A small-molecule c-Rel inhibitor reduces alloactivation of T cells without compromising antitumor activity Academic Article uri icon

Overview

MeSH Major

  • Graft vs Host Disease
  • Lymphocyte Activation
  • Proto-Oncogene Proteins c-rel
  • Small Molecule Libraries
  • T-Lymphocytes

abstract

  • Preventing unfavorable GVHD without inducing broad suppression of the immune system presents a major challenge of allogeneic hematopoietic stem cell transplantation (allo-HSCT). We developed a novel strategy to ameliorate GVHD while preserving graft-versus-tumor (GVT) activity by small molecule-based inhibition of the NF-κB family member c-Rel. Underlying mechanisms included reduced alloactivation, defective gut homing, and impaired negative feedback on interleukin (IL)-2 production, resulting in optimal IL-2 levels, which, in the absence of competition by effector T cells, translated into expansion of regulatory T cells. c-Rel activity was dispensable for antigen-specific T-cell receptor (TCR) activation, allowing c-Rel-deficient T cells to display normal GVT activity. In addition, inhibition of c-Rel activity reduced alloactivation without compromising antigen-specific cytotoxicity of human T cells. Finally, we were able to demonstrate the feasibility and efficacy of systemic c-Rel inhibitor administration. Our findings validate c-Rel as a promising target for immunomodulatory therapy and demonstrate the feasibility and efficacy of pharmaceutical inhibition of c-Rel activity.

publication date

  • January 2014

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC4011979

Digital Object Identifier (DOI)

  • 10.1158/2159-8290.CD-13-0585

PubMed ID

  • 24550032

Additional Document Info

start page

  • 578

end page

  • 91

volume

  • 4

number

  • 5