Review Series ADVANCES IN HEMATOPOIETIC CELL TRANSPLANTATION Acute graft-versus-host disease: a bench-to-bedside update

Acute graft-versus-host disease (aGVHD) is a frequent and at times unpredictably severe inflammatory complication of allogeneic hematopoietic cell transplantation (HCT). Despite over 5 decades of extensive laboratory and clinical investigation into methods to prevent severe aGVHD, this complication remains a significant cause of morbidity and mortality in allogeneic HCT recipients. Each year, ;6800 patients undergo HCT (Center for International Blood & Marrow Transplant Research [CIBMTR] data), and the majority will suffer some manifestations of aGVHD. Several advancements have led to novel aGVHD detection, prophylaxis, and treatment methods. In this review, we highlight aGVHD advancements in the context of current care. With many new modalities that target host and donor responses under investigation, an era of multimodal, personalized immunomodulation in HCT may emerge. However, significant challenges to elimination of aGVHD remain. These include developing treatment regimens that retain infectious immunity and graftversus-tumor effects, as well as identification of effective therapy for steroid-refractory aGVHD. The classic description of aGVHD pathophysiology begins with activation of host antigen-presenting cells (APCs) by danger signals expressed on damaged tissues (damage-associatedmolecular patterns [DAMPs]) and/or pathogens (pathogen-associatedmolecular patterns [PAMPs], eg, lipopolysaccharide). Activated host APCs then present host antigens to donor T cells, leading to alloactivation and inflammatory cytokine release. These inflammatory cytokines then recruit and induce proliferation of additional immune effector cells, perpetuating the cycle of alloreactive tissue injury and inflammation. Although a simplified description of the complexity underlying graft-versus-host (GVH) interactions, it is the established foundation for disentangling the pathways involved. A more detailed overview of each phase of acute GVHD (the initiation, lymphocyte trafficking, expansion and effector, and treatment phases) will serve as background for emerging, novel diagnostic and therapeutic approaches.