Neutralization of Macrophage Migration Inhibitory Factor (MIF) Reduces GVHD but Preserves GVL.

Acute graft versus host disease (aGVHD) is the major complication after allogeneic (allo) stem cell transplantation (SCT). The pathophysiology of aGVHD involves 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 including the induction of T cell activation and inflammatory cytokine secretion. In this study, we tested the hypothesis, that MIF contributes to systemic inflammation and mortality after allo-SCT by using a well established murine model (B6→B6D2F1). Lethally (1300cGy) irradiated B6D2F1 (H-2bxd) mice received SCT either from syngeneic (syn) (B6D2F1) or allo (B6; H2-b) donors. One half of animals after allo SCT was treated with polyclonal antibodies against mouse MIF from day 0 until day 14, whereas syn animals and the other half of allo recipients were treated with control IgG. The severity of GVHD was assessed after SCT by survival and a clinical scoring system that incorporates changes in weight loss, fur texture, skin integrity, mobility and posture. As expected, syn-SCT recipients all survived and were indistinguishable from naïve, untransplanted controls, whereas animals receiving allo-SCT plus control IgG developed significant aGVHD and none of the animals survived by day +28. By contrast, in allo recipients treated with anti-MIF antibodies clinical GVHD (day 21: 4.4±0.4 vs. 5.7±0.5) and weight loss (24.6% vs. 45.4%) were less severe, and this reduction in clinical GVHD translated into significantly improved survival (p<0.05). In addition, 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 recipients were decreased by day 7. 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 (38517±2411 vs. 65076±3959 cpm), IFNγ (832±117 vs. 4604±179 pg/ml) and TNFα (189.0±7.5 vs. 522.9±6.1 pg/ml) secretion. We next challenged syn and allo recipients with P815 tumor cells (H-2d) at the time of transplantation. No tumor cell elimination was seen after syn SCT. In contrast, FACS analysis revealed, that clearance of P815 cells was comparably high in allo recipients treated with either control or anti-MIF IgG. In summary, our data strongly suggest, that neutralizing MIF may be a novel approach to reduce GVHD but maintain GVL.