The role of regulatory T cells in graft-versus-host disease management

ABSTRACT

Introduction: Despite improvements in human leukocyte antigen (HLA) matching algorithms and supportive care, graft-versus-host disease (GVHD) remains the leading cause of non-relapse morbidity and mortality following allogeneic hematopoietic stem cell transplantation (HSCT). Acute GVHD, typically occurring in the first 100 days post-HSCT, is mediated by mature effector T cells from the donor (graft) that become activated after encountering alloantigens in the recipient (host). Chronic GVHD, characterized by aberrant immune responses to both autoantigens and alloantigens, occurs later and arises from a failure to develop tolerance after HSCT. CD4+ CD25+ CD127- FOXP3+ regulatory T cells (Tregs) function to suppress auto- and alloreactive immune responses and are key mediators of immune tolerance.

Areas covered: In this review, authors discuss the biologic and therapeutic roles of Tregs in acute and chronic GVHD, including in vivo and ex vivo strategies for Treg expansion and adoptive Treg cellular therapy.

Expert opinion: Although they comprise only a small subset of circulating CD4 + T cells, Tregs play an important role in establishing and maintaining immune tolerance following allogeneic HSCT. The development of GVHD has been associated with reduced Treg frequency or numbers. Consequently, the immunosuppressive properties of Tregs are being harnessed in clinical trials for GVHD prevention and treatment.

KEYWORDS:

• Allogeneic hematopoietic stem cell transplantation
• acute graft-vs-host disease
• chronic graft-vs-host disease
• regulatory T cell
• adoptive Treg therapy
• interleukin-2

Article highlights

• Regulatory T cells (Tregs) are necessary to establish and maintain immune tolerance following allogeneic hematopoietic stem cell transplantation (alloHSCT)

• Poor Treg reconstitution after alloHSCT is associated with an increased risk of acute and chronic graft-versus-host disease (GVHD)

• GVHD is the leading cause of non-relapse morbidity and mortality following alloHSCT, and treatment for steroid-refractory GVHD is an area of unmet need

• Treg therapy is being developed primarily for acute GVHD prevention and chronic GVHD treatment

• The two main strategies for the use of therapeutic Tregs involve in vivo Treg expansion with low-dose IL-2 or adoptive transfer of freshly isolated or ex vivo-expanded Tregs

• Treg therapies will be broadly beneficial for patients undergoing solid organ transplantation and for patients with autoimmune disorders

Declaration of interest

J Koreth has received research funding from Prometheus Laboratories Inc, Millennium Pharmaceuticals Inc, and Miltenyi Biotec GmBH; consulting fees from Amgen, Equillium, and Fortress Biotech; and advisory board fees from Takeda Pharmaceuticals Inc, Cugene Inc and Kadmon Corp. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.