The role of interleukin-2 in graft-versus-host disease pathogenesis, prevention and therapy

Graft-versus-host disease (GVHD) is a significant complication following allogeneic hematopoietic cell transplantation (allo-HCT), posing substantial risks to patient survival. In the late follow-up phase of transplanted patients, GVHD is also a major cause of morbidity and disability, mostly due to low response to first-line steroids and the lack of effective standard therapies in the second line. This review provides a description of GVHD pathogenesis, with a focus on the central role of Interleukin-2 (IL-2). IL-2 is one of the critical mediators in the complex pathogenesis of GVHD, contributing to the intricate balance between regulatory T cells (Tregs) and effector T cells (Teffs). Due to this pivotal role, several studies investigate the potential of IL-2 as a therapeutic option for GVHD management. We discuss the outcomes of low-dose IL-2 therapies and their impact on Treg proliferation and steroid dependency reduction. Additionally, the effects of combining IL-2 with other treatments, such as extracorporeal photopheresis (ECP) and Treg-enriched lymphocyte infusions, are highlighted. Novel approaches, including modified IL-2 complexes and IL-2 receptor blockade, are explored for their potential in selectively enhancing Treg function and limiting Teff activation. The evolving understanding of IL-2's pivotal role in immune regulation presents promising prospects for applying treatment and prevention strategies for GVHD.