Regulatory T-cell therapy for autoimmune and autoinflammatory diseases: The next frontier

Abstract

Forkhead box P3-expressing regulatory T (Treg) cells are essential for self-tolerance, with an emerging role in tissue repair and regeneration. Their ability to traffic to tissue and perform complex therapeutic tasks in response to the tissue microenvironment make them an attractive candidate for drug development. Early experiences of Treg cell therapy in patients with graft-versus-host disease, type 1 diabetes, and organ transplantation have shown that it is feasible, safe, and potentially efficacious in some settings. Many ongoing trials in patients with a wide variety of diseases will further enhance our knowledge about the optimal approaches for Treg cell manufacturing and dosing. We review the current preclinical rationale supporting Treg cell therapy in a variety of disease settings ranging from tissue transplantation, autoimmune diseases, and non-immunemediated inflammatory settings. We point out challenges in development of Treg cell therapy and speculate how synthetic biology can be used to enhance the feasibility and efficacy of Treg cell therapy for autoimmune and autoinflammatory diseases. (J

The proportion of peripheral blood Tregs among the CD4+ T cells of autoimmune thyroid disease patients: a meta-analysis

“…In conclusion, the proportion of peripheral blood Tregs in CD4+ T cells tends to be lower in untreated and treated AITDs than in HCs. Of note, Foxp3+ Treg-based therapies have been used in preclinical and clinical trials in other autoimmune diseases that are also triggered by impaired Tregs [40], which sheds new light on AITD treatment. Undoubtedly, new studies will improve upon our present analysis.…”

Epigenetically modifying the Foxp3 locus for generation of stable antigen-specific Tregs as cellular therapeutics

“…Our study does not negate the importance of other approaches in producing therapeutic Tregs including in vivo approaches but rather emphasizes the promise of iTregs that are rendered antigen specific. In fact, there have been exciting progresses made recently in expanding polyclonal Foxp3+ Tregs, as well as their use in selective clinical settings 6,7 . Our findings that iTregs can be epigenetically edited ex vivo using the 3C approach and that the 3C‐iTregs exhibit remarkable potency in suppressing autoimmunity and transplant rejection in vivo are a significant step forward in harnessing antigen‐specific iTregs as cellular therapeutics.…”

“…There are many clinical situations where the Foxp3+ Tregs are dysregulated or outperformed by T effector cells, and selectively targeting them, either promoting their suppressive functions (eg, in autoimmune diseases) or inhibiting their inductions (like in tumors), would be an ideal approach in treatment of such disease conditions 5 . Thus, for decades, Foxp3+ Tregs have been an attractive cell type in translational and clinical studies 6,7 . In areas of autoimmune diseases and transplant in particular, there are two broad approaches in manipulating Tregs for therapeutic purposes.…”

TGFβ1 mimetic peptide modulates immune response to grass pollen allergens in mice

“…Treg cells are a heterogeneous population characterized by the constitutive expression of the transcription factor Foxp3 and represent the dominant subset specific for common environmental allergens in healthy individuals. [10][11][12] Transforming growth factor β1 (TGFβ1) is a key cytokine involved in the induction of Treg cells and in the regulation of effector T cells, B cells, and epithelial cells. 13 In mice possessing a disrupted TGFβ1 gene or lacking the TGFβ receptor II (TGFβRII), severe inflammatory responses, tissue necrosis, and early death were observed, 14,15 confirming the broad immune regulatory functions of TGFβ1.…”