PD-1 - PD-L1 pathway is involved in suppressing alloreactivity of heart infiltrating T cells during murine GVHD across minor histocompatibility antigen barriers
PD-1 - PD-L1 pathway is involved in suppressing alloreactivity of heart infiltrating T cells during murine GVHD across minor histocompatibility antigen barriers
复制标题
DOI：
10.1097/01.tp.0000268074.77929.54
复制
发表时间：
2007-07-27
期刊：
影响因子：
6.2
通讯作者：
Eyrich, Matthias
中科院分区：
文献类型：
--
作者：
Schilbach, Karin;Schick, Judith;Eyrich, Matthias
背景资料。移植物抗宿主病(GVHD)仍然是异基因干细胞移植后发病率和死亡率的主要原因。GVHD主要影响皮肤、肝脏和肠道，而其他器官通常不受影响。在目前的研究中，我们想要研究局部调节性T细胞(Treg)或免疫调节分子的差异表达是否与GVHD的器官特异性有关。在小鼠B10.D2->；BALB/c(均为H-2(D))模型中，移植1×10(7)骨髓和1×10(8)脾细胞诱导GVHD。我们比较了T细胞和树突状细胞标志CD40-CD40L、B7家族各成员、FoxP3和Th1/Th2细胞因子在回肠(GVHD靶器官)和心脏(非靶器官)中的表达。移植物抗宿主病在回肠中表现为CD4(+)T细胞增多，并伴有组织破坏，但在心脏中未见。我们发现在移植后第14天和第21天，PD-L1和CTLA-4在心脏中的表达显著增加，而其他分子在心脏和回肠中的表达没有明显差异。在心脏中，PD-L1在淋巴样细胞、内皮细胞、CD8α+CD11c+DC上表达，在GVHD时表达上调。相比之下，在回肠，只有内皮细胞每周染色PD-L1阳性。此外，我们也找不到心脏中存在Tregs的任何证据。我们的数据表明，免疫调节分子，如PD-L1，而不是Tregs，在同种异体反应的组织特异性调节中发挥关键作用。PD-L1通路在GVHD中的意义及其在治疗干预中的多功能性还需要进一步的研究。
Background. Graft-versus-host disease (GVHD) is still a major cause of morbidity and mortality after allogeneic stem cell transplantation. GVHD mainly affects skin, liver, and intestine, whereas other organs usually are spared. In the present study, we wanted to investigate whether local regulatory T cells (Treg) or differential expression of immunomodulatory molecules contribute to organ specificity of GVHD.Methods. In a murine B10.D2->BALB/c (both H-2(d)) model, GVHD was induced by transplantation of 1 x 10(7) bone marrow and 1 x 10(8) spleen cells. We compared expression of T-cell and dendritic cell markers, CD40-CD40L, various B7 family members, FoxP3, and Th1/Th2 cytokines between ileum (GVHD-target organ) and heart (nontarget organ).Results. GVHD was documented by an increase of CD4(+) T cells with accompanying tissue destruction in ileum but not in heart. We found a significantly increased expression of PD-L1 in heart on day 14 and 21 as well as of CTLA-4 on day 21 after transplantation, whereas all other molecules were not different between heart and ileum. In heart, PD-L1 was expressed on lymphoid cells, endothelial cells, CD8 alpha+CD11c+DCs, and up-regulated during GVHD. In contrast, in the ileum only endothelial cells stained weekly positive for PD-L1. Furthermore, we could not find any evidence for the presence of Tregs in the heart.Conclusions. Our data indicate that immunomodulatory molecules such as PD-L1 rather than Tregs play pivotal roles in the tissue-specific regulation of alloresponses. Further studies are needed to refine the significance of the PD-L1 pathway in GVHD and its versatility for therapeutic intervention.