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Allogeneic hematopoietic cell transplantation (alloHCT) represents a definitive therapy for a number of otherwise fatal conditions. Graft-versus-host disease (GVHD) is the major cause of morbidity after transplant and limits the extended use of this critical therapeutic modality. Dendritic cells (DCs), a population of professional antigen-presenting cells (APCs), are thought to play a critical role in the initiation of this devastating disease. In this article, we will discuss studies that have established the role of DCs in GVH reactions, as well as the therapeutic implications of these studies.
DCs belong to a population of hematopoietic cells called APCs that also include B cells and macrophages. The two main DC subsets include conventional DCs and plasmacytoid DCs (PDCs). DCs take up antigens through a wide range of mechanisms 1 and are very well equipped to form peptide-major histocompatibility complex (MHC) class II and peptide-MHC class I complexes, migrate to the draining lymph nodes (LNs), and present tissue-derived MHC-peptide complexes to T lymphocytes.1 Presentation of peptide-MHC class II complexes to CD4 T cells is called direct presentation and can be mediated by all APCs, including DCs, macrophages, and B cells.1 The generation of peptide-MHC class I from soluble antigens2 is called cross-presentation and appears to be specific to DCs.3 Similarly to DCs, PDCs express MHC class II molecules constitutively. Freshly isolated human and mouse PDCs are very poor inducers of T-cell proliferation. However, upon activation PDCs can differentiate into mature DCs with a high level of MHC class II and co-stimulatory molecules and T-cell stimulatory activity.4
AlloHCT has been an experimental tool in mice and a therapeutic modality in humans for almost half a century.6,7 Engraftment of allogeneic stem cells is facilitated by myelosuppressive and immunosuppressive conditioning given just prior to the infusion of stem cells. Mice, after a single dose of total body irradiation (TBI), are able to accommodate completely mismatched transplants without post-transplant immunosuppression. In humans, successful transplantation usually requires five to seven days of conditioning, an MHC geno-identical donor, and post-transplant immunosuppression.8 Even with these measures, GVHD, manifest as inflammation of the skin, bowel, and liver, occurs in 10–50% of human transplants and leads to death in 10–20%.9,10