Introduction

Clinical regimens of immunosuppression involve different types of agents because the targets of each drug are the halfway points of signaling pathways leading to expression of various essential proteins in immune cells activation. Nuclear factor (NF)-?B is one of key transcriptional factors and is located in the down stream of several signaling pathways activated in immune responses. Therefore pharmacological modulation of NF-?B activities may be of great use for the treatment of allograft rejection. In this study, we investigated for an immunosuppressive effect of a novel NF-?B inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), using a rat kidney transplant model between a highly immune reactive combination.

Methods

We performed kidney allograft transplant in a rat acute rejection model (WKAH to LEWIS rats, age 6-8 weeks). Rats were randomly assigned into 3 groups (A: control group, not administrated DHMEQ, B: administration of 12 mg/kg DHMEQ, C: administration of 20 mg/kg DHMEQ). DHMEQ was administrated i.p. once daily for consecutive 10 days. Urine and blood samples were collected every each day. The date of anuria was determined as the date of rejection. Transplanted kidney allografts were also explanted on the 4th postoperative day and the infiltration rates of T cells and monocytes were investigated by immunohistochemistry.

Results

DHMEQ significantly prolonged kidney allograft survival. (7.2 ± 1.4 post-transplant days, 13.5 ± 3.4 post-transplant days, 19.4 ± 4.5 post-transplant days, for a control (group A), 12 mg/kg DHMEQ (group B), 20 mg/kg DHMEQ (group C), respectively). There was a reduction of T cell and macrophage infiltration to DHMEQ-treated kidney allografts compared to control allografts. The production of pro-inflammatory cytokines including IL-6, IL-12 p70, TNF-? in the recipients treated with DHMEQ was significantly decreased compared to that in the control group. No remarkable side effects were observed during the experiments.

Conclusions

DHMEQ is remarkably effective in preventing kidney allograft rejection. DHMEQ can be administrated safely and could be involved in a new immunosuppressive strategy, which allows reducing the dose of current immunosuppressive agents.

Funding

none