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.
Highlights
Since the discovery in 1969 of the suppressor T cells [1], the regulatory T cells (Tregs) research field has undergone an incredible boom over the years
From the mouse counterpart, the sole expression of CD25 and the transcriptional regulator forkhead box P3 (FOXP3) [5] is not sufficient for characterizing human Tregs, since effector T cells can upregulate these markers after activation
We have shown how HLAA2 (MHC class I protein) specific chimeric antigen receptors (CARs) Treg have the capacity to prevent skin-graft rejection in a mouse model compared with polyclonally expanded Tregs [124]
Summary
Since the discovery in 1969 of the suppressor T cells [1], the regulatory T cells (Tregs) research field has undergone an incredible boom over the years. This study showed a feasible and safe therapeutic approach to T1D, with stably suppressive Tregs, the small number of treated patients as well as the early phase of the trial could not help to shed light on the optimal dose and the impact of Tregs on the function of islet cells To address these points, a multicentre phase II randomized, placebo-controlled double blind clinical trial (NCT02691247) is underway, with the purpose to evaluate, in young patients, safety and effect on beta cell function of a single dose (low 2.5 × 106/kg vs high 20 × 106/kg compared to placebo) of autologous ex-vivo expanded polyclonal Tregs. The infused cell product was contaminated with antigen specific effector cells, the authors presented this pilot study as a novel strategy for tolerance induction in patients undergoing liver transplantation for non-immunological diseases To confirm this hypothesis, investigations are currently underway in a large group of patients excluding those ones with autoimmune disorders.
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