A highly selective inhibitor of IkappaB kinase, BMS-345541, augments graft survival mediated by suboptimal immunosuppression in a murine model of cardiac graft rejection.
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.
Townsend
Robert M
RM
Department of Immunology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543, USA. robert.townsend@bms.com
Postelnek
Jennifer
J
Susulic
Vojkan
V
McIntyre
Kim W
KW
Shuster
David J
DJ
Qiu
Yuping
Y
Zusi
F Christopher
FC
Burke
James R
JR
D000818:Animals; D023201:CD40 Ligand / Q000502:physiology; D002102:Cadaver; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D006084:Graft Rejection; D006085:Graft Survival / Q000187:drug effects*; D051550:I-kappa B Kinase; D007093:Imidazoles / Q000494:pharmacology*; D007376:Interleukin-2 / Q000096:biosynthesis; D051379:Mice; D008815:Mice, Inbred Strains; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000502:physiology; D011810:Quinoxalines / Q000494:pharmacology*
C471109:4(2'-aminoethyl)amino-1,8-dimethylimidazo(1,2-a)quinoxaline; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007376:Interleukin-2; D011810:Quinoxalines; D023201:CD40 Ligand; D017346:Protein Serine-Threonine Kinases; C496564:Chuk protein, mouse; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; C496566:Ikbke protein, mouse