Regulatory T Cell Therapy of Graft-versus-Host Disease: Advances and Challenges

Abstract

Graft-versus-host disease (GVHD) is the leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Immunomodulation using regulatory T cells (Tregs) offers an exciting option to prevent and/or treat GVHD as these cells naturally function to maintain immune homeostasis, can induce tolerance following HSCT, and have a tissue reparative function. Studies to date have established a clinical safety profile for polyclonal Tregs. Functional enhancement through genetic engineering offers the possibility of improved potency, specificity, and persistence. In this review, we provide the most up to date preclinical and clinical data on Treg cell therapy with a particular focus on GVHD. We discuss the different Treg subtypes and highlight the pharmacological and genetic approaches under investigation to enhance the application of Tregs in allo-HSCT. Lastly, we discuss the remaining challenges for optimal clinical translation and provide insights as to future directions of the field.

Regulatory T cells as a therapeutic approach for inflammatory bowel disease

“…CAR Tregs suppress inflammation and reduce disease in mouse models, including EAE [162,166] and GVHD [163,[167][168][169]. This ultimately led to the first CAR-Treg clinical trial using HLA-A2 CAR Treg cells in kidney transplant patients (EUCTR2019-001730-34-NL) [170]. However, in other disease models, localization and persistence of antigen-specific Treg cells was not sufficient to ameliorate disease; insulin-specific CAR Treg cells were stable, antigen-specific, suppressive, and long-lived; however, these CAR Treg cells did not prevent the development of diabetes [164].…”

Stepwise acquisition of unique epigenetic signatures during differentiation of tissue Treg cells

“…In a translational study, an analogous cell type to murine tissue Treg cells was recently proposed for the human system ( 82 ), and further investigations regarding the development and epigenetic programming are necessary to fully understand this cell type and also understand their future therapeutic potential. Owing to their special tissue-regenerative properties on top of classical Treg cell functions, tissue Treg cells make an attractive candidate for adoptive T cell transfer therapies in autoimmune settings like graft-versus-host disease (GvHD) or solid organ transplantation ( 87 , 88 ). A major limitation here is the small number of tissue Treg cells that can be isolated from biopsies or even re-circulating tissue Treg cells from the peripheral blood of the patient.…”

Collection of peripheral blood mononucleated cells for chronic graft-versus-host disease immunology research: safety and effectiveness of leukapheresis in 132 patients

“…Routine use of leukapheresis to acquire larger MNC numbers solely for research purposes in chronic GVHD has not been done due to concerns of logistics, feasibility and patient safety. This current study provides the evidence for the use of leukapheresis as a safe and powerful research tool for advancing knowledge about chronic GVHD and provides benchmarks for developing novel therapeutic interventions such as regulatory T cells infusion for GVHD [ 25 ] or CAR T cell therapy [ 26 , 27 ].…”