Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-γ-dependent mechanism
Blockade of programmed death-1 engagement accelerates graft-versus-host disease lethality by an IFN-γ-dependent mechanism
复制标题
DOI：
10.4049/jimmunol.171.3.1272
复制
发表时间：
2003-08-01
影响因子：
4.4
通讯作者：
Taylor, PA
中科院分区：
文献类型：
--
作者：
Blazar, BR;Carreno, BM;Taylor, PA
急性移植物抗宿主病(GVHD)受多种途径的影响，这些途径可以通过向供者T细胞提供积极或消极的信号来增强或降低致死性。到目前为止，唯一报道的抑制GVHD的途径是CTLA-4：B7途径。由于程序性死亡-1(PD-1)通路的缺失与自身免疫的易感性有关，因此缺乏负面信号，因此用几种不同的方法探讨了PD-1通路阻断对GVHD的影响。在每一种情况下，移植物抗宿主病的致死率都明显加快。CTLA-4和PD-1的共同阻断在GVHD的增加中是相加的，表明这些通路并不是完全冗余的。虽然GVHD的增强既不需要穿孔素也不需要Fas配体的表达，但在没有PD-1结扎的情况下，供体干扰素-γ的产生是GVHD最佳加速所必需的。这些数据表明，PD-1结扎通过调节干扰素-γ的产生而下调GVHD，并为抑制GVHD的致死性提供了一个新的治疗靶点。
Acute graft-vs-host disease (GVHD) is influenced by pathways that can enhance or reduce lethality by providing positive or negative signals to donor T cells. To date, the only reported pathway to inhibit GVHD is the CTLA-4:B7 pathway. Because absence of the programmed death-1 (PD-1) pathway has been implicated in a predisposition to autoimmunity and hence a lack of negative signals, the effect of PD-1 pathway blockade on GVHD was explored using several distinct approaches. In each, GVHD lethality was markedly accelerated. Coblockade of CTLA-4 and PD-1 was additive in augmenting GVHD, indicating that these pathways are not fully redundant. Although neither perforin nor Fas ligand expression was required for GVHD enhancement, donor IFN-gamma production was required for optimal GVHD acceleration in the absence of PD-1 ligation. These data indicate that PD-1 ligation down-regulates GVHD through modulation of IFN-gamma production and suggest a novel therapeutic target for inhibiting GVHD lethality.