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, Ǵerard Socíe, David H Munn, William J. Murphy, Jonathan S. Serody, Le Shara M. Fulton, Takanori Teshima, Roshantha A. Chandraratna, Ethan Dmitrovsky, Yanxia Guo, Randolph J. Noelle, Bruce R. Blazar

Research output: Contribution to journalArticle

20 Citations (Scopus)

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 languageEnglish (US)
Pages (from-to)2125-2134
Number of pages10
JournalBlood
Volume122
Issue number12
DOIs
StatePublished - Jan 1 2013

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T-cells
Graft vs Host Disease
Tretinoin
Grafts
Cell Differentiation
T-Lymphocytes
Retinoic Acid Receptors
Vitamin A
Intestines
Eragrostis
Transplantation (surgical)
Homologous Transplantation
Response Elements
Antigen-Presenting Cells
Luciferases
Bone Marrow Transplantation
Pathology
Metabolites
Metabolism
Permeability

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Aoyama, K., Saha, A., Tolar, J., Riddle, M. J., Veenstra, R. G., Taylor, P. A., ... 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

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 journalArticle

Aoyama, K, Saha, A, Tolar, J, Riddle, MJ, Veenstra, RG, Taylor, PA, Blomhoff, R, Panoskaltsis-Mortari, A, Klebanoff, CA, Socíe, Ǵ, Munn, DH, Murphy, WJ, Serody, JS, Fulton, LSM, Teshima, T, Chandraratna, RA, Dmitrovsky, E, Guo, Y, Noelle, RJ & Blazar, BR 2013, 'Inhibiting retinoic acid signaling ameliorates graft-versus-host disease by modifying T-cell differentiation and intestinal migration', Blood, vol. 122, no. 12, pp. 2125-2134. https://doi.org/10.1182/blood-2012-11-470252
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. / Inhibiting retinoic acid signaling ameliorates graft-versus-host disease by modifying T-cell differentiation and intestinal migration. In: Blood. 2013 ; Vol. 122, No. 12. pp. 2125-2134.
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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.

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