Larsen C P, Elwood E T, Alexander D Z, Ritchie S C, Hendrix R, Tucker-Burden C, Cho H R, Aruffo A, Hollenbaugh D, Linsley P S, Winn K J, Pearson T C
The Carlos and Marguerite Mason Transplantation Research Center, Emory University School of Medicine, Atlanta, Georgia 30322, USA.
Nature. 1996 May 30;381(6581):434-8. doi: 10.1038/381434a0.
The receptor-ligand pairs CD28-B7 and CD40-gp39 are essential for the initiation and amplification of T-cell-dependent immune responses. CD28-B7 interactions provide 'second signals' necessary for optimal T-cell activation and IL-2 production, whereas CD40-gp39 signals co-stimulate B-cell, macrophage, endothelial cell and T-cell activation. Nonetheless, blockade of either of these pathways alone is not sufficient to permit engraftment of highly immunogenic allografts. Here we report that simultaneous but not independent blockade of the CD28 and CD40 pathways effectively aborts T-cell clonal expansion in vitro and in vivo, promotes long-term survival of fully allogeneic skin grafts, and inhibits the development of chronic vascular rejection of primarily vascularized cardiac allografts. The requirement for simultaneous blockade of these pathways for effective inhibition of alloimmunity indicates that, although they are interrelated, the CD28 and CD40 pathways are critical independent regulators of T-cell-dependent immune responses.
受体-配体对CD28-B7和CD40-gp39对于T细胞依赖性免疫反应的启动和放大至关重要。CD28-B7相互作用提供了最佳T细胞激活和白细胞介素-2产生所需的“第二信号”，而CD40-gp39信号则共同刺激B细胞、巨噬细胞、内皮细胞和T细胞的激活。然而，单独阻断这些途径中的任何一条都不足以允许高度免疫原性同种异体移植物的植入。在此，我们报告同时而非独立地阻断CD28和CD40途径可有效在体外和体内中止T细胞克隆扩增，促进完全同种异体皮肤移植物的长期存活，并抑制主要血管化心脏同种异体移植物慢性血管排斥反应的发展。有效抑制同种免疫需要同时阻断这些途径，这表明尽管它们相互关联，但CD28和CD40途径是T细胞依赖性免疫反应的关键独立调节因子。
