsy-matched urines from 34 kidney allograft recipients from the Clinical Trials in Organ Transplantation-04(CTOT-04) study and TCMR biopsies (TCMR Cohort); and 161 biopsy-matched urines from 124 recipients from CTOT-04 study with No Rejection biopsies (NR Cohort).
Results
In accord with negative immune regulation in tolerant patients, urinary cell mRNA levels of CTLA-4 were significantly higher in the FCR DC off or on IS than the TCMR cohort or the NR Cohort (P <0.05, Wilcoxon rank sum test, Table 1). In accord with lack of cytopathic activity in tolerant patients, levels of Granzyme B and Perforin were significantly lower or no different in the FCR DC off or on IS compared to the NR cohort (Table 1). Levels of additional mRNAs in the FCR DC on or off IS were significantly lower than the TCMR Cohort and mostly similar to that in the NR Cohort (Table 1).
Conclusion
Tolerance induced with a nonmyeloablative conditioning regimen and CD8+/TCR- facilitating cells is characterized by tipping of the balance towards immune down regulation and away from cytopathic activity.
Table 1
| Gene | FCR Durable off IS Median Copies | FCR Durable on IS Median Copies | No Rejection Group Median Copies | TCMR Group Median Copies | FCR Durable off IS vs. No Rejection P Value | FCR Durable off IS vs. TCMR P value | FCR Durable on IS vs. No Rejection P value | FCR Durable on IS vs. TCMR P value | TCMR vs. No Rejection P Value |
| CTLA4 | 439 | 575 | 13 | 135 | 6 x 10^-15 | 0.005 | 4 x 10^-14 | 4 x10^-4 | 2 x 10^-12 |
| CD3 | 1239 | 1782 | 360 | 8826 | 0.06 | 5 x 10^-5 | 0.002 | 0.006 | 7 x 10^-11 |
| Granzyme B | 106 | 207 | 337 | 3304 | 0.008 | 3 x10^-9 | 0.47 | 4 x10^-6 | 8 x10^-10 |
| Perforin | 92 | 277 | 223 | 4119 | 0.25 | 2 x 10^-8 | 0.48 | 1 x 10^-5 | 9 x 10^-11 |
| IP10 | 153 | 266 | 75 | 1445 | 0.17 | 1 x 10^-5 | 0.03 | 0.002 | 1 x 10^-10 |
| FoxP3 | 13 | 13 | 13 | 73 | 0.33 | 0.007 | 0.20 | 0.03 | 2 x 10^-5 |
| TGFb1 | 2182 | 3045 | 4589 | 15142 | 0.01 | 1 x 10^-7 | 0.68 | 2 x 10^-4 | 1 x 10^-5 |
| 18S rRNA | 4 x 10^8 | 6 x 10^8 | 7 x 10^8 | 2 x 10^9 | 0.08 | 1 x10 ^-5 | 0.41 | 0.003 | 6 x 10^-5 |
| CTLA4/Granzyme B Ratio | 5.62 | 1.36 | 0.04 | 0.03 | 7 x 10^-15 | 6 x10^-16 | 3 x10^-12 | 3 x10^-10 | 0.61 |