Pharmacokinetics, lineage identity, and trafficking of ex vivo expanded polyclonal regulatory T cells in a prospective randomized clinical trial of kidney transplant recipients with allograft inflammation

Regulatory T cells (Tregs) can reverse inflammation in animal models. We conducted a randomized controlled clinical trial of Treg therapy in kidney transplant recipients with subclinical graft inflammation (NCT02711826). The primary endpoint was the change in graft inflammation on a follow-up biopsy 6 months after Treg infusion. The trial accrued 8 control group participants and 7 polyclonal Treg group participants; the latter received 400 × 10 6 to 1 × 10 9 polyclonally expanded Tregs without adverse events. Graft inflammation decreased substantially in both groups at 6 months; however, the degree of change was not significantly different between the groups. The peak of infused Tregs in circulation correlated positively with the pre-existing circulating CD4 + T cell numbers, suggesting that Treg engraftment was limited by the size of the endogenous CD4 + T cell compartment. Infused Tregs were detected in 14-day postinfusion biopsies, albeit at lower frequencies than in circulation. Unlike prior experiences, some infused Tregs emerged among non-Treg CD4 + T cells in 4 participants; these patients had higher concentrations of serum cytokines, indicative of more systemic inflammation. The study failed to show the efficacy of polyclonal Tregs due to self-resolving graft inflammation but identified the importance of monitoring Treg product identity and their stability and trafficking after infusion.