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

Franziska Leonhardt, Sebastian Grundmann, Martin Behe, Franziska Bluhm, Rebecca A. Dumont, Friederike Braun, Melpomeni Fani, Katarina Riesner, Gabriele Prinz, Anne-Kathrin Hechinger, Ulrike V. Gerlach, Heide Dierbach, Olaf Penack, Annette Schmmitt-Gräff, Jürgen Finke, Wolfgang A. Weber, Robert Zeiser

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.