A major minor for GVHD

Acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT) is a complex process that involves donor T cells and multiple cellular and cytokine effectors. Detailed knowledge of T-cell responses to minor histocompatibility (H) antigens is scant. In this issue Choi and colleagues (page 4259) used mouse models of GVHD to multiple minor H antigens in order to track donor T cells through several GVHD target organs (spleen, liver, lung) in real time and completed this picture in several important ways. First, they demonstrate that nearly a quarter of the donor cells respond to a single minor antigen, H60. This response occurred in several donor/recipient strain combinations, suggesting that strong immunodominance will be broadly applicable; additional matches at a handful of “major” minors may therefore significantly reduce the risk of GVHD between HLA-identical donors and recipients. Second, the donor T cells expanded simultaneously in the liver, lung, and spleen, suggesting that donor T cells interact directly with antigen-presenting cells of the host not only in secondary lymphoid tissue but in target organs as well. Third, clonal T-cell expansion occurred early and contracted back to baseline by day 14, before the onset of GVHD mortality. Three weeks after transplantation, target organs are infiltrated by cells of the myeloid lineage, suggesting an important role for non–T cells as GVHD effectors. Although the conclusions of all animal models must be extrapolated to the clinical setting with caution, such real time, detailed analysis sheds significant light on important aspects of GVHD pathophysiology that have heretofore remained murky.