Steiner David, Brunicki Noga, Bachar-Lustig Esther, Taylor Patricia A, Blazar Bruce R, Reisner Yair
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Exp Hematol. 2006 Jun;34(6):802-8. doi: 10.1016/j.exphem.2006.02.017.
Recently, we have shown that anti-third-party cytotoxic T lymphocytes (CTLs) depleted of alloreactivity against the host are endowed with marked veto activity and can facilitate bone marrow (BM) allografting without graft-versus-host disease. We also demonstrated synergism between rapamycin (RAPA) and the veto cells. CD4(+)CD25(+) T-regulatory (Treg) cells are suppressor cells that can enhance alloengraftment. We investigated whether donor Tregs would be synergistic with veto CTLs and RAPA in augmenting alloengraftment or, conversely, would suppress veto CTL effects. Lethally irradiated C3H mice were transplanted at day 2 after irradiation with Balb-nude BM. Graft rejection was induced by purified host-type T cells infused 1 day prior to BMT. The addition of Tregs led to moderate enhancement of engraftment. RAPA at different doses was synergistic with Tregs. The addition of veto CTLs to Tregs enabled reducing the effective RAPA dose fourfold. Combining all three agents was necessary to overcome rejection at low-dose RAPA. Chimerism analysis at 5 to 9 months revealed a significant presence of host-type cells coexisting with the predominant donor T cells, suggesting that tolerance had been attained. The synergistic effects between Tregs, veto CTLs, and RAPA offer an attractive approach for facilitating alloengraftment.
最近，我们已经表明，去除对宿主的同种异体反应性的抗第三方细胞毒性T淋巴细胞（CTL）具有显著的否决活性，并且可以促进骨髓（BM）同种异体移植而不发生移植物抗宿主病。我们还证明了雷帕霉素（RAPA）与否决细胞之间的协同作用。CD4(+)CD25(+) T调节（Treg）细胞是能够增强同种异体移植的抑制细胞。我们研究了供体Treg在增强同种异体移植方面是否会与否决CTL和RAPA协同作用，或者相反，是否会抑制否决CTL的作用。用Balb裸鼠骨髓在照射后第2天对致死性照射的C3H小鼠进行移植。在骨髓移植前1天注入纯化的宿主型T细胞诱导移植排斥。添加Treg导致移植的适度增强。不同剂量的RAPA与Treg具有协同作用。在Treg中添加否决CTL能够将有效RAPA剂量降低四倍。联合使用这三种药物对于在低剂量RAPA时克服排斥反应是必要的。5至9个月时的嵌合体分析显示，宿主型细胞与主要的供体T细胞共存，表明已获得耐受性。Treg、否决CTL和RAPA之间的协同作用为促进同种异体移植提供了一种有吸引力的方法。
