By Nelson Chao, MD

2009-05-01

Dr. Chao indicated no relevant conflicts of interest.

Haniffa M, Ginhoux F, Wang XN, et al. Differential rates of replacement of human dermal dendritic cells and macrophages during hematopoietic stem cell transplantation. J Exp Med. 2009;206:371-85.

Graft-versus-host disease (GVHD) remains a major obstacle for successful hematopoietic cell transplantation. A better understanding of this process is needed and is an area of extensive research. It is always more difficult to explain GVHD to patients and families than a solid organ rejection. Patients seem to be able to understand rejection of a kidney or heart but have more difficulty with the graft (or the organ in this case) rejecting the host. While the principles of antigen presentation and recognition are similar, in fact, the immunological responses can be quite different between GVHD and solid organ rejection. Not the least of these differences is that there are two immune systems to contend with in GVHD. While organ rejection is relatively straightforward, GVHD is a more complex interaction between donor and recipient cells, including the possibility of host-versus-graft (HVG) and therefore graft rejection. Thus, the process of obtaining a functioning allograft requires sufficient suppression of the host to allow donor engraftment. The effector cells of GVHD are from the donor, but the ability to activate these cells could come from either the donor or the recipient and both appear to be able to present host antigens to the donor cells. Analyses of the process of antigen presentation would improve our understanding of GVHD. Recall that the risk of GVHD is not usually instantaneous but a process that can span several weeks to months. This prolonged or continued risk could be related to extended survival of recipient antigen-presenting cells (APCs).

This paper by Haniffa, et al., from Matthew Collin’s laboratory at Newcastle University, goes a long way in helping with understanding the role of recipient APCs in the generation of GVHD. They studied specifically the turnover of APCs in the human dermis. Human dermal APCs consist primarily of three subsets of CD45+/HLA-DR+ cells:  CD1a+/CD14- DC, CD1a-/CD14+ DC, and CD1a-/CD14+/FXIIIa+ macrophages — each with specific properties. Following transplantation, the CD1a+ and CD14+ cells are rapidly depleted, but recipient macrophages are found in the dermis and can persist for many months, up to and including the time frame at which cutaneous GVHD develops. The implications from these data are that the origin of these cells could be from different lineages or that there is a significant resistance to the preparatory regimen, especially in the setting of a non-myeloablative regimen. These macrophages are not likely the sole basis for activation of donor T cells, but these macrophages do produce inflammatory cytokines and can activate and help in the proliferation of CD8+ T cells (in contrast to some gastrointestinal macrophages, which seem to produce IL-10 and induce regulatory T cells). Since these dermal macrophages persist, the continued presence of these cells could contribute to the continued risk of GVHD many months after transplantation.

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