Ex vivo inhibition of NF-κB signaling in alloreactive T-cells prevents graft-versus-host disease

M. J. O'Shaughnessy, C. Vogtenhuber, K. Sun, R. Sitcheran, A. S. Baldwin, William J Murphy, L. Dang, B. Jaffee, E. Palmer, J. S. Serody, B. R. Blazar

Research output: Contribution to journalArticle

14 Citations (Scopus)

Abstract

The ex vivo induction of alloantigen-specific hyporesponsiveness by costimulatory pathway blockade or exposure to immunoregulatory cytokines has been shown to inhibit proliferation, IL-2 production, and the graft-versus-host disease (GVHD) capacity of adoptively transferred T-cells. We hypothesized that inhibition of the intracellular NF-κB pathway in alloreactive T-cells, which is critical for T-cell activation events including IL-2 transcription, could lead to alloantigen hyporesponsiveness and loss of GVHD capacity. We demonstrate that treatment of mixed lymphocyte reaction (MLR) cultures with PS1145, a potent inhibitor of NF-κB activation, can induce T-cell hyporesponsiveness to alloantigen in primary and secondary responses while preserving in vitro responses to potent mitogenic stimulation. GVHD lethality in recipients of ex vivo PS1145-treated cells was profoundly inhibited. Parking of control or PS1145-treated MLR cells in syngeneic Rag -/- recipients resulted in intact contact hypersensitivity (CHS) responses. However, GVHD lethality capacity also was restored, suggesting that lymphopenic expansion uncoupled alloantigen hyporesponsiveness. These results indicate that the NF-κB pathway is a critical regulator of alloresponses and provide a novel small molecule inhibitor based approach that is effective in preventing early posttransplant GVHD lethality but that also permits donor T-cell responses to recover after a period of lymphopenic expansion.

Original languageEnglish (US)
Pages (from-to)452-462
Number of pages11
JournalAmerican Journal of Transplantation
Volume9
Issue number3
DOIs
StatePublished - Mar 2009
Externally publishedYes

Fingerprint

Graft vs Host Disease
Isoantigens
T-Lymphocytes
Mixed Lymphocyte Culture Test
Interleukin-2
Contact Dermatitis
Cytokines
PS1145

Keywords

  • Alloantigens
  • Allogeneic
  • Allograft tolreance
  • Alloreactive T cells
  • Allorecognition
  • Allotransplantation
  • Bone marrow transplantation
  • CD4+ T cells
  • Donor T-cell
  • Graft-versus-host disease
  • Immune tolerance
  • Nuclear factor - kappa B (NF-κB)
  • T cell

ASJC Scopus subject areas

  • Transplantation
  • Immunology and Allergy
  • Pharmacology (medical)

Cite this

Ex vivo inhibition of NF-κB signaling in alloreactive T-cells prevents graft-versus-host disease. / O'Shaughnessy, M. J.; Vogtenhuber, C.; Sun, K.; Sitcheran, R.; Baldwin, A. S.; Murphy, William J; Dang, L.; Jaffee, B.; Palmer, E.; Serody, J. S.; Blazar, B. R.

In: American Journal of Transplantation, Vol. 9, No. 3, 03.2009, p. 452-462.

Research output: Contribution to journalArticle

O'Shaughnessy, MJ, Vogtenhuber, C, Sun, K, Sitcheran, R, Baldwin, AS, Murphy, WJ, Dang, L, Jaffee, B, Palmer, E, Serody, JS & Blazar, BR 2009, 'Ex vivo inhibition of NF-κB signaling in alloreactive T-cells prevents graft-versus-host disease', American Journal of Transplantation, vol. 9, no. 3, pp. 452-462. https://doi.org/10.1111/j.1600-6143.2008.02533.x
O'Shaughnessy, M. J. ; Vogtenhuber, C. ; Sun, K. ; Sitcheran, R. ; Baldwin, A. S. ; Murphy, William J ; Dang, L. ; Jaffee, B. ; Palmer, E. ; Serody, J. S. ; Blazar, B. R. / Ex vivo inhibition of NF-κB signaling in alloreactive T-cells prevents graft-versus-host disease. In: American Journal of Transplantation. 2009 ; Vol. 9, No. 3. pp. 452-462.
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AU - Baldwin, A. S.

AU - Murphy, William J

AU - Dang, L.

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