Donor bone marrow together with recipient regulatory T cells induces chimerism without irradiation in kidney transplantation.

Cotransplantation of donor bone marrow (BM) has yielded a therapeutic benefit in clinical trials of kidney transplantation by inducing chimerism-based tolerance, but this was dependent on unfavorable recipient irradiation. Additional regulatory T (Treg) cell administration can overcome the need for myelosuppression, but this has been demonstrated only in mice so far. Here, we conducted a controlled, phase 1/2a trial of combined BM and Treg cell therapy in HLA-mismatched living-donor kidney transplantation (NCT03867617). Six patients received polyclonal recipient Treg cells and donor BM cells (BMCs) immediately posttransplant. Immunosuppression consisted of thymoglobulin, belatacept, sirolimus, steroids, and short-course tocilizumab. The control group received no Treg cells, BMCs, or tocilizumab. Total leukocyte donor chimerism was detected across all patients in the study group posttransplantation. This was not observed in any patient belonging to the control group, consequently meeting the primary end point of higher chimerism levels in the study versus control groups (P = 0.001). Chimerism was observed across multiple lineages, with up to 4% in T cells. For three patients in the study group, immunosuppression could be minimized to belatacept monotherapy. Antidonor reactivity was decreased in in vitro T cell proliferation assays, suggesting specific downmodulation of the antidonor T cell response. In addition, expansion of antidonor T cell clones was shown by T cell receptor sequencing analysis to be dampened in the study versus control groups. This trial serves as a proof of concept for a combination cell therapy that induces chimerism-based immunomodulation in kidney transplantation without the need for irradiation.