Gao D, Li J, Orosz C G, Bumgardner G L
The Ohio State University College of Medicine, Department of Surgery, Columbus, Ohio, USA.
Hepatology. 2000 Nov;32(5):1018-28. doi: 10.1053/jhep.2000.19325.
The current study evaluated the role of CD40/CD40 ligand (CD40L) and CD28/B7 costimulation signals during alloimmune responses independently mediated by CD4(+) or CD8(+) T cells. Allogeneic hepatocytes were transplanted into CD8 or CD4 knock out (KO) mice under cover of costimulatory blockade. Rejection of FVB/N (H-2(q)) hepatocytes occurred by day 10 posttransplant in untreated CD8 or CD4 KO (H-2(b)) mice. Treatment of CD8 or CD4 KO mice with anti-CD40L monoclonal antibody (mAb; MR1) resulted in significant prolongation of hepatocyte survival indicating that CD40/CD40L interactions were critical in both CD4(+) and CD8(+) T-cell initiated hepatocyte rejection. Anti-CD40L mAb also prolonged hepatocyte survival in B-cell KO (H-2(b)) mice, indicating that the efficacy of CD40/CD40L blockade in preventing hepatocyte rejection was B-cell (and antibody) independent. In contrast, treatment with CTLA4 fusion protein (CTLA4Ig), prolonged hepatocyte survival in CD8 KO but not CD4 KO mice, showing that CD28/B7 interactions were important in CD4(+) but not CD8(+) T-cell initiated hepatocyte rejection. Under selected circumstances, such as in CD40 KO mice, both CD4(+) and CD8(+) T cells mediate hepatocyte rejection in the absence of CD40/CD40L costimulation and without a significant contribution from CD28/B7 costimulation signals. These results highlight the disparate roles of CD40/CD40L and CD28/B7 costimulation signals in CD4(+) versus CD8(+) T-cell mediated immune responses to allogeneic hepatocytes. The CD4(+) T-cell independent, CD40L-sensitive, CD28/B7-independent pathway of CD8(+) T-cell activation in response to transplantation antigens is novel.
本研究评估了CD40/CD40配体（CD40L）和CD28/B7共刺激信号在由CD4(+)或CD8(+) T细胞独立介导的同种免疫反应中的作用。在共刺激阻断的掩护下，将同种异体肝细胞移植到CD8或CD4基因敲除（KO）小鼠体内。在未处理的CD8或CD4 KO（H-2(b)）小鼠中，移植后第10天出现FVB/N（H-2(q)）肝细胞排斥反应。用抗CD40L单克隆抗体（mAb；MR1）处理CD8或CD4 KO小鼠可显著延长肝细胞存活时间，表明CD40/CD40L相互作用在CD4(+)和CD8(+) T细胞引发的肝细胞排斥反应中均至关重要。抗CD40L mAb也延长了B细胞KO（H-2(b)）小鼠的肝细胞存活时间，表明CD40/CD40L阻断在预防肝细胞排斥反应中的疗效不依赖于B细胞（和抗体）。相反，用CTLA4融合蛋白（CTLA4Ig）处理可延长CD8 KO小鼠而非CD4 KO小鼠的肝细胞存活时间，表明CD28/B7相互作用在CD4(+)而非CD8(+) T细胞引发的肝细胞排斥反应中很重要。在特定情况下，如在CD40 KO小鼠中，CD4(+)和CD8(+) T细胞在缺乏CD40/CD40L共刺激且CD28/B7共刺激信号无显著作用的情况下介导肝细胞排斥反应。这些结果突出了CD40/CD40L和CD28/B7共刺激信号在CD4(+)与CD8(+) T细胞介导的对同种异体肝细胞免疫反应中的不同作用。CD8(+) T细胞对移植抗原反应的CD4(+) T细胞非依赖性、CD40L敏感性、CD28/B7非依赖性激活途径是新颖的。
