Regulatory T-Cell Therapy in Transplantation: Moving to the Clinic

Abstract

Regulatory T cells (Tregs) are essential to transplantation tolerance and their therapeutic efficacy is well documented in animal models. Moreover, human Tregs can be identified, isolated, and expanded in short-term ex vivo cultures so that a therapeutic product can be manufactured at relevant doses. Treg therapy is being planned at multiple transplant centers around the world. In this article, we review topics critical to effective implementation of Treg therapy in transplantation. We will address issues such as Treg dose, antigen specificity, and adjunct therapies required for transplant tolerance induction. We will summarize technical advances in Treg manufacturing and provide guidelines for identity and purity assurance of Treg products. Clinical trial designs and Treg manufacturing plans that incorporate the most up-to-date scientific understanding in Treg biology will be essential for harnessing the tolerogenic potential of Treg therapy in transplantation.

Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner

“…Although it has been reported that Tregs could be used as novel immune suppressants in various settings, including transplantation, iTregs have never been considered as a source of Tregs for therapeutic purposes because of the issues related to CNS2 demethylation and Foxp3 stability (66). Because vitamin C-treated iTregs have demethylated CNS2 and express Foxp3 stably, we checked the immune suppressive potential of vitamin C-treated iTregs by using the allogeneic skin graft model.…”

T cells in the control of organ-specific autoimmunity

“…The favorable therapeutic profile of Tregs has led to strong interest in Treg-based cellular therapy in transplantation and autoimmune diseases (182). Adoptive transfer of Tregs suppressed inflammation and disease in EAE, NOD mice, and mouse models of IBD and SLE (59, 60, 183-185).…”

Constitutive Activation of MEK1 Promotes Treg Cell Instability in Vivo

“…Foxp3 ϩ regulatory T (Treg) 2 cells play central roles in maintaining immune homeostasis and self-tolerance, which is essential for the control of pathogenic T cell responses (2,3). Recently, Treg cells have demonstrated promising potential in clinical therapy for autoimmune diseases (4,5).…”