Acute graft-versus-host disease: from the bench to the bedside

Abstract

During the past decade, progress in basic immunology has been impressive. In parallel, whereas our understanding of the pathophysiology of acute graft-versus-host disease (GVHD) has greatly improved, so has our knowledge of the complexities of the immune system. Much of the immunobiology of acute GVHD has been gleaned from preclinical models and far less from correlations with clinical observations or therapeutic interventions. In this review, we summarize some of the major advances in GVHD pathophysiology, including the translation of these from the bench to the bedside, and discuss preclinical approaches that warrant further exploration in the clinic.

Figure 1

Step 1: priming of the immune response. Conditioning regimens used to prepare recipients for allogeneic hematopoietic stem cell transplantation (HSCT) cause graft-versus-host disease (GVHD) parenchymal organ injury and the release of proinflammatory cytokines that initiates allogeneic priming. The red boxes below the mouse and the human recipient serve to highlight distinct features between these species. A major unresolved issue not explained by this schema is shown in the middle red box. RIC denotes reduced-intensity conditioning.

Figure 2

Step 2: T-cell activation and costimulation. Donor T cells that express positive or inhibitory costimulatory pathway receptors encounter host antigen-presenting cells (APCs) that express major histocompatibility complex (MHC) antigens and ligands for these receptors. A host peptide is shown in the context of MHC/T-cell receptor (TCR) interactions. The red boxes below the mouse and the human recipient serve to highlight distinct features between these species. MiH indicates minor histocompatibility; MiHa, minor histocompatibility antigen; and Ab, antibody.

Figure 3

Step 3: regulation of acute GVHD by T-cell subpopulations. T-cell subsets that have been implicated in GVHD generation include naive and effector T cells, and Th1, Th2, and Th17 cells. More uncertain is the role of memory T cells. Inhibitory T-cell populations include CD4⁺CD25⁺ regulator T cells and natural killer T cells. In rodents, a T-cell population with stem cell properties has been implicated in acute GVHD generation. The red boxes below the mouse and the human recipient serve to highlight distinct features between these species. Question marks denote uncertain conclusions. Treg indicates T regulatory cell; and NKT, natural killer T cell.

Figure 4

Step 4: T-cell trafficking. In rodents, secondary lymphoid organs are known to facilitate GVHD initiation. In both rodents and humans, GVHD tissue injury requires migration of such activated donor T cells into GVHD target organs that is orchestrated by chemokines, selectin, and adhesion molecules. An example of the homing process into the skin is depicted. The red boxes below the mouse and the human recipient serve to highlight distinct features between these species. Question marks denote uncertain conclusions. In the center red box, we note that clinical translational approaches to prevent GVHD by blocking individual chemokine/receptor interactions may be difficult due to known redundancies that exist for many pathways.

Figure 5

Step 5: effector phase. Cells implicated in the GVHD effector process are illustrated. In the gray box are the known mediators of tissue injury. IDO inhibits GVHD pathology by reducing the frequency of T-effector cells present in the colon. The red boxes below the mouse and the human recipient serve to highlight distinct features between these species. Question marks denote uncertain conclusions. NK indicates natural killer; TNF, tumor necrosis factor; and TNFa, tumor necrosis factor alpha.