Ex Vivo Blockade of NF-[dappa]B Signaling in Alloreactive T Cells Prevents Murine Graft-Versus-Host Disease (GVHD). Academic Article uri icon

abstract

  • Abstract A failure of IL-2 transcription has been associated with tolerance induction. We hypothesized that inhibition of the NF-B pathway in alloreactive T-cells, which is critical for IL-2 transcription, could lead to alloantigen-specific hyporesponsiveness and prevention of GVHD. PS1145, a potent inhibitor of IB kinase, and hence NF-B activation, was added to an MLR culture consisting of CD4+ T-cells and MHC class II-disparate stimulators. Inhibition of NF-B activity was verified by EMSA and confocal microscopy. Global inhibition of cytokine production and T-cell hyporesponsiveness was observed which persisted after washing T-cells and re-exposure to alloantigen. Responses to non-specific mitogens remained largely intact and alloantigen hyporesponsiveness was reversed by exogenous IL-2. Treatment of T cells and stimulator cells with PS1145 was required for maximal effect. Depletion of CD4+CD25+ cells from the MLR indicated that these cells were not required for tolerance induction in this system. Using an MLR system containing alloreactive and non-alloreactive transgenic T cells indicated that PS1145 treatment increased the rate of T-cell apoptosis selectively in alloreactive cells. Data from each of 4 experiments showed that GVHD in recipients of ex vivo PS1145 treated cells was profoundly inhibited, whereas CD4+ T-cells recovered from a vehicle-treated 7-day MLR were uniformly fatal upon adoptive transfer into sublethally irradiated MHC class II-disparate recipients. Studies addressing non-alloreactive in vivo responses of PS1145 treated T cells will also be presented. Our studies indicate that the NF-B pathway is a critical regulator of productive alloresponses and provide a novel ex vivo approach to induce alloantigen-specific tolerance as a means of preventing GVHD.

published proceedings

  • Blood

author list (cited authors)

  • OShaughnessy, M. J., Vogtenhuber, C., Serody, J. S., Sitcheran, R., Baldwin, A. S., Dang, L., Jaffee, B., & Blazar, B. R.

complete list of authors

  • O’Shaughnessy, Matthew J||Vogtenhuber, Christine||Serody, Jonathon S||Sitcheran, Raquel||Baldwin, Albert S||Dang, Lenny||Jaffee, Bruce||Blazar, Bruce R

publication date

  • November 2004

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