Inhibiting retinoic acid signaling ameliorates graft-versus-host disease by modifying T-cell differentiation and intestinal migration.

Kazutoshi Aoyama, Asim Saha, Jakub Tolar, Megan J. Riddle, Rachelle G. Veenstra, Patricia A. Taylor, Rune Blomhoff, Angela Panoskaltsis-Mortari, Christopher A. Klebanoff, Gérard Socié, David H. Munn, William J Murphy, Jonathan S. Serody, Leshara M. Fulton, Takanori Teshima, Roshantha A. Chandraratna, Ethan Dmitrovsky, Yanxia Guo, Randolph J. Noelle, Bruce R. Blazar

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Graft-versus-host disease (GVHD) is a critical complication after allogeneic bone marrow transplantation. During GVHD, donor T cells are activated by host antigen-presenting cells and differentiate into T-effector cells (Teffs) that migrate to GVHD target organs. However, local environmental factors influencing Teff differentiation and migration are largely unknown. Vitamin A metabolism within the intestine produces retinoic acid, which contributes to intestinal homeostasis and tolerance induction. Here, we show that the expression and function of vitamin A-metabolizing enzymes were increased in the intestine and mesenteric lymph nodes in mice with active GVHD. Moreover, transgenic donor T cells expressing a retinoic acid receptor (RAR) response element luciferase reporter responded to increased vitamin A metabolites in GVHD-affected organs. Increasing RAR signaling accelerated GVHD lethality, whereas donor T cells expressing a dominant-negative RARα (dnRARα) showed markedly diminished lethality. The dnRARα transgenic T cells showed reduced Th1 differentiation and α4β7 and CCR9 expression associated with poor intestinal migration, low GVHD pathology, and reduced intestinal permeability, primarily via CD4(+) T cells. The inhibition of RAR signaling augmented donor-induced Treg generation and expansion in vivo, while preserving graft-versus-leukemia effects. Together, these results suggested that reagents blunting donor T-cell RAR signaling may possess therapeutic anti-GVHD properties.

Original languageEnglish (US)
Pages (from-to)2125-2134
Number of pages10
JournalBlood
Volume122
Issue number12
DOIs
StatePublished - Sep 19 2013

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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    Aoyama, K., Saha, A., Tolar, J., Riddle, M. J., Veenstra, R. G., Taylor, P. A., Blomhoff, R., Panoskaltsis-Mortari, A., Klebanoff, C. A., Socié, G., Munn, D. H., Murphy, W. J., Serody, J. S., Fulton, L. M., Teshima, T., Chandraratna, R. A., Dmitrovsky, E., Guo, Y., Noelle, R. J., & Blazar, B. R. (2013). Inhibiting retinoic acid signaling ameliorates graft-versus-host disease by modifying T-cell differentiation and intestinal migration. Blood, 122(12), 2125-2134. https://doi.org/10.1182/blood-2012-11-470252