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, W. J. Murphy, L. Dang, B. Jaffee, E. Palmer, J. S. Serody, B. R. Blazar

Research output: Contribution to journalArticle

14 Scopus citations

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

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

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