Abstract
The limiting factor for successful hematopoietic stem cell transplantation (HSCT) is graft-versus-host disease (GvHD), a post-transplant disorder that results from immune-mediated attack of recipient tissue by donor T cells contained in the transplant. Mouse models of GvHD have provided important insights into the pathophysiology of this disease, which have helped to improve the success rate of HSCT in humans. The kinetics with which GvHD develops distinguishes acute from chronic GvHD, and it is clear from studies of mouse models of GvHD (and studies of human HSCT) that the pathophysiology of these two forms is also distinct. Mouse models also further the basic understanding of the immunological responses involved in GvHD pathology, such as antigen recognition and presentation, the involvement of the thymus and immune reconstitution after transplantation. In this Perspective, we provide an overview of currently available mouse models of acute and chronic GvHD, highlighting their benefits and limitations, and discuss research and clinical opportunities for the future.
Highlights
A major complication and limitation to the broad application of hematopoietic stem cell transplantation (HSCT) is graft-versushost disease (GvHD), which results from immune-mediated attack of recipient tissue by donor T cells contained in the transplant
In a series of adoptive transfer studies, it was shown that CD4+ T cells isolated from C3H/HeN recipients of major histocompatibility complex (MHC)-II-deficient bone marrow that develop chronic GvHD (cGvHD) caused acute GvHD (aGvHD) when transferred to the C57/Bl6 donor strain, but caused cGvHD when transferred to established chimeric mice created from a C57/Bl6 r C3H/HeN transfer
The exact mechanism is unknown, but these data suggest that the thymus-educated donor CD4+ T cells that should be self-tolerant are autoreactive, suggesting that the link between aGvHD and cGvHD is related to the targeting to the thymus by alloreactive T cells and subsequent elimination or alteration of the function of thymic cellular elements that are essential for appropriate negative selection
Summary
A major complication and limitation to the broad application of hematopoietic stem cell transplantation (HSCT) is graft-versushost disease (GvHD), which results from immune-mediated attack of recipient tissue by donor T cells contained in the transplant. GvHD accounts for 15-30% of deaths that occur following allogeneic HSCT that is carried out to treat malignant diseases, and is a major cause of morbidity in up to 50% of transplant recipients (Ferrara et al, 2009). This high incidence is despite the use of aggressive immunosuppressive therapies after transplantation, as well as allele-level human leukocyte antigen (HLA) matching between donor and recipient. We begin by describing the clinical symptoms and immunopathology of GvHD
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