EXPERIMENTAL IMMUNOBIOLOGY

K. Shinoda¹, K. Nakagawa², H. Kono³, E. Kikuchi¹, A. Miyajima¹, M. Oya^1
1, Keio University, Tokyo/JAPAN, ²Urology, Keio University, Tokyo/JAPAN, ³Department Of Urology, Keio University, Tokyo/JAPAN

Body: Introduction: Nuclear factor κB (NFκB) is a key transcriptional factor that promotes the transcription of a series of genes of cytokines and adhesion molecules which are highly involved in the onset of T cell mediated acute rejection in organ transplantation. We previously synthesized a novel NF-κB inhibitor, dehydroxymethylepoxyquinomicin (DHMEQ), which is a highly specific NF-κB inhibitor that interferes with the nuclear translocation of activated NF-κB. Therefore, we examined the effects of DHMEQ as a possible immunosuppressive agent by investigating whether DHMEQ could prolong animal survival in a rat renal allograft model. Method: Heterotopic rat ranal transplantation was performed (WKAH-Lewis). Recipients were divided into three groups. Group1 and 2 were given DHMEQ (12 or 20 mg/kg, respectively) and Group 3 were given control vehicle (0.5% DMSO) for 7 days, starting from day0 (n = 6 each). Twenty-four-hour urine and serum samples were collected on alternate days following transplantation. The time of rejection was defined as the anuric day. On day 4, recipients in each groups (n = 5) were sacrificed and examined for histology (HE, PAS, and immunohistochemical study) and the transcription and the production of cytokines (RT-PCR and ELISA). Results: Renal allograft survival was significantly prolonged in group 1 and 2 as compared to control group (group1: 13.5 ± 3.4 and group2: 19.4 ± 4.5 vs. group3: 7.2 ± 1.4 days, p< 0.05 and p < 0.01, respectively). Moreover, graft survival in DHMEQ-treated groups was prolonged in a dose-dependent manner. Graft function (serum creatinine on day4, group 1: 0.99 ± 0.14 and group 2: 0.98 ± 0.14 vs. group 3: 2.4 ± 0.32, p< 0.05 and p < 0.01, respectively) and histological structure was well preserved in DHMEQ-treated groups. Cellular infiltration into allografts and the expression of adhesion molecules (CD4, CD8, ED1, MCP-1, and ICAM-1 by immunohistochemistry) were significantly decreased in DHMEQ-treated groups. Furthermore, the transcription and the production of proinflammatory cytokines (IL-2, IL-6, iNOS, MCP-1, and TNF-a) were also significantly inhibited in DHMEQ-treated groups. Conclusion: DHMEQ markedly prolonged renal allograft survival and inhibited cellular infiltration into allografts and the expression of proinflammatory proteins. DHMEQ is a promising specific NF-κB inhibitor and future clinical application is expected.

Disclosure: All authors have declared no conflicts of interest.