No abstract

In this study, we investigated the effect of an agonistic mAb (DTA-1) against glucocorticoid-induced TNF receptor (GITR) in a murine model of systemic lupus erythematosus-like chronic graft-vs-host disease (cGVHD). A single dose of DTA-1 inhibited the production of anti-DNA IgG1 autoantibody and the development of glomerulonephritis, typical symptoms of cGVHD. DTA-1-treated mice showed clinical and pathological signs of acute GVHD (aGVHD), such as lymphopenia, loss of body weight, increase of donor cell engraftment, and intestinal damage, indicating that DTA-1 shifted cGVHD toward aGVHD. The conversion of cGVHD to aGVHD occurred because DTA-1 prevented donor CD8+ T cell anergy. Functionally active donor CD8+ T cells produced high levels of IFN-γ and had an elevated CTL activity against host Ags. In in vitro MLR, anergic responder CD8+ T cells were generated, and DTA-1 stimulated the activation of these anergic CD8+ T cells. We further confirmed in vivo that donor CD8+ T cells, but not donor CD4+ T cells, were responsible for the DTA-1-mediated conversion of cGVHD to aGVHD. These results indicate that donor CD8+ T cell anergy is a restriction factor in the development of aGVHD and that in vivo ligation of GITR prevents CD8+ T cell anergy by activating donor CD8+ T cells that otherwise become anergic. In sum, our data suggest GITR as an important costimulatory molecule regulating cGVHD vs aGVHD and as a target for therapeutic intervention in a variety of related diseases.

In a murine model of systemic lupus erythematosus (SLE)-like chronic graft-versus-host disease (cGVHD), donor CD8 + T cells rapidly fall into anergy to host cells, while donor CD4 + T cells hyperactivate B cells and break B-cell tolerance to self-Ags in the recipient mouse. The functional recovery of donor CD8 + T cells can result in the conversion of cGVHD to acute GVHD (aGVHD), indicating that donor CD8 + T-cell anergy is a restriction factor in the development of cGVHD. In this report, we present evidence that donor CD4 + CD25 + regulatory T cells (T reg cells) are critical in maintaining the donor CD8 + T-cell anergy and thus suppressing the development of aGVHD in mice that are naturally prone to cGVHD. Our results provide a novel insight into the role of T reg cells in determining cGVHD versus aGVHD.

No abstract

In this study, we investigated the effect of an agonistic mAb (DTA-1) against glucocorticoid-induced tumor necrosis factor receptor (GITR) in a murine model of systemic lupus erythematosus (SLE)-like chronic graft-versus-host disease (cGVHD). A single dose of DTA-1 inhibited the production of anti-DNA IgG1 autoantibody and the development of glomerulonephritis, typical symptoms of cGVHD. DTA-1-treated mice showed clinical and pathological signs of acute GVHD (aGVHD), such as lymphopenia, loss of body weight, increase of donor cell engraftment, and intestinal damage, indicating that DTA-1 shifted cGVHD towards aGVHD. The conversion of cGVHD to aGVHD occurred because DTA-1 prevented donor CD8+ T cells from being anergic. Functionally active donor CD8+ T cells produced high levels of IFN-γ and had an elevated CTL activity against host antigens. In in vitro MLR, anergic responder CD8+ T cells were generated and DTA-1 stimulated the activation of responder CD8+ T cells that were fated to be anergic. We further confirmed in vivo that donor CD8+ T cells, but not donor CD4+ T cells, are responsible for the DTA-1-mediated conversion of cGVHD to aGVHD in a CD4+CD25+ regulatory T cell-independent manner. These results indicate that donor CD8+ T-cell anergy is a restriction factor in the development of aGVHD and that GITR stimulation prevent CD8+ T-cell anergy by activating CD8+ T cells prone to anergy. In sum, our data suggest GITR as an important costimulatory molecule regulating cGVHD versus aGVHD and as a target for therapeutic intervention in a variety of related diseases.