Wang Yue, Gao Donghong, Lunsford Keri E, Frankel Wendy L, Bumgardner Ginny L
Department of Surgery, The Ohio State University Medical Center, Columbus, OH, USA.
Am J Transplant. 2003 Oct;3(10):1251-8. doi: 10.1046/j.1600-6143.2003.00201.x.
Allogeneic hepatocytes elicit CD4-dependent and (CD4-independent) CD8+ T-cell-initiated graft rejection. The (CD4-independent) CD8+ T-cell pathway is resistant to immunosuppressive strategies that readily and indefinitely suppress CD4+ T-cell-dependent rejection responses. Consequently, successful immunoregulation of hepatocyte-initiated immune responses requires a strategy which regulates both CD4-dependent and CD8-dependent rejection responses. Interference with CD40/CD40 ligand (CD40L) costimulation only transiently suppresses CD4- and CD8-dependent hepatocyte rejection. Interference with CD28/B7 costimulation transiently suppresses CD4-dependent hepatocyte rejection, but is ineffective for suppression of CD8-dependent hepatocyte rejection. To date, hepatocyte survival > 60 days post-transplant has not been achieved by any immunotherapeutic strategy. In the current study, we evaluated a novel immunosuppressive strategy which targets both LFA-1 and CD40L-mediated signals. Targeting LFA-1 suppressed (CD4-independent) CD8+ T-cell-initiated hepatocyte rejection such that allogeneic hepatocyte survival > 60 days was achieved in 70% of CD4 KO mice. Targeting both LFA-1-mediated signals and CD40/CD40L costimulation resulted in synergistic effects, such that hepatocellular survival > 60 days was achieved in 100% of C57BL/6 mice (which have both CD4- and CD8-dependent T-cell pathways available).
同种异体肝细胞引发CD4依赖性和（不依赖CD4的）CD8+T细胞介导的移植排斥反应。不依赖CD4的CD8+T细胞途径对免疫抑制策略具有抗性，这些策略能够轻易且持久地抑制CD4+T细胞依赖性排斥反应。因此，成功免疫调节肝细胞引发的免疫反应需要一种能够同时调节CD4依赖性和CD8依赖性排斥反应的策略。干扰CD40/CD40配体（CD40L）共刺激仅能短暂抑制CD4和CD8依赖性肝细胞排斥反应。干扰CD28/B7共刺激能短暂抑制CD4依赖性肝细胞排斥反应，但对抑制CD8依赖性肝细胞排斥反应无效。迄今为止，尚未有任何免疫治疗策略能使移植后肝细胞存活超过60天。在当前研究中，我们评估了一种针对LFA-1和CD40L介导信号的新型免疫抑制策略。靶向LFA-1可抑制不依赖CD4的CD8+T细胞介导的肝细胞排斥反应，从而使70%的CD4基因敲除小鼠的同种异体肝细胞存活超过60天。同时靶向LFA-1介导的信号和CD40/CD40L共刺激产生了协同效应，使得100%的C57BL/6小鼠（其同时具备CD4和CD8依赖性T细胞途径）的肝细胞存活超过60天。
