The role of antigen-presenting cells in triggering graft-versus-host disease and graft-versus-leukemia

Abstract

After allogeneic blood or bone marrow transplantation, donor T cells interact with a distorted antigen-presenting cell (APC) environment in which some, but not all, host APCs are replaced by APCs from the donor. Significantly, host APCs are required for the priming of acute graft-versus-host disease (GVHD). Donor APCs play a lesser role in the induction of acute GVHD despite their predicted capacity to cross-present host antigens. In contrast, donor APCs may play a role in perpetuating the tissue injury observed in chronic GVHD. Host APCs are also required for maximal graft-versus-leukemia responses. Recent studies have suggested potential strategies by which the continued presence of host APCs can be exploited to prime strong donor immunity to tumors without the induction of GVHD.

Figure 1

Pathways of antigen presentation after allogeneic stem cell transplantation. Host alloantigens can be presented by host APC (direct presentation) or crosspresented by donor APC after uptake of particulate host material (indirect presentation). In direct presentation, donor T cells can potentially recognize allogeneic MHC antigens on host APC (MHC shown in red with or without a requirement for peptide) or may recognize host alloantigens (including allogeneic MHC or minor H antigens) that have been processed and presented by host APC. Alternatively, host allogeneic MHC or minor H antigens may be presented indirectly by donor APC.

Figure 2

Antigen-presenting cells can influence development of GVHD at multiple levels. Initial tissue injury and innate immune activation may trigger APC within tissues and induce certain APC populations such as DCs to migrate to draining lymph nodes. Migrating DCs or other lymph node resident APCs “trap” graft-versus-host-reactive T cells at this site for 3 to 4 days where they induce T cell activation and may “imprint” a homing phenotype that permits selective trafficking of effector cells to GVHD target organs. APCs within inflamed tissues may act to amplify the developing GVH response by providing further priming signals to T cells in situ by producing proinflammatory cytokines or actively recruiting T cells and other cellular effectors to this site.