Durable chimerism is currently the most reliable biomarker of donor specific tolerance. Identifying and validating other predictive biomarkers is therefore a high priority. Since 2009 we have conducted a Phase 2 tolerance induction trial of combined stem cell/living donor kidney transplantation (KTx) in mismatched and unrelated subjects to establish donor macrochimerism. Our protocol is based upon tolerogenic CD8+/TCR-facilitating cells (FCRx) and nonmyeloablative conditioning. Recipients are conditioned with fludarabine (30mg/m2/dose, days -5,-4,-3), cyclophosphamide (50mg/kg/dose, day-3 and+3), 200 cGy TBI (day-1) followed by a KTx (day0) and FCRx infusion (day +1), and maintained on tacrolimus and MMF. Those with high levels of chimerism are weaned completely from IS by 12 months. Twenty-six chimeric patients have been removed from IS (1-86 months). Six transiently donor chimeric (TDC) patients are maintained on tacrolimus monotherapy. The primary objective of this study is to determine biomarkers predictive of chimerism and tolerance. mRNA from PBMC from 9 stable donor chimeric (SDC) patients and 4 TDC patients at pre-transplant, 9 months, and 18 months post-transplant were analyzed by microarray. Select immunomodulatory markers were then analyzed by qPCR and flow cytometry. The microarray revealed 681 and 129 differentially expressed genes after transplant in SDC patients and TCD patients, respectively, indicating that SDC patients had more profound and lasting biological changes. We found 311 genes differentially expressed before transplant between the two groups. PD-L1 was one of the most differentially expressed genes before transplant in patients who became durably chimeric vs. ones that were only transiently chimeric (1.33 fold change; P<0.001). The PD-L1/CD86 ratio gives an integrated snapshot of the strength of regulatory events relative to inflammatory events and has been used to predict outcomes in liver transplant. qPCR analysis showed that SDC patients experienced a 13.2 fold increase in PD-L1 expression after transplant while TDC patients experienced only a 0.9 fold increase. The PD-L1/CD86 ratio became higher overall in SDC patients. In addition, SDC patients showed an increase in PD-L1/CD86 ratio 18 months after transplant while TCD chimeric patients showed no change. In conclusion, the PD-L1/CD86 ratio might serve as a biomarker to predict success in clinical FCRx tolerance trials.

CITATION INFORMATION: Merchak A., Khalil A., Chhabra A., Leventhal J., Ildstad S. PD-L1 May Serve as a Biomarker for Chimerism-Induced Tolerance in Kidney Transplant Recipients Am J Transplant. 2017;17 (suppl 3).

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