LAUSR

Acute gut graft-versus-host disease (GVHD) is the major contributor to mortality and morbidity of allogeneic hematopoietic stem cell transplantation recipients. Steroids are the first-line therapy for acute GVHD, but approximately 30% of patients develop steroid refractory GVHD (SR-GVHD). The pathophysiology of SR-GVHD is poorly understood. In the current studies, we explored the mechanisms of SR-GVHD, using a murine model of MHC-mismatched HCT with C57BL/6 donors and BALB/c recipients. Acute GVHD can be mediated by either Th/Tc1 or Th/Tc17 T cells. We evaluated the impact of dexamethasone (DEX) treatment on acute GVHD induced by spleen and BM cells from WT, IFN-γ-/- or RORγt-/- C57BL/6 donors. WT donor T cells give rise predominantly to Th/Tc1 cells early after HCT, but Th/Tc17 cells can expand as time goes on. IFN-γ-/- donor T cells give rise to Th/Tc17 cells but not to IFN-γ-producing Th/Tc1 cells, while RORγt-/- donor T cells give rise to Th/Tc1 cells but not to Th/Tc17 cells. BALB/c recipients were treated with single dose dexamethasone (DEX) at 5 mg/Kg on day 3 after HCT. DEX treatment effectively prevented acute GVHD in recipients given WT or RORγt-/- grafts for up to 20 days after HCT. GVHD then recurred in recipients grafted with WT cells but not in recipients grafted with RORγt-/- cells. In contrast, DEX treatment had no effect on acute GVHD in recipients grafted with IFN-γ-/- cells. Recurrence of GVHD in DEX-treated recipients grafted with WT cells and the lack of DEX effect in recipients grafted with IFN-γ-/- cells was associated with expansion of Th/Tc17 cells that produced both IL-17 and IL-22. In recipients grafted with IFN-γ-/- cells, we also observed marked reduction of donor-type CX3CR1+ intestinal macrophages that play a critical role in controlling bacterial translocation from the intestinal lumen to the liver and blood. In addition, the DEX-treated recipients showed augmentation of Th/Tc17 differentiation and exacerbation of acute GVHD, When CX3CR1GFP/GFP mice that are deficient in generating CX3CR1+ intestinal macrophages were used as donors. These results indicate that DEX-treatment can cause expansion of Th/Tc17 and loss of protective donor-type CX3CR1+ intestinal macrophages, leading to SR-GVHD. Martin: Abgenomics: Research Funding; Enlivex Therapeutics: Consultancy; Genentech: Consultancy, Other: One-time advisory board; Neovii: Other: One-time advisory board; Pfizer: Other: Data and Safety Monitoring Committee; Pharmacyclics LLC: Other: One-time advisory board; Procter and Gamble: Equity Ownership; Xenikos: Research Funding.