Regulatory T Cells in GVHD Therapy

Abstract

Graft versus host disease (GVHD) is a common complication and the leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Pharmacological immunosuppression used in GVHD prophylaxis and treatment lacks specificity and can increase the likelihood of infection and relapse. Regulatory T lymphocytes (Tregs) play a vital role in restraining excessive immune responses and inducing peripheral immune tolerance. In particular, clinical trials have demonstrated that Tregs can prevent and treat GVHD, without increasing the risk of relapse and infection. Hence, adoptive transfer of Tregs to control GVHD using their immunosuppressive properties represents a promising therapeutic approach. To optimally apply Tregs for control of GVHD, a thorough understanding of their biology is necessary. In this review, we describe the biological characteristics of Tregs, including how the stability of FOXP3 expression can be maintained. We will also discuss the mechanisms underlying Tregs-mediated modulation of GVHD and approaches to effectively increase Tregs’ numbers. Finally, we will examine the developing trends in the use of Tregs for clinical therapy.

Current Prophylaxis and Treatment Approaches for Acute Graft-Versus-Host Disease in Haematopoietic Stem Cell Transplantation for Children With Acute Lymphoblastic Leukaemia

“…Several studies, mainly in reduced intensity conditioning HSCT for non-mailgnant diseases showed that alemtuzumab levels impact aGvHD, chimerism and lymphocyte recovery ( 59 , 60 ), but also in malignant diseases ( 61 ). Although alemtuzumab abrogated severe GvHD this was not necessarily associated with improved OS ( 62 ). In a study of 148 patients comparing alemtuzumab and ATG, alemtuzumab delayed T and natural killer cell recovery compared with ATG and overall and event-free survival were lower in patients who received alemtuzumab.…”

“…Nonetheless, in this small, highly selected patient group, the rate of NRM was very high (50%). These deaths, mostly early post-transplant, were due to either regiment-related toxicity or infectious complications, indicating that despite accelerated immune recovery, this type of immune engineering still requires proof of clinical benefit ( 30 , 62 ). Another cell type with immunomodulatory activity are invariant natural killer T cells (iNKT), which secrete interleukin (IL)-4 and IL-10( 63 ).…”

CAR-T Regulatory (CAR-Treg) Cells: Engineering and Applications

“…Modulation of Tregs for therapeutic use has become an important area of investigation in GvHD, with the majority of studies focusing on in vitro-expanded polyclonal Tregs [ 75 , 76 , 77 , 78 ]. The first clinical trial of Tregs in GvHD showed modest impacts on acute GvHD symptoms but significant alleviation of the symptoms in chronic GvHD and reduction in the use of immunosuppressive agents [ 10 ].…”

T Helper Cell Lineage-Defining Transcription Factors: Potent Targets for Specific GVHD Therapy?

“…Despite this broad outline of Treg research in GVHD, many recent publications have already summarized the role of Tregs in GVHD in a detailed way (126)(127)(128), for which reason we will not go into further details at this point.…”