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 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
Externally publishedYes

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)

Fingerprint Dive into the research topics of 'Ex vivo inhibition of NF-κB signaling in alloreactive T-cells prevents graft-versus-host disease'. Together they form a unique fingerprint.

Cite this