Wang Z, Larregina A T, Shufesky W J, Perone M J, Montecalvo A, Zahorchak A F, Thomson A W, Morelli A E
Thomas E. Starzl Transplantation Institute and Department of Surgery, University of Pittsburgh Medical Center, Pittsburgh, PA 15213, USA.
Am J Transplant. 2006 Jun;6(6):1297-311. doi: 10.1111/j.1600-6143.2006.01308.x.
Tolerance induction against donor allo-antigens (allo-Ag) remains one of the most challenging aspects of transplant immunology. The ability of dendritic cells (DC) to participate in immunity and tolerance makes them an excellent tool for tolerance induction. Here, we employed the immunosuppressive properties of apoptotic cells to deliver simultaneously an inhibitory signal and donor allo-Ag to recipient DC for treatment of allograft rejection. DC that captured apoptotic cells remained immature and activated deficiently anti-donor CD4(+) T cells that were unable to upregulate T-cell activation markers, to secrete IL-2 and IFN-gamma and to survive under homeostatic conditions due to low expression of Bcl-X(L), IL-7R and IL-15R. Administration of donor apoptotic cells decreased the systemic anti-donor T- and B-cell response and prolonged cardiac allograft survival in mice. The effect was donor specific and required the interaction of donor apoptotic cells with recipient quiescent CD8alpha(+) DC. When combined with CD40-CD154-blockade, administration of donor apoptotic cells resulted in indefinite graft survival mediated by generation of regulatory T cells. The use of the inhibitory effects of apoptotic cells on the anti-donor response provides a new approach to treat transplant rejection.
诱导对供体同种异体抗原（allo-Ag）的耐受性仍然是移植免疫学中最具挑战性的方面之一。树突状细胞（DC）参与免疫和耐受的能力使其成为诱导耐受性的理想工具。在此，我们利用凋亡细胞的免疫抑制特性，将抑制信号和供体allo-Ag同时传递给受体DC，以治疗同种异体移植排斥反应。捕获凋亡细胞的DC保持不成熟状态，激活缺陷的抗供体CD4(+) T细胞，这些T细胞由于Bcl-X(L)、IL-7R和IL-15R表达较低，无法上调T细胞激活标志物，无法分泌IL-2和IFN-γ，也无法在稳态条件下存活。给予供体凋亡细胞可降低全身性抗供体T细胞和B细胞反应，并延长小鼠心脏同种异体移植的存活时间。这种效应具有供体特异性，需要供体凋亡细胞与受体静止的CD8α(+) DC相互作用。当与CD40-CD154阻断联合使用时，给予供体凋亡细胞可通过产生调节性T细胞介导实现移植的长期存活。利用凋亡细胞对抗供体反应的抑制作用为治疗移植排斥反应提供了一种新方法。
