Limits...
Mouse models of graft-versus-host disease: advances and limitations.

Schroeder MA, DiPersio JF - Dis Model Mech (2011)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Oncology, Siteman Cancer Center, Washington University School of Medicine, St Louis, MO 63110, USA.

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.

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Steps to aGvHD in mice. The progression of events occurring in the development of aGvHD in the mouse is illustrated. The five crucial steps of immune priming (A), activation (B), T-cell expansion (C), T-cell trafficking (D) and host tissue injury (E) are outlined. DC, dendritic cell; XRT, radiation conditioning. See main text for full details.
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f1-0040318: Steps to aGvHD in mice. The progression of events occurring in the development of aGvHD in the mouse is illustrated. The five crucial steps of immune priming (A), activation (B), T-cell expansion (C), T-cell trafficking (D) and host tissue injury (E) are outlined. DC, dendritic cell; XRT, radiation conditioning. See main text for full details.

Mentions: Key events involved in the development of aGvHD in mice are illustrated in Fig. 1. First, priming of the immune response establishes a milieu for enhanced T-cell activation and expansion, and occurs as a direct result of ‘conditioning’. Conditioning suppresses the recipient’s immune system and is applied to allow engraftment of donor hematopoietic stem cells. It can be achieved with cytotoxic agents such as irradiation or chemotherapy, or with immunosuppressive agents such as anti-thymocyte globulin or drugs that target recipient T cells, such as fludarabine. The most common method of conditioning in mouse models is total body irradiation, which ablates the recipient’s bone marrow, allowing donor stem cell engraftment and preventing rejection of the graft by limiting the proliferation of recipient T cells in response to donor cells. Subsequent activation of donor T cells depends on cognate antigen recognition. T cells are also activated by non-cognate stimulation by cytokines such as IL-1 and TNFα that are released during priming by many different cell types (Ferrara et al., 1993). Subsequent expansion of donor T cells and release of cytokines such as IFNγ leads to the activation of additional effector cell types, including neutrophils, monocytes and natural killer (NK) cells, which can result in further donor T-cell proliferation independent of their interactions with cognate antigen (Teshima et al., 2002). In addition, proinflammatory macrophages are activated, which can release IL-1β, TNFα and nitric oxide (Nestel et al., 1992; Cooke et al., 1998).


Mouse models of graft-versus-host disease: advances and limitations.

Schroeder MA, DiPersio JF - Dis Model Mech (2011)

Steps to aGvHD in mice. The progression of events occurring in the development of aGvHD in the mouse is illustrated. The five crucial steps of immune priming (A), activation (B), T-cell expansion (C), T-cell trafficking (D) and host tissue injury (E) are outlined. DC, dendritic cell; XRT, radiation conditioning. See main text for full details.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3097454&req=5

f1-0040318: Steps to aGvHD in mice. The progression of events occurring in the development of aGvHD in the mouse is illustrated. The five crucial steps of immune priming (A), activation (B), T-cell expansion (C), T-cell trafficking (D) and host tissue injury (E) are outlined. DC, dendritic cell; XRT, radiation conditioning. See main text for full details.
Mentions: Key events involved in the development of aGvHD in mice are illustrated in Fig. 1. First, priming of the immune response establishes a milieu for enhanced T-cell activation and expansion, and occurs as a direct result of ‘conditioning’. Conditioning suppresses the recipient’s immune system and is applied to allow engraftment of donor hematopoietic stem cells. It can be achieved with cytotoxic agents such as irradiation or chemotherapy, or with immunosuppressive agents such as anti-thymocyte globulin or drugs that target recipient T cells, such as fludarabine. The most common method of conditioning in mouse models is total body irradiation, which ablates the recipient’s bone marrow, allowing donor stem cell engraftment and preventing rejection of the graft by limiting the proliferation of recipient T cells in response to donor cells. Subsequent activation of donor T cells depends on cognate antigen recognition. T cells are also activated by non-cognate stimulation by cytokines such as IL-1 and TNFα that are released during priming by many different cell types (Ferrara et al., 1993). Subsequent expansion of donor T cells and release of cytokines such as IFNγ leads to the activation of additional effector cell types, including neutrophils, monocytes and natural killer (NK) cells, which can result in further donor T-cell proliferation independent of their interactions with cognate antigen (Teshima et al., 2002). In addition, proinflammatory macrophages are activated, which can release IL-1β, TNFα and nitric oxide (Nestel et al., 1992; Cooke et al., 1998).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Oncology, Siteman Cancer Center, Washington University School of Medicine, St Louis, MO 63110, USA.

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.

Show MeSH
Related in: MedlinePlus