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 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 2125-2134 |
| Number of pages | 10 |
| Journal | Blood |
| Volume | 122 |
| Issue number | 12 |
| DOIs | |
| State | Published - Jan 1 2013 |
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ASJC Scopus subject areas
- Biochemistry
- Immunology
- Hematology
- Cell Biology
Cite this
Inhibiting retinoic acid signaling ameliorates graft-versus-host disease by modifying T-cell differentiation and intestinal migration. / Aoyama, Kazutoshi; Saha, Asim; Tolar, Jakub; Riddle, Megan J.; Veenstra, Rachelle G.; Taylor, Patricia A.; Blomhoff, Rune; Panoskaltsis-Mortari, Angela; Klebanoff, Christopher A.; Socíe, Ǵerard; Munn, David H.; Murphy, William J.; Serody, Jonathan S.; Fulton, Le Shara M.; Teshima, Takanori; Chandraratna, Roshantha A.; Dmitrovsky, Ethan; Guo, Yanxia; Noelle, Randolph J.; Blazar, Bruce R.
In: Blood, Vol. 122, No. 12, 01.01.2013, p. 2125-2134.Research output: Contribution to journal › Article
}
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.
PY - 2013/1/1
Y1 - 2013/1/1
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.
UR - http://www.scopus.com/inward/record.url?scp=84885458195&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84885458195&partnerID=8YFLogxK
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 -