Transplanting Kidney Donor Bone Marrow, Tregs Results in Chimerism

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https://www.renalandurologynews.com/reports/transplanting-kidney-donor-bone-marrow-chimerism-treatment-risk/

Transplanting Kidney Donor Bone Marrow, Tregs Results in Chimerism
Jessica Nye June 27, 2025

Inducing temporary chimerism by transplanting donor Tregs and bone marrow after kidney transplantation was successful in a phase 1 and 2a trial. The hope is that it will reduce the risk for graft loss.

A first-in-human, proof-of-concept trial finds that combined bone marrow and regulatory T-cell (Treg) transplantation is safe and feasible and induces low-level temporary chimerism after living donor kidney transplantation. Rainer Oberbauer, MD, PhD, of the Medical University of Vienna, presented the findings at the 62nd European Renal Association (ERA) congress in Vienna, Austria.
Inducing chimerism-based tolerance via cotransplantation of hematopoietic stem cells shortly after kidney transplantation has the potential to decrease graft loss.
In 2021, Dr Oberbauer published the proposal for this phase 1/2a trial (NCT03867617) in Frontiers in Medicine that tested the safety and efficacy of induced chimerism among kidney transplant recipients. The prospective, open-label, controlled, single-center trial recruited patients (N=12) undergoing major histocompatibility complex (HLA)-mismatched living donor kidney transplantation at Vienna General Hospital.
In the intervention group (n=6), living donors gave both a kidney and bone marrow tissues via leukapheresis. The bone marrow samples were used for in vitro expansion of CD45RA+CD4+CD25highCD127low/neg Tregs and bone marrow cells. The transplant recipients underwent kidney transplantation and received Treg (range, 1.0-1.5×107 cells/kg) and bone marrow (range, 0.7-1.9×108 nucleated cells/kg) infusion within 3 days of kidney transplantation. In addition, the patients received 4 subcutaneous injections of 162 mg tocilizumab on days 0, 5, 15, and 21 and immunosuppression with 6 mg/kg intravenous (IV) thymoglobulin 2 weeks prior to transplant; 10 mg/kg IV belatacept on days 0, 4, 13, and 27 and weeks 8 and 12, followed by 5 mg/kg every 4 weeks; sirolimus dosed to maintain trough levels at 7 to 12 ng/mL; and corticosteroids. At 6 months, sirolimus and corticosteroids were withdrawn gradually among stable patients.
The control group (n=6) received kidney transplantation and the same immunosuppression intervention, with the exception that thymoglobulin was administered at the time of transplantation.
The coprimary outcomes were leukocyte donor chimerism and safety.
All study participants were men aged 25 to 63 years. The patients received kidney transplantation between 2019 and 2023.
After a Treg culture lasting between 14 and 21 days, patients in the intervention group received Treg infusions with doses ranging between 74.2×107 and 150.7×107 cells/kg and bone marrow infusions with doses ranging between 59.2×108 and 196.9×108 nucleated cells/kg. No infusion-related safety signals were observed.
All infusion recipients developed total leukocyte donor chimerism at a level of less than 1% (P =.001). No chimerism was observed among the control group.
A transcriptomics analysis found no humoral activity in the intervention group. A sequencing analysis indicated that infusion recipients had undergone significantly more clonal deletion of donor-specific T-cells at 1 (P =.035) and 3 (P =.047) months but only tended to have sustained lower levels at 6 months (P =.054). The T-cell proliferation assay identified a downregulation of anti-donor responses of CD4 (P =.032) and CD8 (P =.016) T cells at 12 months in the intervention cohort compared with the control group.
At a median follow-up of 32 months, patients in the intervention group had glomerular filtration rates (GFRs) ranging from 33 to 99 mL/min/1.72 m2, which did not differ from the control group (P =.42).
To date, withdrawal of sirolimus and corticosteroids has been successfully achieved among half of the intervention cohort, and they are currently receiving belatacept maintenance monotherapy. Two patients remain on dual therapy immunosuppression.
No graft versus host disease occurred, and only 1 patient developed de novo donor-specific antibodies with no clinical effects.
Dr Oberbauer concluded, "Combined Treg therapy and bone marrow transplantation is safe and feasible in living donor kidney transplantation and induces low-level chimerism which is sufficient to cause clonal deletion of donor-specific T-cells. These data provide insight into the immunomodulatory effect of combination cell therapy, which allowed for a safe minimization of immunosuppression."