Significance and regulatory mechanisms of Fas/Fas L expression in the process of epidermal injury mediated by T cells

Fas/Fas L表达在T细胞介导的表皮损伤过程中的意义及调控机制

基本信息

批准号：
09470191
负责人：
SHIOHARA Tetsuo
金额：
$ 6.91万
依托单位：
Kyorin University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09470191/
关键词：
cutaneous GVHD Fas Fas ligand GVHD resistance lpr lpr mouse gld gld mouse autoreactive T cells GVHD抵抗性 GVHD 自己反応T細胞 Fas・Fas L 表皮傷害

项目摘要

We previously established a murine model for cutaneous graft-versus-host disease (GVHD) in which selective destruction of epidermal structures can be induced by local injection of αβィイD1+ィエD1, CD4ィイD1+ィエD1 autoreactive T cells capable of invading and destroying the epidermis in a site-restricted manner. In this custaneous GVHD, the epidermis spontaneously recovered from the destruction became resistant to subsequent attempt to induce the GVHD. In this study, we asked whether Fas/Fas L interactions could be involved in the induction of the GVHD and the subsequent induction of the resistance to the custaneous GVHD.1. Our immunohistochemical studies and PCR analyses demonstrated that Fas antigen was expressed on keratinocytes in the lesional epidermis during the cutaneous GVHD and after spontaneous recovery; and Fas L-bearing keratinocytes were also observed during the GVHD but not after spontaneous recovery. The injected autoreactive T cells were found to express both Fas and Fas L at bo … More th time points. These expression was confirmed at protein and mRNA levels.2. We next investigated whether the GVHD and the subsequent resistance after recovery could be induced in lpr and gld mice which have been shown to have defects in the genes encoding Fas and Fas L, respectively. Although the GVHD was also induced in B6 lpr/lpr mice, the grade was much less prominent than control mice. Of interest was that the resistance was never induced in those lpr mice after spontaneous recovery. In contrast, the ability to induce GVHD and the resistance was not impaired in these gld mice.3. We next asked whether monoclonal antibodies (mAb) to Fas L could affect the course of GVHD and the induction of the resistance. Injection with anti-Fas L mAb marginally inhibited the induction of GVHD, while the induction of the resistance was totally prevented by injection of anti-Fas L mAb. These results indicate that Fas/Fas L interactions play an important role in inducing the GVHD resistance rather than inducing GVHD and that Fas expression on lesional keratinocytes serves to allow their destruction by Fas L-bearing autoaggressive T cells. Less

我们之前建立了皮肤移植物抗宿主病（GVHD）的小鼠模型，其中可以通过局部注射能够侵入并破坏表皮的αβD1+D1、CD4D1+D1自身反应性T细胞来诱导表皮结构的选择性破坏。在这种持续性 GVHD 中，表皮从破坏中自发恢复，对随后诱导 GVHD 的尝试产生了抵抗力。 GVHD。在这项研究中，我们询问 Fas/Fas L 相互作用是否可能参与 GVHD 的诱导以及随后对皮肤 GVHD 的抵抗。1 我们的免疫组织化学研究和 PCR 分析表明，Fas 抗原在 GVHD 上表达。在皮肤GVHD期间和自然恢复后，在病灶表皮中观察到了角质形成细胞；在GVHD期间也观察到了带有Fas L的角质形成细胞，但在自然恢复后没有观察到。发现注射的自身反应性 T 细胞在第 th 个时间点表达 Fas 和 Fas L，这些表达在蛋白质和 mRNA 水平上得到了证实。2. 接下来我们研究了 lpr 是否可以诱导 GVHD 和恢复后的耐药性。和gld小鼠分别被证明在编码Fas和Fas L的基因中存在缺陷，尽管在B6 lpr/lpr小鼠中也诱导了GVHD，但是其等级远不如对照小鼠显着。自发恢复后的 lpr 小鼠中从未诱导过 GVHD，而这些 gld 小鼠中诱导 GVHD 的能力和抵抗力并未受损。 3. 接下来我们询问 Fas L 的单克隆抗体 (mAb) 是否会影响 GVHD 的进程。注射抗Fas L mAb 轻微抑制了GVHD 的诱导，而注射抗Fas L mAb 则完全阻止了抗药性的诱导。这些结果表明Fas/Fas。 L 相互作用在诱导 GVHD 抵抗而不是诱导 GVHD 方面发挥着重要作用，并且病变角质形成细胞上的 Fas 表达有助于减少带有 Fas L 的自攻击性 T 细胞对其的破坏。