TY - JOUR
T1 - Inhibiting retinoic acid signaling ameliorates graft-versus-host disease by modifying T-cell differentiation and intestinal migration
AU - Aoyama, Kazutoshi
AU - Saha, Asim
AU - Tolar, Jakub
AU - Riddle, Megan J.
AU - Veenstra, Rachelle G.
AU - Taylor, Patricia A.
AU - Blomhoff, Rune
AU - Panoskaltsis-Mortari, Angela
AU - Klebanoff, Christopher A.
AU - Socíe, Ǵerard
AU - Munn, David H.
AU - Murphy, William J.
AU - Serody, Jonathan S.
AU - Fulton, Le Shara M.
AU - Teshima, Takanori
AU - Chandraratna, Roshantha A.
AU - Dmitrovsky, Ethan
AU - Guo, Yanxia
AU - Noelle, Randolph J.
AU - Blazar, Bruce R.
N1 - Funding Information:
1University of Minnesota Cancer Center and Department of Pediatrics, Division of Blood and Marrow Transplantation, Minneapolis, MN; 2Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, Oslo, Norway; 3Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD; 4Service d’Hématologie-Greffe, Hôpital Saint-Louis, Assistance Publique-Hopitaux de Paris, Université Paris VII Denis-Diderot, and Unité Institut National de la Santéet de la Recherche Médicale U940, Paris, France; 5Department of Pediatrics, Medical College of Georgia, Augusta, GA, and Immunotherapy Center, Medical College of Georgia, Augusta, GA; 6Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA; 7Lineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC; 8Department of Hematology, Hokkaido University Graduate School of Medicine, Sapporo, Japan; 9Drug Discovery and Development, IO Therapeutics Inc., Santa Ana, CA; and 10Department of Pharmacology and Toxicology and the11Department of Microbiology and Immunology at the Geisel School of Medicine at Dartmouth, Norris Cotton Cancer Center, Lebanon, NH
PY - 2013
Y1 - 2013
N2 - 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 RARa (dnRARa) showed markedly diminished lethality. The dnRARa transgenic T cells showed reduced Th1 differentiation and a4b7 and CCR9 expression associated with poor intestinal migration, low GVHD pathology, and reduced intestinal permeability, primarily via CD41 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.
AB - 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 RARa (dnRARa) showed markedly diminished lethality. The dnRARa transgenic T cells showed reduced Th1 differentiation and a4b7 and CCR9 expression associated with poor intestinal migration, low GVHD pathology, and reduced intestinal permeability, primarily via CD41 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.
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U2 - 10.1182/blood-2012-11-470252
DO - 10.1182/blood-2012-11-470252
M3 - Article
C2 - 23814022
AN - SCOPUS:84885458195
VL - 122
SP - 2125
EP - 2134
JO - Blood
JF - Blood
SN - 0006-4971
IS - 12
ER -