Past, Present, and Future of Regulatory T Cell Therapy in Transplantation and Autoimmunity

Abstract

Regulatory T cells (Tregs) are important for the induction and maintenance of peripheral tolerance therefore, they are key in preventing excessive immune responses and autoimmunity. In the last decades, several reports have been focussed on understanding the biology of Tregs and their mechanisms of action. Preclinical studies have demonstrated the ability of Tregs to delay/prevent graft rejection and to control autoimmune responses following adoptive transfer in vivo. Due to these promising results, Tregs have been extensively studied as a potential new tool for the prevention of graft rejection and/or the treatment of autoimmune diseases. Currently, solid organ transplantation remains the treatment of choice for end-stage organ failure. However, chronic rejection and the ensuing side effects of immunosuppressants represent the main limiting factors for organ acceptance and patient survival. Autoimmune disorders are chronic diseases caused by the breakdown of tolerance against self-antigens. This is triggered either by a numerical or functional Treg defect, or by the resistance of effector T cells to suppression. In this scenario, patients receiving high doses of immunosuppressant are left susceptible to life-threatening opportunistic infections and have increased risk of malignancies. In the last 10 years, a few phase I clinical trials aiming to investigate safety and feasibility of Treg-based therapy have been completed and published, whilst an increasing numbers of trials are still ongoing. The first results showed safety and feasibility of Treg therapy and phase II clinical trials are already enrolling. In this review, we describe our understanding of Tregs focussing primarily on their ontogenesis, mechanisms of action and methods used in the clinic for isolation and expansion. Furthermore, we will describe the ongoing studies and the results from the first clinical trials with Tregs in the setting of solid organ transplantation and autoimmune disorders. Finally, we will discuss strategies to further improve the success of Treg therapy.

Applicability, safety, and biological activity of regulatory T cell therapy in liver transplantation

“…Animal studies indicate that Tregs play a key role in maintaining immune homeostasis and preventing autoimmunity . Furthermore, they can recognize allogeneic major histocompatibility complex (MHC) molecules and suppress allograft rejection, and are essential for the induction and maintenance of transplantation tolerance through the mechanisms of “linked suppression” and “infectious tolerance.”…”

“…1 Furthermore, they can recognize allogeneic major histocompatibility complex (MHC) molecules and suppress allograft rejection, and are essential for the induction and maintenance of transplantation tolerance through the mechanisms of "linked suppression" and "infectious tolerance." 2 Although human Tregs constitute a small proportion (5%-7%) of circulating CD4 + T cells, they are attractive candidates for immunotherapeutic purposes given that they can be isolated and expanded in large numbers in vitro without losing their immunoregulatory properties. 3 Clinical studies have demonstrated the safety of Treg adoptive transfer in graft-versus-host disease and type 1 diabetes mellitus.…”

Autoimmunity in Acute Myocarditis: How Immunopathogenesis Steers New Directions for Diagnosis and Treatment

“…Regulatory T cells (CD25 + FoxP3+) have been at the forefront of new therapeutic strategies of adoptive cell transfer for a variety of autoimmune diseases [71]. Retrospective studies in patients with myocarditis with progression to DCM have shown that they shared a decreased Treg population while their Th17 population was concomitantly increased [72].…”

Encapsulation of Human Natural and Induced Regulatory T‐Cells in IL‐2 and CCL1 Supplemented Alginate‐GelMA Hydrogel for 3D Bioprinting

“…[ 12 ] With such versatility in modes and targets of action, immunotherapies utilizing Tregs have been extensively investigated for the treatment of autoimmunity and allogeneic transplantation. [ 13 ]…”

“…[ 16 ] While this method has shown promising results in clinical trials, [ 17,18 ] ex vivo expansion of Tregs requires extremely time‐consuming and costly protocols to generate appropriate numbers of cells for clinically significant results, due to the low frequency of Tregs in human peripheral blood. [ 13,19 ] Thus, it would be advantageous to employ more targeted approaches requiring less Tregs, such as hydrogel encapsulation to provide localized immunosuppression.…”