Harnessing Regulatory T Cells for Clinical Use in Transplantation: The End of the Beginning

Abstract

Owing to the adverse effects of immunosuppression and an inability to prevent chronic rejection, there is a pressing need for alternative strategies to control alloimmunity. In three decades, regulatory T cells (Tregs) have evolved from a hypothetical mediator of adoptively transferred tolerance to a well-defined population that can be expanded ex vivo and returned safely to patients in clinical trials. Herein, we review the historical developments that have permitted these advances and the current status of clinical trials examining Tregs as a cellular therapy in transplantation. We conclude by discussing the critical unanswered questions that face this field in the coming years.

Mesenchymal stem cells for kidney transplantation

“…This multifaceted approach to immunosuppression makes Tregs a promising therapy to facilitate long term graft survival. Recently there have been advances in the methods for Treg isolation and expansion, with large scale expansion from peripheral blood (PB), umbilical cord blood (UBC), and induced Tregs from naive peripheral blood precursors [23] . There have also been positive results from experimental animal models [24] .…”

“…Another concern is the source of the Tregs. Currently, the most appropriate source for therapy is unknown, with uncertainty focused on whether alloantigen or antibody mediated expansion is the safest and most effective method [23] . The stability of Tregs in vivo has also been found to be problematic with studies finding that Tregs can lose FoxP3 expression and develop an effector cell phenotype, becoming pathogenic [28] .…”

“…Currently the ONE study is examining the use of polyclonally expanded Tregs and alloantigen driven Tregs in kidney transplantation at doses of 1, 3, 6 and 10 × 10 6 Tregs/kg. As of writing this no results have been published [23] .…”

Preparation of Complexes between Ovalbumin Nanoparticles and Retinoic Acid for Efficient Induction of Tolerogenic Dendritic Cells

“…Several molecules such as anti-inflammatory cytokines (IL-10, TGF-β) and small molecules including immunosuppressing drugs and all-trans retinoic acid (ATRA) have been reported to induce tDCs. [11][12][13] Among these molecules, small molecules will be suitable to prepare formulation for co-administration with antigen proteins. Kishimoto's group reported that biodegradable poly(lactide-co-glycolide) nanoparticles containing antigens and immunosuppressing drug (rapamycin) effectively induce antigen-specific immunotolerance.…”

The future direction and unmet needs of transplant immunosuppression

“…This has spurred the concept of ex vivo expansion of regulator T cells whose subsequent administration might lead to organ tolerance. There are ongoing clinical trials utilizing the infusion of ex vivo generated regulator T cells in renal transplantation with eagerly anticipated results [30]. Improving the consistency and safety of 'tolerogenic' protocols with the expansion to deceased donor transplantation is among the next crucial step to its wider application.…”