Preformed T cell alloimmunity and HLA eplet mismatch to guide immunosuppression minimization with tacrolimus monotherapy in kidney transplantation: Results of the CELLIMIN trial

Personalizing immunosuppression is a major objective in transplantation. Transplant recipients are heterogeneous regarding their immunological memory and primary alloimmune susceptibility. This biomarker-guided trial investigated whether in low immunological-risk kidney transplants without pretransplant DSA and donor-specific T cells assessed by a standardized IFN-γ ELISPOT, low immunosuppression (LI) with tacrolimus monotherapy would be non-inferior regarding 6-month BPAR than tacrolimus-based standard of care (SOC). Due to low recruitment rates, the trial was terminated when 167 patients were enrolled. ELISPOT negatives (E–) were randomized to LI (n= 48) or SOC (n= 53), E+ received the same SOC. Six- and 12-month BPAR rates were higher among LI than SOC/E– (4/35 [13%] vs. 1/43 [2%], p= .15 and 12/48 [25%] vs. 6/53 [11.3%], p= .073, respectively). E+ patients showed similarly high BPAR rates than LI at 6 and 12 months (12/55 [22%] and 13/66 [20%], respectively). These differences were stronger in per-protocolanalyses. Post-hoc analysis revealed that poor class-II eplet matching, especially DQ, discriminated E– patients, notably E–/LI, developing BPAR (4/28 [14%] low risk vs. 8/20 [40%] high risk, p= .043). Eplet mismatch also predicted anti-class-I (p= .05) and anti-DQ (p< .001) de novoDSA. Adverse events were similar, but E–/LI developed fewer viral infections, particularly polyoma-virus-associated nephropathy (p= .021). Preformed T cell alloreactivity and HLA eplet mismatch assessment may refine current baseline immune-risk stratification and guide immunosuppression decision-making in kidney transplantation.