Control of allograft rejection by applying a novel nuclear factor-kappaB inhibitor, dehydroxymethylepoxyquinomicin.
BACKGROUND
Nuclear factor (NF)-kappaB plays a crucial role in lymphocyte activation, proliferation, and survival. We examined the immunosuppressive effect of a newly developed NF-kappaB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ) in allotransplantation.


METHODS
Purified C57BL/6 (H-2b) T cells were used for in vitro studies examining activation, proliferation, cytokine production and nuclear NF-kappaB and nuclear factor of activated T cells (NFAT) protein levels. A fully major histocompatibility complex incompatible BALB/c (H-2d)-to-C57BL/6 mice cardiac transplantation model was utilized for in vivo studies. DHMEQ was given intraperitoneally to transplant recipients at a various dose starting from day 0. In some, DHMEQ was administered concomitantly with tacrolimus.


RESULTS
DHMEQ significantly suppressed alphaCD3 + alphaCD28 monoclonal antibody-triggered T-cell proliferation, CD25/CD69 expressions, and both interleukin-2 and interferon (IFN)-gamma production in a dose-dependent fashion. DHMEQ blocked nuclear translocation of NF-kappaB but not NFAT in activated T cells. Combined treatment with DHMEQ and tacrolimus significantly suppressed T cell activation as compared to that of mono-therapy with either agent alone. Single DHMEQ treatment moderately prolonged cardiac allograft survival. Further, combination of DHMEQ plus tacrolimus markedly prolonged graft mean survival time (MST) to 59.5 days when compared to either DHMEQ (MST: 10 days) or tacrolimus (MST: 13 days) treatment alone. Such effect was associated with inhibition of mixed lymphocyte reaction against donor antigen, IFN-gamma producing splenocytes and graft cellular infiltration as examined at 5 and 12 days posttransplantation.


CONCLUSIONS
DHMEQ inhibits nuclear translocation of NF-kappaB but not NFAT in activated T cells, and prolongs allograft survival. Blocking both NF-kappaB and NFAT by DHMEQ and tacrolimus induces potent immunosuppression, which may become a new modality in controlling allograft rejection.
Ueki
Shinya
S
First Department of Surgery, Hokkaido University, Sapporo, Japan.
Yamashita
Kenichiro
K
Aoyagi
Takeshi
T
Haga
Sanae
S
Suzuki
Tomomi
T
Itoh
Tomoo
T
Taniguchi
Masahiko
M
Shimamura
Tsuyoshi
T
Furukawa
Hiroyuki
H
Ozaki
Michitaka
M
Umezawa
Kazuo
K
Todo
Satoru
S
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001549:Benzamides / Q000627:therapeutic use*; D018106:CD28 Antigens / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D003512:Cyclohexanones / Q000627:therapeutic use*; D004359:Drug Therapy, Combination; D006084:Graft Rejection / Q000517:prevention & control*; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016559:Tacrolimus / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D001549:Benzamides; D018106:CD28 Antigens; D017252:CD3 Complex; D003512:Cyclohexanones; D007166:Immunosuppressive Agents; D016328:NF-kappa B; C464444:dehydroxymethylepoxyquinomicin; D016559:Tacrolimus