Inhibiting retinoic acid signaling ameliorates graft-versus-host disease by modifying T-cell differentiation and intestinal migration
Year: 2013
Type: article
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.
Source: Blood
Authors: 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
Institutions: University of Minnesota, Masonic Cancer Center, University of Oslo, National Institutes of Health, National Cancer Institute, Center for Cancer Research, Inserm, Assistance Publique – Hôpitaux de Paris, Hôpital Saint-Louis, Université Paris Diderot, Augusta University, University of California, Davis, University of North Carolina at Chapel Hill, UNC Lineberger Comprehensive Cancer Center, Hokkaido University, Io Therapeutics (United States), Dartmouth College, Dartmouth Cancer Center
Language: English
Subfield: Hematology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: A novel mechanism of posttransplant female infertiliy, T-Cell Targeting for GVHD, In vivo Prevention of Murine GVHD, The cellular and molecular basis for the impact of vitamin A on immunity., Retinoic Acid Paradox and Promyelocitic Leukemia, Mechanisms of disruption of homeostasis in GVHD, Mechanisms, Prevention and Treatment of Chronic Graft-vs.-Host Disease, Cytotoxic-T-Lymphocyte (CTL) Therapy of AML, MRC Centre for Transplantation, Targeting CCR7 for the Prevention/Treatment of GvHD, Vitamin A and acquired immune privilege, ROLE OF TNF FAMILY MEMBERS IN MEMORY B CELL DEVELOPMENT, T Cell Costimulatory Pathways: Functions and Interactions, Th1/Th17 Macrophage Interactions in Cutaneous GVHD, Cancer Center Support Grant, Off-the-Shelf Immune Effector Cells for Hematological Malignancies, Cancer Center Support Grant
OpenAlex ID: W2021689228