Abstract
Acute graft versus host disease (GVHD) is the major complication after allogeneic (allo) stem cell transplantation (SCT) involving injury to host tissues by both inflammatory cytokines and donor-derived cellular effectors. Macrophage migration inhibitory factor (MIF) is produced by various cell types and has a broad range of proinflammatory properties. We tested, whether MIF contributes to GVHD by using a well established murine model. Lethally (1300 cGy) irradiated B6D2F1 (H-2bxd) mice received SCT either from syngeneic (syn) (B6D2F1) or allo (B6; H-2b) donors. One half of animals after either syn or allo SCT were treated with polyclonal antibodies against mouse MIF from day 0 until day 14, whereas the other halves of syn and allo recipients received control IgG. GVHD severity was assessed after SCT by survival and a clinical scoring system assessing weight changes, fur texture, skin integrity, mobility and posture. Syn recipients stayed clinically well and all animals survived regardless their treatment with control or anti-MIF. Animals receiving allo-SCT plus control IgG developed significant aGVHD and high mortality. By contrast, in allo anti-MIF treated recipients, GVHD scores (day 21: 4.4 ± 0.4 vs. 5.7 ± 0.5) and weight loss (24.6% vs. 45.4%) were reduced, and survival significantly improved (p < 0.05). In addition, target organ injury to the gut (histopathology score: 4.3 ± 0.7 vs. 8.0 ± 2.6) as well as serum IFNγ (4397 ± 995 vs. 6070 ± 525 pg/ml) and TNFα (113.9 ± 12.7 vs. 159.2 ± 22.5 pg/ml) levels of anti-MIF treated allo recipients were decreased by day 7 when compared to controls. Alloantigen-specific T cell activation in vitro was significantly suppressed in the presence of anti-MIF, as determined by a reduction in T cell proliferation, IFNγ and TNFα secretion.We next challenged syn and allo recipients with P815 lymphoblast-like mastocytoma cells (H-2d) at the time of transplantation to asses the effect of anti-MIF on graft versus leukemia (GVL) responses. Significant P815 cell infiltration was seen after syn SCT as demonstrated by FACS analysis of the spleens (67.2% infiltration) and by histopathology of the liver between day 14 and day 21 after SCT. In contrast, P815 cells were significantly cleared in allo recipients treated with either control or anti-MIF (0.81% and 12.1% infiltration).In summary, our data show an important role for MIF in GVHD pathophysiology and suggest MIF as a promising target in reducing GVHD without the loss of GVL. Acute graft versus host disease (GVHD) is the major complication after allogeneic (allo) stem cell transplantation (SCT) involving injury to host tissues by both inflammatory cytokines and donor-derived cellular effectors. Macrophage migration inhibitory factor (MIF) is produced by various cell types and has a broad range of proinflammatory properties. We tested, whether MIF contributes to GVHD by using a well established murine model. Lethally (1300 cGy) irradiated B6D2F1 (H-2bxd) mice received SCT either from syngeneic (syn) (B6D2F1) or allo (B6; H-2b) donors. One half of animals after either syn or allo SCT were treated with polyclonal antibodies against mouse MIF from day 0 until day 14, whereas the other halves of syn and allo recipients received control IgG. GVHD severity was assessed after SCT by survival and a clinical scoring system assessing weight changes, fur texture, skin integrity, mobility and posture. Syn recipients stayed clinically well and all animals survived regardless their treatment with control or anti-MIF. Animals receiving allo-SCT plus control IgG developed significant aGVHD and high mortality. By contrast, in allo anti-MIF treated recipients, GVHD scores (day 21: 4.4 ± 0.4 vs. 5.7 ± 0.5) and weight loss (24.6% vs. 45.4%) were reduced, and survival significantly improved (p < 0.05). In addition, target organ injury to the gut (histopathology score: 4.3 ± 0.7 vs. 8.0 ± 2.6) as well as serum IFNγ (4397 ± 995 vs. 6070 ± 525 pg/ml) and TNFα (113.9 ± 12.7 vs. 159.2 ± 22.5 pg/ml) levels of anti-MIF treated allo recipients were decreased by day 7 when compared to controls. Alloantigen-specific T cell activation in vitro was significantly suppressed in the presence of anti-MIF, as determined by a reduction in T cell proliferation, IFNγ and TNFα secretion. We next challenged syn and allo recipients with P815 lymphoblast-like mastocytoma cells (H-2d) at the time of transplantation to asses the effect of anti-MIF on graft versus leukemia (GVL) responses. Significant P815 cell infiltration was seen after syn SCT as demonstrated by FACS analysis of the spleens (67.2% infiltration) and by histopathology of the liver between day 14 and day 21 after SCT. In contrast, P815 cells were significantly cleared in allo recipients treated with either control or anti-MIF (0.81% and 12.1% infiltration). In summary, our data show an important role for MIF in GVHD pathophysiology and suggest MIF as a promising target in reducing GVHD without the loss of GVL.
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