Alternative mechanisms that mediate graft-versus-host disease in allogeneic hematopoietic cell transplants

Abstract

Allogeneic hematopoietic cell transplantation (alloHCT) benefits increasing numbers of patients with otherwise lethal diseases. Graft-versus-host disease (GVHD), however, remains one of the most potentially life-threatening complications due to its own comorbidities and the side effects of its treatment. In this issue of the JCI, two groups have turned dogma on its head by providing evidence for alternative mechanisms of acute GVHD (aGVHD) in humans. The principle of donor T cell reactivity elicited by host antigen-presenting cells (APCs) expressing MHC-encoded major HLA disparities or expressing minor histocompatibility antigen (miHA) differences presented by identical HLA molecules remains intact. These reports, however, demonstrate that GVHD can additionally result from peripheral host T cells resident in skin and gut being stimulated against donor APCs in the form of monocyte-derived macrophages. Moreover, these donor monocyte-derived macrophages can themselves mediate cytopathic effects against resident host T cells in skin explants and against a keratinocyte-derived cell line.

Figure 1. Canonical versus alternative GVHD model.

(A) In canonical GVHD, host APCs stimulate donor T cells, which in turn attack host cells in tissue (primarily in the skin, gut, and liver). (B) The alternative GVHD mechanism, supported by data from Divito et al. and Jardine et al. (9, 10), results from resident host memory T cells’ being stimulated by inflammatory CD1c^neg, CD11c^pos, CD14^pos donor–derived macrophages in the skin and gut in what amounts to HVG reactivity that is clinically indistinguishable from GVHD. In this alternative GVHD mechanism, inflammatory donor-derived macrophages also mediate a direct cytopathic effect against resident host T cells in skin explants and against a keratinocyte-derived cell line.