Treg Therapies Revisited: Tolerance Beyond Deletion

Abstract

Induction of immune tolerance is the Holy Grail in transplantation medicine and autoimmunity. Currently, patients are required to use immunosuppressive drugs for the rest of their lives, resulting in unwanted side effects and complication from global suppression of the immune response. It is well established that regulatory T cells (Tregs) are critical for the maintenance of immune tolerance towards self-antigens by several mechanisms of immune regulation, in parallel with intrathymic deletion of self-reactive T cells during ontogeny. Therefore, approaches for increasing Treg numbers or function in vivo could provide an all-purpose solution for tolerance induction. Currently, most state-of-the-art therapeutics for treating autoimmune diseases or preventing allograft rejection work either by general immunosuppression or blocking inflammatory reactions and are non-specific. Hence, these approaches cannot provide satisfactory long-term results, let alone a cure. However, in animal models the therapeutic potential of Treg expansion for inducing effective tolerance has now been demonstrated in various models of autoimmunity and allogeneic transplantation. Here, we focus on therapies for increasing the size of the Treg pool by expanding endogenous Treg numbers in vivo or by adoptive transfer of Tregs. In particular, we discuss IL-2 based approaches (low dose IL-2, IL-2 complexes) for inducing Treg expansion in vivo as well as cell-based approaches (polyclonal, antigen specific, or cell engineered) for adoptive Treg therapy. We also mention new questions arising from the first clinical studies on Treg therapy in the fields of transplantation and autoimmunity.

Regulatory T cells and transplantation tolerance: Emerging from the darkness?

“…In search for distinct functional targets to enable privileged microenvironments, a number of possible candidate areas have emerged. For example, The high expression of CD25 on Treg [17] has raised the possibility that some engineered form of IL‐2 might be used to selectively expand Treg in vivo and enable therapeutic benefit in preclinical studies [78–83]. Distinctive metabolic features of Treg in use of glycolysis, oxidative phosphorylation, and lipid metabolism have also attracted much interest if suitable drug candidates could be identified [84–93].…”

“…The high expression of CD25 on Treg [17] has raised the possibility that some engineered form of IL‐2 might be used to selectively expand Treg in vivo and enable therapeutic benefit in preclinical studies [78–83].…”

“…In search for distinct functional targets to enable privileged microenvironments, a number of possible candidate areas have emerged. For example, (a) The high expression of CD25 on Treg [17] has raised the possibility that some engineered form of IL-2 might be used to selectively expand Treg in vivo and enable therapeutic benefit in preclinical studies [78][79][80][81][82][83].…”

mSOD1-NSG mice: a new in vivo model to test human T cells in ALS

“…Human Tregs are cultured in high amounts of IL-2 and NSG mice do not have an endogenous source of IL-2. This dependence on IL-2 may result in a loss of human Tregs in vivo, and IL-2 has been given to clinical patients injected with in vitro expanded Tregs (18,22,35). To test whether additional IL2 treatment would promote the persistence of Tregs in these mSOD1-NSG mice, mice were given injections of IL-2 i.p.…”

“…T regulatory cells (Tregs) are a subset of immune T cells that limits inflammation, autoimmunity and helps to maintain homeostasis. Tregs can be isolated and expanded in vitro, genetically engineered with defined specificities, and they are being explored as adoptive cell therapy for autoimmune diseases and transplantation (17)(18)(19). As ALS disease progresses, the number of Tregs decreases and a low number of Tregs is associated with worse outcomes in patients (20,21).…”