Neutrophils provide cellular communication between ileum and mesenteric lymph nodes at graft-versus-host disease onset

Conditioning-induced damage of the intestinal tract plays a critical role during the onset of acute graft-versus-host disease (GVHD). Therapeutic interference with these early events of GVHD is difficult, and currently used immunosuppressive drugs mainly target donor T-cells. However not donor T-cells but neutrophils reach the sites of tissue injury first and therefore could be a potential target for GVHD-prevention. A detailed analysis of neutrophil fate during acute GVHD and impact on T-cells is difficult due to the short life-span of this cell type. By using a novel photoconverter reporter system we show that neutrophils that had been photoconverted in the ileum post-conditioning later migrated to mesenteric lymph nodes (mLN). This neutrophil migration was dependent on the intestinal microflora. In the mLN neutrophils colocalized with T-cells and presented antigen on MHC-II, thereby impacting T-cell expansion. Pharmacological JAK1/2 inhibition reduced neutrophil influx into the mLN and MHC-II expression thereby interfering with an early event in acute GVHD pathogenesis. In agreement with this finding, neutrophil-depletion reduced aGVHD. We conclude that neutrophils are attracted to the ileum, where the intestinal barrier is disrupted, and then migrate to the mLN where they participate in alloantigen-presentation. JAK1/2-inhibition can interfere with this process, which provides a potential therapeutic strategy to prevent early events of tissue damage-related innate immune cell activation and ultimately GVHD

Exogenous TNFR2 activation protects from acute GvHD via host T reg cell expansion

Donor CD4(+) Foxp(3+) regulatory T cells (T reg cells) suppress graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (HCT [allo-HCT]). Current clinical study protocols rely on the ex vivo expansion of donor T reg cells and their infusion in high numbers. In this study, we present a novel strategy for inhibiting GvHD that is based on the in vivo expansion of recipient T reg cells before allo-HCT, exploiting the crucial role of tumor necrosis factor receptor 2 (TNFR2) in T reg cell biology. Expanding radiation-resistant host T reg cells in recipient mice using a mouse TNFR2-selective agonist before allo-HCT significantly prolonged survival and reduced GvHD severity in a TNFR2-and T reg cell-dependent manner. The beneficial effects of transplanted T cells against leukemia cells and infectious pathogens remained unaffected. A corresponding human TNFR2-specific agonist expanded human T reg cells in vitro. These observations indicate the potential of our strategy to protect allo-HCT patients from acute GvHD by expanding T reg cells via selective TNFR2 activation in vivo