Abstract
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 the effect on T cells is difficult because of the short lifespan of this cell type. By using a novel photoconverter reporter system, we show that neutrophils that had been photoconverted in the ileum postconditioning 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 major histocompatibility complex (MHC)-II, thereby affecting T cell expansion. Pharmacological JAK1/JAK2 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 acute GVHD. 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/JAK2-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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1858-1869 |
| Number of pages | 12 |
| Journal | Blood |
| Volume | 131 |
| Issue number | 16 |
| DOIs | |
| State | Published - Apr 19 2018 |
Bibliographical note
Funding Information:This study was supported by the Deutsche Forschungsgemeinschaft, Germany, SFB1160, project P14, ZE 872/4-1 (R.Z.), TRR167-NeuroMAC (R.Z.), ERC Consolidator grant (681012 GvHDCure) (R.Z.), Wilhelm Sander Stiftung (grant 2008.046.4), and Deutsche Krebshilfe (No. 111639) (R.Z. and G.H.), and from the National Institutes of Health, National Institute of Allergy and Infectious Diseases (U01 AI22285) (M.J.B.) and National Institutes of Health, National Heart, Lung, and Blood Institute (R01 HL56067) (B.R.B.), and the C & D Fund (M.J.B). This study was also supported in part by the Excellence Initiative of the German Research Foundation (GSC-4, Spemann Graduate School).
Funding Information:
The authors thank the staff of the Life Imaging Center in the Center for Biological Systems Analysis of the Albert-Ludwigs-University Freiburg and the Core Facility of the University Medical Center Freiburg for help with their confocal microscopy and flow cytometry resources. The authors further thank Gabriele Niedermann and Simone Gaedicke for providing the irradiation source for certain animals. This study was supported by the Deutsche Forschungsgemeinschaft, Germany, SFB1160, project P14, ZE 872/4-1 (R.Z.), TRR167-NeuroMAC (R.Z.), ERC Consolidator grant (681012 GvHDCure) (R.Z.), Wilhelm Sander Stiftung (grant 2008.046.4), and Deutsche Krebshilfe (No. 111639) (R.Z. and G.H.), and from the National Institutes of Health, National Institute of Allergy and Infectious Diseases (U01 AI22285) (M.J.B.) and National Institutes of Health, National Heart, Lung, and Blood Institute (R01 HL56067) (B.R.B.), and the C & D Fund (M.J.B). This study was also supported in part by the Excellence Initiative of the German Research Foundation (GSC-4, Spemann Graduate School).
Publisher Copyright:
© 2018 by The American Society of Hematology
