The importance of bone marrow involvement in GVHD.

To paraphrase Oscar Wilde, one could say that clinical transplantation imitates mouse models. This has led to extensive knowledge of graft-versus-host disease (GVHD) pathophysiology, although it remains a serious complication after transplant. The pervasive nature of acute GVHD is becoming increasingly apparent, as the list of potential targets has expanded beyond the skin, liver, and gastrointestinal tract to include the lungs, central nervous system, and thymus. Myelosuppression has long been appreciated clinically in patients experiencing GVHD, and recent data from mouse models have indicated that the bone marrow itself may be a target of acute GVHD, leading to impaired hematopoiesis due to damage of the bone marrowniche. Similar to the thymus’s role in T-cell development, the bone marrow is an important site of immune reconstitution after transplant, in this case for B-cell development. Although it is appreciated that B-cell recovery can be impaired in patients with GVHD, little is known about bone marrow involvement in clinical GVHD and the relationship this may have with B-cell reconstitution. Armed with knowledge gained from mouse models, Mensen et al set out to characterize B-cell reconstitution after allogeneic transplant in patients. Using mobilized peripheral blood transplantation into allogeneic recipients with acute leukemia as their model system, the authors performed an encyclopedic assessment of the kinetics of reconstitution for various B-cell subsets. They found that delayed B-cell reconstitution correlated with development of GVHD, as well as with high intensity conditioning (see figure). This connection between GVHD and B-cell deficiency is consistent with 2 other recent studies. However, the latter point is particularly interesting given reports indicating the importance of pretransplant conditioning for B-cell reconstitution in pediatric patients with severe combined immunodeficiency disease. After characterizing the B-cell recovery deficit in GVHD, the authors then performed further evaluation of the site of B-cell development, the bone marrow niche, determining that impairment of B-cell reconstitution correlated with the degree of T-cell infiltration in the bone marrow. Furthermore, in a subset of patients, the authors were able to perform chimerism analysis on the bone marrow T cells, confirming that they were indeed of donor origin. This valuable insight indicated that the infiltratingT cells were not residual hostT cells impairing donor hematopoiesis and B-cell development by mediating occult subclinical host vs graft rejection responses. The work of Mensen et al makes a compelling association betweenGVHD,T-cell infiltration of the marrow, and impaired B-cell recovery. Although the role of B cells in GVHD has become a major point of interest in the field recently, as evidencedby the scientific session on B cells in GVHD at the 2013 ASH Annual Meeting, here the authors focus on how GVHD regulates B cells. Their findings raise several important questions. It is not clear how much of the B-cell deficiency they identified was due to GVHD directly as opposed to immunosuppressive GVHD treatment. Additionally, if GVHDwas directly responsible for delayedB-cell recovery, it is possible that the T-cell marrow infiltration is a nonspecific finding in GVHD patients and not causative for B-cell deficiency. These are important areas for future research. Another critical issue is the significance of T-cell marrow infiltration and B-cell development for transplant outcome. Although the authors showed that impaired B-cell reconstitution after transplant was associated with reduced B-cell function ex vivo, it is Mensen et al present data indicating that GVHD, donor T-cell infiltration in recipient marrow, and high intensity pretransplant conditioning were associated with impaired B-cell reconstitution in adult patients who underwent allogeneic hematopoietic transplantation for treatment of acute leukemia. Professional illustration by Patrick Lane, ScEYEnce Studios.