Regulatory T cell therapy is associated with distinct immune regulatory lymphocytic infiltrates in kidney transplants

Oliver McCallion; Amy R Cross; Matthew O Brook; Conor Hennessy; Ricardo Ferreira; Dominik Trzupek; William R Mulley; Sandeep Kumar; Maria Soares; Ian S Roberts; Peter J Friend; Giovanna Lombardi; Kathryn J Wood; Paul N Harden; Joanna Hester; Fadi Issa

doi:10.1016/j.medj.2024.11.014

Regulatory T cell therapy is associated with distinct immune regulatory lymphocytic infiltrates in kidney transplants

Med. 2024 Dec 20:S2666-6340(24)00455-0. doi: 10.1016/j.medj.2024.11.014. Online ahead of print.

Authors

Affiliations

¹ Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, UK.
² Department of Renal Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 7LH, UK.
³ Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford OX3 7BN, UK.
⁴ Department of Nephrology, Monash Medical Centre & Department of Medicine, Monash University, Clayton, VIC 3168, Australia.
⁵ Advanced Therapy Manufacturing (GMP) Unit, Guy's & St Thomas' NHS Foundation Trust and King's College London, London SE1 9RT, UK.
⁶ Department of Cellular Pathology, Oxford University Hospitals NHS Foundation Trust, Oxford OX3 9DU, UK.
⁷ MRC Centre for Transplantation, King's College London, London SE1 9RT, UK.
⁸ Nuffield Department of Surgical Sciences, University of Oxford, Oxford OX3 9DU, UK. Electronic address: fadi.issa@nds.ox.ac.uk.

PMID: 39731908
DOI: 10.1016/j.medj.2024.11.014

Abstract

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 7^th EU Framework Programme, grant/award no. 260687, and the National Institute for Health Research (NIHR).

Keywords: Translation to patients; cellular therapy; immune infiltrates; immunosuppression minimization; kidney transplantation; regulatory T cells; spatial profiling.

Associated data

ClinicalTrials.gov/NCT02129881