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Regulation of acute graft-versus-host disease by microRNA-155

Parvathi Ranganathan, Catherine E.A. Heaphy, Stefan Costinean, Nicole Stauffer, Caroline Na, Mehdi Hamadani, Ramasamy Santhanam, Charlene Mao, Patricia A. Taylor, Sukhinder Sandhu, Gang He, Arwa Shana'ah, Gerard J. Nuovo, Susanna Obad, Oliver Broom, Sakari Kauppinen, John C. Byrd, Michael Caligiuri, Danilo Perrotti, Gregg A. Hadley, Guido Marcucci, Steven M. Devine, Bruce R. Blazar, Carlo M. Croce and Ramiro Garzon

Abstract

Acute graft-versus-host disease (aGVHD) remains a major complication of allogeneic hematopoietic stem cell transplant (alloHSCT), underscoring the need to further elucidate its mechanisms and develop novel treatments. Based on recent observations that miR-155 is up-regulated during T cell activation, we hypothesized that miR-155 is involved in the modulation of aGVHD. Here we show that miR-155 expression was up-regulated in T cells from mice developing aGVHD following alloHSCT. Mice receiving miR-155 deficient donor lymphocytes had markedly reduced lethal aGVHD, while lethal aGVHD developed rapidly in mice recipients of miR-155 over-expressing T cells. Blocking miR-155 expression using a synthetic antimiR-155 following alloHSCT decreased aGVHD severity and prolonged survival in mice. Finally, miR-155 up-regulation was shown in specimens from patients with pathological evidence of intestinal aGVHD. Altogether our data indicate a role for miR-155 in the regulation of GVHD, and point to miR-155 as a novel target for therapeutic intervention in this disease.

  • Submitted October 21, 2011.
  • Accepted March 1, 2012.