Regulatory T Cells: Serious Contenders in the Promise for Immunological Tolerance in Transplantation

Abstract

Regulatory T cells (Tregs) play an important role in immunoregulation and have been shown in animal models to promote transplantation tolerance and curb autoimmunity following their adoptive transfer. The safety and potential therapeutic efficacy of these cells has already been reported in Phase I trials of bone-marrow transplantation and type I diabetes, the success of which has motivated the broadened application of these cells in solid-organ transplantation. Despite major advances in the clinical translation of these cells, there are still key questions to be addressed to ensure that Tregs attest their reputation as ideal candidates for tolerance induction. In this review, we will discuss the unique traits of Tregs that have attracted such fame in the arena of tolerance induction. We will outline the protocols used for their ex vivo expansion and discuss the future directions of Treg cell therapy. In this regard, we will review the concept of Treg heterogeneity, the desire to isolate and expand a functionally superior Treg population and report on the effect of differing culture conditions. The relevance of Treg migratory capacity will also be discussed together with methods of in vivo visualization of the infused cells. Moreover, we will highlight key advances in the identification and expansion of antigen-specific Tregs and discuss their significance for cell therapy application. We will also summarize the clinical parameters that are of importance, alongside cell manufacture, from the choice of immunosuppression regimens to the number of injections in order to direct the success of future efficacy trials of Treg cell therapy. Years of research in the field of tolerance have seen an accumulation of knowledge and expertise in the field of Treg biology. This perpetual progression has been the driving force behind the many successes to date and has put us now within touching distance of our ultimate success, immunological tolerance.

Antigen-specificity using chimeric antigen receptors: the future of regulatory T-cell therapy?

“…Unlike drug-based immunosuppressive regimens which have detrimental effects on the patient's wellbeing [25] and do not offer a complete treatment option [14,23], Treg therapy has the potential to be a highly personalized technique which allows for the manipulation of a patient's immune system in order to promote immunological tolerance. The essence of what Treg therapy entails can be split into three key steps: cell isolation, ex vivo expansion and subsequent re-infusion of Tregs ( Figure 1A).…”

“…Although not as well characterized as tTregs, pTregs have been implicated with the induction and maintenance of tolerance in vivo, mostly through the secretion of immunosuppressive cytokines. It is believed that at least two types of pTregs exist, namely Type-I regulatory T-cells (Tr1) and T helper 3 cells (Th3) which secrete high levels of IL-10 and transforming growth factor (TGF)-β, respectively [23]. A feature of particular interest is the fact that pTregs may be generated from naïve T-cells in vitro, a phenomenon which has been applied to generate Tr1 cells for clinical application in Crohn's disease [24] (detailed below).…”

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“…35 The general consensus throughout these studies concluded that donor antigen-specific regulatory T cells are more effective compared with polyclonal regulatory T cells. 36 In a pilot study, 37 tolerance was induced by using a novel regulatory T-cell-based cell therapy in livingdonor liver transplant. Adoptive transfer of an ex vivo-generated regulatory T-cell-enriched cell product was conducted in 10 consecutive adult patients early after liver transplant.…”

IL-33 improves the suppressive capacity of human regulatory T cells

“…The most reported protocols include anti-CD3/anti-CD28-coated beads for T cell stimulation, along with administration of human IL-2 and the immunosuppressor drug Rapamycin [2,3], which favors Tregs growth instead of the proliferation of effector CD4+ T. To date, several clinical studies have been performed, and the data indicates that the administration of huTregs is safe even in high doses [4] and seems to ameliorate the symptoms of Graft versus Host Disease (GvHD) in some cases; however, this has not been accomplished in all patients, thus demonstrating the need for more knowledge and treatment alternatives [5][6][7][8]. One of the limitations of huTregs effectiveness is the potential lost of their functional stability (or plasticity); in other words, huTregs may convert from a suppressive to an inflammatory phenotype [9]. Among the molecules that could be considered to optimize the production of huTregs, we sought to study IL-33 based on its recent role in the generation of tolerance [10,11].…”