Pathophysiology of acute graft-versus-host disease: recent advances

Abstract

Allogeneic hematopoietic stem cell transplantation (HSCT) is a potentially curative therapy for many malignant and non-malignant hematological diseases. Donor T cells from the allografts are critical for the success of this effective therapy. Unfortunately these T cells not only recognize and attack the disease cells/tissues but also the other normal tissues of the recipient as 'foreign' or 'nonself' and cause severe immune mediated toxicity, Graft-versus-Host Disease (GVHD). Several insights into the complex pathophysiology of GVHD have been gained from recent experimental observations, which show that acute graft-vs.-host disease (GVHD) is a consequence of interactions between both the donor and the host innate and adaptive immune systems. These insights have identified a role for a variety of cytokines, chemokines, novel T cell subsets (naïve, memory, regulatory and NKT cells) and also for non-T cells of both the donor and host (antigen presenting cells, γδ T cells, B cells and and NK cells) in modulating the induction, severity and maintenance of acute GVHD. This review will focus on the immunobiology of experimental acute GVHD with an emphasis on the recent observations.

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.…”

Suppression of lentivirus-mediated transgenic dendritic cells in graft-versus-host disease after allogeneic bone marrow transplantation in mice

“…GVHD involves an extremely complex pathophysiological process. It is currently believed that the activation and amplification of donor T lymphocytes as well as the release of a large number of inflammatory cytokines are the two main factors involved in the occurrence of acute GVHD (Sun et al, 2007;Reddy et al, 2009). CD 4 + T cells, especially Th cells, play an important role in the initiation and amplification of the severe GVHD pathological process.…”

Progress and prospects: graft-versus-host disease

“…11,39 An alternative approach relies on the infusion of specific cell types with immunoregulatory effects: clinical phase I-II trials have underlined the efficacy and safety of mesenchymal stem cells in combination with immunosuppressive drugs in the treatment of steroid-resistant GvHD, although subsequent studies, including phase III trials, failed in reproducing initial results. 40,41 Finally, after encouraging results from studies in murine models, [42][43][44] several groups are currently exploring the immunosuppressive activity of regulatory T cells, such as natural CD4+CD25+Foxp3+ and Tr1 lymphocytes, in preventing or controlling GvHD in clinical trials. 45 Suicide gene therapy is a novel promising application that exploits alloreactivity against malignant cells with a safe control of GvHD…”