Tabata Akihiro, Morikawa Masayuki, Miyajima Masahiro, Bennett Brydon L, Satoh Yoshitaka, Huang Jianhua, Tamura Yasuaki, Sato Noriyuki, Abe Tomio
Department of Thoracic and Cardiovascular Surgery, Sapporo Medical University School of Medicine, Sapporo, Japan.
Transplantation. 2007 May 27;83(10):1358-64. doi: 10.1097/01.tp.0000264196.23944.90.
c-Jun N-terminal kinase (JNK) is reported to play crucial roles in T-cell activation and differentiation, and SP600125 is a small molecule that inhibits JNK. The aim of this study was to examine immunosuppressive action of this compound.
Rat heterotopic heart transplantation, popliteal lymph node (PLN) hyperplasia bioassay and lymphocyte proliferation assay.
SP600125 treatment reduced histological rejection, and dose-dependently extended median survival time of cardiac allografts from 7 days (vehicle) up to 20 days (40 mg/kg/day). Alloantigen-induced PLN hyperplasia was also inhibited by SP600125 in a similar fashion. SP600125 suppressed mixed lymphocyte reaction and OX52-positive lymphocyte proliferation (IC50: 1.5-5.7 microM). Thus, SP600125 inhibits both T-lymphocyte expansion in vitro and T-cell-mediated alloimmune responses in vivo. In addition, SP600125 interacted with cyclosporine additively to prolong cardiac allograft survival.
Our data provide the first evidence indicating the potential for JNK as a therapeutic target to inhibit the alloimmune response.
据报道，c-Jun氨基末端激酶（JNK）在T细胞活化和分化中起关键作用，而SP600125是一种抑制JNK的小分子。本研究旨在检测该化合物的免疫抑制作用。
大鼠异位心脏移植、腘窝淋巴结（PLN）增生生物测定和淋巴细胞增殖测定。
SP600125治疗减轻了组织学排斥反应，并剂量依赖性地将心脏同种异体移植物的中位存活时间从7天（载体）延长至20天（40mg/kg/天）。SP600125也以类似方式抑制同种抗原诱导的PLN增生。SP600125抑制混合淋巴细胞反应和OX52阳性淋巴细胞增殖（IC50：1.5 - 5.7 microM）。因此，SP600125在体外抑制T淋巴细胞扩增，在体内抑制T细胞介导的同种免疫反应。此外，SP600125与环孢素联合作用可延长心脏同种异体移植物的存活时间。
我们的数据提供了首个证据，表明JNK作为抑制同种免疫反应的治疗靶点具有潜力。
