Ex vivo inhibition of NF-kappaB signaling in alloreactive T-cells prevents graft-versus-host disease. Academic Article uri icon

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-kappaB 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-kappaB 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-kappaB 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.

published proceedings

  • Am J Transplant

author list (cited authors)

  • O'Shaughnessy, M. J., Vogtenhuber, C., Sun, K., Sitcheran, R., Baldwin, A. S., Murphy, W. J., ... Blazar, B. R.

citation count

  • 13

complete list of authors

  • O'Shaughnessy, MJ||Vogtenhuber, C||Sun, K||Sitcheran, R||Baldwin, AS||Murphy, WJ||Dang, L||Jaffee, B||Palmer, E||Serody, JS||Blazar, BR

publication date

  • March 2009

publisher