Blood Journal
Leading the way in experimental and clinical research in hematology

Inflammatory neovascularization during graft-versus-host disease is regulated by αv integrin and miR-100

  1. Franziska Leonhardt1,
  2. Sebastian Grundmann2,
  3. Martin Behe3,
  4. Franziska Bluhm4,
  5. Rebecca A. Dumont5,
  6. Friederike Braun6,
  7. Melpomeni Fani7,
  8. Katarina Riesner8,
  9. Gabriele Prinz1,
  10. Anne-Kathrin Hechinger1,
  11. Ulrike V. Gerlach9,
  12. Heide Dierbach1,
  13. Olaf Penack8,
  14. Annette Schmmitt-Gräff9,
  15. Jürgen Finke1,
  16. Wolfgang A. Weber6, and
  17. Robert Zeiser1,*
  1. 1 Department of Hematology and Oncology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany;
  2. 2 Department of Cardiology and Angiology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany;
  3. 3 Department of Nuclear Medicine, Universitaetsspital Zurich, Switzerland;
  4. 4 Department of Biology, Albert-Ludwigs-University, Freiburg, Germany;
  5. 5 Department of Radiology, David Geffen School of Medicine at University of California, Los Angeles, CA, United States;
  6. 6 Department of Nuclear Medicine, Freiburg University Medical Center, University of Freiburg, Germany;
  7. 7 Department of Nuclear Medicine, Universitaetsspital Basel, Basel, Switzerland;
  8. 8 Department of Hematology, Oncology and Tumorimmunology, Charite University Medicine Berlin, Campus Virchow Klinikum, Berlin, Germany;
  9. 9 Department of Pathology, Freiburg University Medical Center, Albert-Ludwigs-University, Freiburg, Germany
  1. * Corresponding author; email: robert.zeiser{at}uniklinik-freiburg.de

Key points

  • Our data from the mouse model and patients indicate that inflammatory neovascularization during GvHD is targetable via alpha v integrin.

  • We identify a negative regulation of GvHD related neovascularization by miR-100.

Abstract

Acute graft-versus-host disease (aGvHD) is a complex process that involves endothelial damage and neovascularization. A better understanding of the pathophysiology of neovascularization during GvHD could help to target this process while leaving T cell (Tc) function intact. Under ischemic conditions neovascularization is regulated by different microRNAs (miRs) which potentially also play a role in inflamed hypoxic GvHD target organs. We observed strong neovascularization in the murine inflamed intestinal tract (IT) during GvHD. Positron-emission-tomography-imaging demonstrated abundant αvβ3integrin expression within intestinal neovascularization areas. To interfere with neovascularization we targeted αvintegrin expressing endothelial cells which blocked their accumulation in the IT and reduced GvHD severity independent of immune reconstitution and graft-versus-tumor effects. Additionally, enhanced neovascularization and αvintegrin expression correlated with GvHD severity in humans. Expression analysis of microRNAs in the inflamed IT of mice developing GvHD identified miR-100 as significantly downregulated. Inactivation of miR-100 enhanced GvHD indicating a protective role for miR-100 via blocking inflammatory neovascularization. Our data from the mouse model and patients indicate that inflammatory neovascularization is a central event during intestinal GvHD that can be inhibited by targeting αvintegrin. We identify a negative regulation of GvHD related neovascularization by miR-100 which indicates common pathomechanistic features of GvHD and ischemia.

  • Submitted July 11, 2012.
  • Accepted January 9, 2013.