Adoptive Cell Therapy with Tregs to Improve Transplant Outcomes: The Promise and the Stumbling Blocks

Abstract

The contribution of regulatory T cells (Treg) to the induction and maintenance of tolerance is well-recognized in rodents and may contribute to long-term human organ allograft survival. The therapeutic efficacy of adoptively-transferred Treg in promoting tolerance to organ allografts is well-recognized in mouse models. Early phase 1/2 clinical studies of Treg therapy have been conducted in patients with type-1 (autoimmune) diabetes and refractory Crohn's disease, and for inhibition of graft-versus-host disease following bone marrow transplantation with proven safety. The feasibility of adoptive Treg therapy in the clinic is subject to various parameters, including optimal cell source, isolation procedure, expansion, target dose, time of infusion, as well as generation of a GMP-cell product. Several phase 1/2 Treg dose-escalation studies are underway in organ transplantation. Recent evidence suggests that additional factors are critical to ensure Treg safety and efficacy in allograft recipients, including Treg characterization, stability, longevity, trafficking, concomitant immunosuppression, and donor antigen specificity. Accordingly, Treg therapy in the context of organ transplantation may prove more challenging in comparison to other prospective clinical settings of Treg immunotherapy, such as type-1 diabetes.

Keywords: cell therapy; regulatory T cells; transplantation.

Figure 1. Percentages of CD8⁺ effector memory T cells in peripheral blood of lymphodepleted heart allograft recipient cynomologus monkeys without or with multiple Treg infusions

Heart allograft recipient monkeys received immunosuppression in the form of lymphodepletion with ATG and maintenance with Tacrolimus, rapamycin and IL-6 receptor antagonist, as described [91]. In two recipients, multiple infusions of autologous polyclonal ex vivo expanded Treg were given between days 3 and 31 post-transplant (solid lines). Tmem subsets were identified in peripheral blood based on their differential expression of CD45RA and CD62L. Effector memory (Tem; CD45RA⁻CD62L⁺) CD8⁺ T cells were evaluated sequentially in heart allograft recipients before (Pre-Tx), then 2, 4, 8 and 12 weeks post-transplant. In the control group (with no Treg infusion), percentages of CD8⁺Tem were either modestly increased or remained comparable to baseline. However, CD8⁺Tem were markedly increased above baseline levels at 2 and 4 weeks in the two recipients given multiple Treg infusions.