New method to minimize immunosuppression after organ transplantation

A clinical strategy delivered non-myeloablative conditioning followed by a delayed hematopoietic stem cell graft depleted of naïve (CD45RA+) T cells and supplemented with CD34+ progenitors plus CD45RA− memory donor lymphocytes to induce transient mixed chimerism after solid organ transplantation. Two patients received this regimen under compassionate use: one received alemtuzumab and methylprednisolone with HSCT 88 days after a multivisceral and kidney transplant. The goal was to reduce long-term pharmacologic immunosuppression by removing highly alloreactive naïve T cells while providing memory T cells for infection control. Functional assays and molecular tracking were used to monitor immune reconstitution and alloreactivity.

Both recipients have remained on minimal immunosuppression with no rejection for more than five years. Mixed lymphocyte reactions performed 31 and 41 months post-transplant showed recipient hyporesponsiveness to donor and third-party cells but preserved anti-CMV responses. Deep TCRβ sequencing and clonotype frequency analysis identified donor-reactive T-cell clones present before HSCT and allowed longitudinal tracking afterward. The approach proved feasible and safe across heterogeneous clinical scenarios (different organs, donor sources, HLA compatibility) and motivated a phase I clinical trial (NCT06997471) to evaluate safety and tolerability of delayed naïve T-cell-depleted HSCT with memory T-lymphocyte infusion in solid organ recipients.