A highly selective inhibitor of IkappaB kinase, BMS-345541, augments graft survival mediated by suboptimal immunosuppression in a murine model of cardiac graft rejection

Transplantation. 2004 Apr 15;77(7):1090-4. doi: 10.1097/01.tp.0000118407.05205.05.

Abstract

Background: We previously demonstrated in vitro and in vivo that an IkappaB kinase (IKK) inhibitor blocks cytokine production and suppresses immune responses. These results indicate that a potent IKK inhibitor may have the potential of being a novel therapeutic agent for the prevention of graft rejection.

Methods: The IKK inhibitor BMS-345541 was tested in mice for its ability to inhibit anti-CD3-induced interleukin (IL)-2 and tumor necrosis factor (TNF)-alpha production and T-cell proliferation in an in vivo mixed lymphocyte reaction. BMS-345541 was further tested for its ability to suppress graft rejection in a murine nonvascularized heterotopic cardiac allograft model. BMS-345541 was tested as a single agent and in combination with other immunomodulators for inhibition of T-cell proliferation and graft rejection in vivo.

Results: BMS-345541 suppressed, in a dose-dependent manner, the production of both IL-2 and TNF-alpha in mice stimulated with an injection of anti-CD3 antibody. Approximately 70% inhibition of both IL-2 and TNF were observed at a dose of 100 mg/kg. When BMS-345541 was administered at 100 mg/kg as a single agent, in vivo T-cell proliferation was not inhibited. However, when combined with a suboptimal dose of cytotoxic T-lymphocyte antigen-4 immunoglobulin (200 microg), a synergistic antiproliferative effect was observed, resulting in 77% inhibition of CD4+ T-cell proliferation. In the murine heterotopic heart transplant model, BMS-345541 did not prolong graft survival when administered at 50 mg/kg as a single agent. However, when administered with a suboptimal dose of cytotoxic T-lymphocyte antigen-4 immunoglobulin or cyclosporine A (15 mg/kg), graft survival was significantly increased compared with either agent alone.

Conclusions: These results indicate that inhibition of IKK may serve as novel adjunctive therapy for the prevention of graft rejection.

MeSH terms

  • Animals
  • CD40 Ligand / physiology
  • Cadaver
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Graft Rejection
  • Graft Survival / drug effects*
  • I-kappa B Kinase
  • Imidazoles / pharmacology*
  • Interleukin-2 / biosynthesis
  • Mice
  • Mice, Inbred Strains
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / physiology
  • Quinoxalines / pharmacology*

Substances

  • 4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline
  • Enzyme Inhibitors
  • Imidazoles
  • Interleukin-2
  • Quinoxalines
  • CD40 Ligand
  • Protein-Serine-Threonine Kinases
  • Chuk protein, mouse
  • I-kappa B Kinase
  • Ikbkb protein, mouse
  • Ikbke protein, mouse