EBioMedicine · 2024
Combination cell therapy leads to clonal deletion of donor-specific T cells in kidney transplant recipients.
СтатьяКлиническое исследование II фазыКлиническое исследование I фазыНазвание и аннотация: Перевод в очереди
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David Ana F, Heinzel Andreas, Kammer Michael, Aschauer Constantin, Reindl-Schwaighofer Roman, Hu Karin, Chen Hao-Shan, Muckenhuber Moritz, Kubetz Anna, Weijler Anna Marianne, Worel Nina, Edinger Matthias, Berlakovich Gabriela, Lion Thomas, Sykes Megan, Wekerle Thomas, Oberbauer Rainer
Аннотация
BACKGROUND: Induction of donor-specific tolerance is a promising approach to achieve long-term graft patency in transplantation with little to no maintenance immunosuppression. Changes to the recipient's T cell receptor (TCR) repertoire are understood to play a pivotal role in the establishment of a robust state of tolerance in chimerism-based transplantation protocols.
METHODS: We investigated changes to the TCR repertoires of patients participating in an ongoing prospective, controlled, phase I/IIa trial designed to evaluate the safety and efficacy of combination cell therapy in living donor kidney transplantation. Using high-throughput sequencing, we characterized the repertoires of six kidney recipients who also received bone marrow from the same donor (CKBMT), together with an infusion of polyclonal autologous Treg cells instead of myelosuppression.
FINDINGS: Patients undergoing combination cell therapy exhibited partial clonal deletion of donor-reactive CD4+ T cells at one, three, and six months post-transplant, compared to control patients receiving the same immunosuppression regimen but no cell therapy (p = 0.024). The clonality, R20 and turnover rates of the CD4+ and CD8+ TCR repertoires were comparable in both groups, showing our protocol caused no excessive repertoire shift or loss of diversity. Treg clonality was lower in the case group than in control (p = 0.033), suggesting combination cell therapy helps to preserve Treg diversity.
INTERPRETATION: Overall, our data indicate that combining Treg cell therapy with CKBMT dampens the alloimmune response to transplanted kidneys in humans in the absence of myelosuppression.
FUNDING: This study was funded by the Vienna Science and Technology Fund (WWTF).
METHODS: We investigated changes to the TCR repertoires of patients participating in an ongoing prospective, controlled, phase I/IIa trial designed to evaluate the safety and efficacy of combination cell therapy in living donor kidney transplantation. Using high-throughput sequencing, we characterized the repertoires of six kidney recipients who also received bone marrow from the same donor (CKBMT), together with an infusion of polyclonal autologous Treg cells instead of myelosuppression.
FINDINGS: Patients undergoing combination cell therapy exhibited partial clonal deletion of donor-reactive CD4+ T cells at one, three, and six months post-transplant, compared to control patients receiving the same immunosuppression regimen but no cell therapy (p = 0.024). The clonality, R20 and turnover rates of the CD4+ and CD8+ TCR repertoires were comparable in both groups, showing our protocol caused no excessive repertoire shift or loss of diversity. Treg clonality was lower in the case group than in control (p = 0.033), suggesting combination cell therapy helps to preserve Treg diversity.
INTERPRETATION: Overall, our data indicate that combining Treg cell therapy with CKBMT dampens the alloimmune response to transplanted kidneys in humans in the absence of myelosuppression.
FUNDING: This study was funded by the Vienna Science and Technology Fund (WWTF).