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BACKGROUND: Adoptive transfer of autologous regulatory T cells (Tregs) is a promising therapeutic strategy aimed at enabling immunosuppression minimization following kidney transplantation. In our phase 1 clinical trial of Treg therapy in living donor renal transplantation, the ONE Study (ClinicalTrials.gov: NCT02129881), we observed focal lymphocytic infiltrates in protocol kidney transplant biopsies that are not regularly seen in biopsies of patients receiving standard immunosuppression. METHODS: We present 7 years of follow-up data on patients treated with adoptive Treg therapy early post-transplantation who exhibited focal lymphocytic infiltrates on a 9-month protocol biopsy. We phenotyped their adoptively transferred and peripherally circulating Treg compartments using CITE-seq and investigated the focal lymphocytic infiltrates with spatial proteomic and transcriptomic technologies. FINDINGS: Graft survival rates were not significantly different between Treg-treated patients and the control reference group. None of the Treg-treated patients experienced clinical rejection episodes or developed de novo donor-specific antibodies, and three of ten successfully reduced their immunosuppression to tacrolimus monotherapy. All Treg-treated patients who underwent a protocol biopsy 9 months post-transplantation exhibited focal lymphocytic infiltrates. Spatial profiling analysis revealed prominent CD20+ B cell and regulatory (IKZF2, IL10, PD-L1, TIGIT) signatures within cell-therapy-associated immune infiltrates, distinct from the pro-inflammatory myeloid signature associated with rejection biopsies. CONCLUSIONS: We demonstrate for the first time that immune cell infiltrates in transplanted kidneys can occur following adoptive Treg therapy in humans, potentially facilitating within-graft T:B cell interactions that promote local immune regulation. FUNDING: This work was funded by the 7th EU Framework Programme, grant/award no. 260687, and the National Institute for Health Research (NIHR).

Original publication

DOI

10.1016/j.medj.2024.11.014

Type

Journal article

Journal

Med

Publication Date

20/12/2024

Keywords

Translation to patients, cellular therapy, immune infiltrates, immunosuppression minimization, kidney transplantation, regulatory T cells, spatial profiling