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Regulatory T cell kinetics following adoptive transfer of expanded allogeneic regulatory T cells into patients with chronic graft-versus host disease

      T regulatory cell (Treg) therapy has been exploited in autoimmune disease, solid organ transplantation and to prevent or treat graft-versus-host disease (GvHD). The first clinical trials could prove safety and indicate a clinical benefit in several cases. Knowledge on in vivo persistence of transfused Treg is limited. Whether Treg transfusion leads to notable changes in the overall Treg repertoire and whether longevity of Treg in the periphery is restricted to certain clones is unknown.We successfully developed a protocol for the efficient isolation and in vitro expansion of stem cell donor-derived Treg and applied Treg preparations at 2–6 × 106 Treg/kg in nine patients with otherwise treatment-refractory chronic GvHD (cGvHD) within a compassionate use program. We explored whether high-throughput T cell receptor alpha chain sequencing (TCRα-NGS) can serve as a tool to monitor clonal changes in the repertoire of Treg upon polyclonal expansion and after subsequent adoptive transfer. We applied TCRα-NGS in two cGvHD patients infused with comparable doses of stem cell donor derived expanded Treg. Patient 1 showed a transient clinical response accompanied with remarkable enumerations of peripheral Treg upon Treg cell therapy, whereas Patient 2 reported with stable disease and showed no incidence of elevated Treg levels post cell therapy by flow cytometry. Using TCRα-NGS we found that polyclonal expansion can lead to notable repertoire changes in vitro and that Treg cell therapy considerably alters the peripheral Treg repertoire to different degrees. Some of the transferred Treg clones appeared to reside longer in the periphery than others. Overall clonal changes were of transient nature and correlated well with the clinical parameters. We anticipate our study to be a starting point for detailed Treg clonotype analyses in future clinical studies that would help us to relate longevity and specificity of adoptively transferred Treg to clinical outcome and ultimately lead to optimized Treg cell therapy.
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