Graft-versus-host disease of the skin: life and death on the epidermal edge

Abstract

Despite impressive advances in the field of allogeneic hematopoietic transplantation, graft versus host disease (GVHD) remains a significant obstacle to be overcome; it would enhance the safety and efficacy of this life-saving therapy. This review provides a framework for understanding the molecular and cellular basis underlying GVHD. We propose a 3-phase model of GVHD that highlights the importance of the conditioning regimen on the recipient tissues administered prior to infusion of donor bone marrow inoculum. A novel skin explant model, designed to take into consideration the immunobiological consequences of conditioning regimens on resident host cells, is proposed to advance our understanding of GVHD and serve as a potential prognostic tool when allogeneic recipient/donor combinations are being contemplated in the clinic. Within this review, specific emphasis is placed on the importance of defining the apoptotic machinery engaged in epidermal keratinocytes triggered by both conditioning regimens, and by host resident and recruited immunocytes and soluble mediators produced at sites of injury. The review is completed with a working model for cutaneous GVHD. Although the skin is highlighted because of its accessibility for clinical observations and serial sampling opportunities, lessons learned from studies of cutaneous GVHD are likely to provide valuable insights into GVHD occurring in the gastrointestinal tract, lung, and liver. With new insights designed to better predict and prevent GVHD and novel agents designed to treat GVHD, overcoming this current impediment to successful bone marrow transplantation should become increasingly feasible.

Donor-derived cells and human graft-versus-host disease of the skin

“…This has been confirmed both in humans and in experimental models. [13][14][15] The epidermal rete ridge microdomain is strongly associated with vascular capillary loops in the upper dermis where we found donor-derived endothelial cells. This suggests that endothelial cells of donor origin are mainly found at the site of the first immune injury during the effector phase of acute GvHD.…”

GVHD after chemotherapy conditioning in allogeneic transplanted mice

“…[43][44][45] Our results showed pathological alterations in skin and large intestine, but not the liver at day 0 which probably is because the liver is highly specialized to detoxify xenobiotics, and that the threshold of BU-CY induced toxicity in the liver is higher than that for skin, large intestine and lymphoid organs. Several studies have shown that donor T cells are activated by recipients/donor antigen-presenting cells in the secondary lymphoid organs such as the spleen, lymph nodes and Peyer's patches.…”

“…However, in a 3-phase model proposed for the pathogenesis of aGVHD, [43][44][45] including phase 1, where the conditioning regimen leads to the initial damage and activation of dendritic cells of the host tissues which provides a condition for the migration and activation of donor T cells to the target organ tissue in phase-2. [43][44][45] The importance of donor T cells in target organ pathology has been shown earlier.…”

“…However, in a 3-phase model proposed for the pathogenesis of aGVHD, [43][44][45] including phase 1, where the conditioning regimen leads to the initial damage and activation of dendritic cells of the host tissues which provides a condition for the migration and activation of donor T cells to the target organ tissue in phase-2. [43][44][45] The importance of donor T cells in target organ pathology has been shown earlier. [46][47][48] In a mouse model of GVHD based on irradiation, Baker et al and Nikolic et al 47,48 have reported skin and intestine damage in the allogeneic setting and they showed the presence of T cells in the skin lesion and GI; however, they did not confirm the origin of these cells.…”

Cutaneous Graft-versus-Host Disease: A Guide for the Dermatologist

“…The skin has been used in basic, animal and clinical research as a model organ for GVHD since the very beginning, which has led to a fairly good understanding of some aspects of that disease [40, 41]. Figure 2 outlines the main principles of acute GVHD in a simplified 3-step process [42, 43]. Conditioning regimens such as total body irradiation result in initial toxic epithelial injuries of highly proliferating organs such as the gut, liver and skin, thereby causing a cell-damage-induced proinflammatory cytokine milieu.…”