Ligation of OX40 (CD134) regulates graft-versus-host disease (GVHD) and graft rejection in allogeneic bone marrow transplant recipients
Ligation of OX40 (CD134) regulates graft-versus-host disease (GVHD) and graft rejection in allogeneic bone marrow transplant recipients
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DOI：
10.1182/blood-2002-10-3048
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发表时间：
2003-05-01
期刊：
影响因子：
20.3
通讯作者：
Taylor, PA
中科院分区：
文献类型：
--
作者：
Blazar, BR;Sharpe, AH;Taylor, PA
OX 40（CD 134）在活化的T细胞上表达;其配体OX 40配体（OX 40 L）在树突状细胞、B细胞和活化的内皮细胞上表达。为了确定0X 40 - 0X 40 L相互作用如何影响移植物抗宿主病（GVHD），我们使用拮抗性抗0X 40 L单克隆抗体（mAb）或0X 40（-/-）供体或0X 40 L（-/-）受体小鼠。用每种方法观察到相似程度的GVHD减少。尽管在GVHD期间分离的CD 4（+）和CD 8（+）T细胞上OX 40都上调，但在GVHD和移植模型系统中评估的OX 40连接的主要作用是CD 4（+）而不是CD 8（+）T细胞介导的同种异体应答。通过阻断OX 40/OX 40 L途径抑制GVHD不需要CD 28信号传导。一些研究表明，OX 40是诱导辅助性T细胞2型（Th 2）反应所必需的。然而，体内阻断OX 40-OX 40 L相互作用降低了由信号转导和转录激活因子-6（-/-）（Stat-6（-/-））（Th 2缺陷型）或Stat-4（-/-）（Th 1缺陷型）主要组织相容性复合体（MHC）-不同脾细胞诱导的GVHD死亡率，表明GVHD-amellorating效应不需要Stat-4或Stat-6信号传导。尽管已经报道了OX 40 L在活化的T细胞上表达，但是当在不同模型中输注OX 40 L（-/-）与OX 40 L（+/+）T细胞时，没有观察到对GVHD的影响。这些数据提供了关于负责OX 40/OX 40 L调节GVHD的机制的见解。(C)2003年，美国血液学会。
OX40 (CD134) is expressed on activated T cells; its ligand, OX40 ligand (OX40L) is expressed on dendritic cells, B cells, and activated endothelial cells. To determine how OX40-OX40L interaction affects graft-versus-host disease (GVHD), we used antagonistic anti-OX40L monoclonal antibody (mAb) or OX40(-/-) donor or OX40L(-/-) recipient mice. Similar degrees of GVHD reduction were observed with each approach. Despite the fact that OX40 is up-regulated on both CD4(+) and CD8(+) T cells isolated during GVHD, the major effects of OX40 ligation were on CD4(+) and not CD8(+) T-cell-mediated alloresponses as assessed in both GVHD and engraftment model systems. GVHD inhibition by blockade of the OX40/OX40L pathway did not require CD28 signaling. Some studies have indicated OX40 is essential for inducing T-helper type 2 (Th2) responses. However, in vivo blockade of OX40-OX40L interactions reduced GVHD mortality induced by either signal transducer and activator of transcription-6(-/-) (Stat-6(-/-)) (Th2-defective) or Stat-4(-/-) (Th1-defective) major histocompatibility complex (MHC)-disparate splenocytes, indicating that the GVHD-amellorating effects did not require Stat-4 or Stat-6 signaling. Although OX40L has been reported to be expressed on activated T cells, no effects on GVHD were observed when OX40L(-/-) versus OX40L(+/+) T cells were infused in different models. These data provide insights as to the mechanisms responsible for OX40/OX40L regulation of GVHD. (C) 2003 by The American Society of Hematology.