Selective Upregulation of Fibroblast Fas Ligand Expression, and Prolongation of Fas/Fas Ligand-Mediated Skin Allograft Survial, by Retinoic Acid: the Skin as a Retinoide-Inducible Immune Privilege Site

Fas/Fas配体介导的淋巴细胞凋亡与免疫反应的抑制有关，并可能导致免疫特权。人类角膜具有免疫特权，无需免疫抑制治疗即可跨越异体屏障进行移植，这可能是因为角膜角质形成细胞表达Fas配体。为了表征Fas和Fas配体在皮肤中的表达，我们检测了小鼠角质形成细胞、真皮成纤维细胞、黑素细胞和人脐带内皮细胞的表达。我们还研究了维甲酸、维生素D3、地塞米松以及各种细胞因子对皮肤细胞中Fas和Fas配体的调节作用。在所测试的分子和细胞中，维甲酸选择性上调成纤维细胞Fas配体分子的表达。视黄酸诱导的Fas配体+成纤维细胞杀伤Fas+靶细胞，这种杀伤作用被抗Fas配体抗体阻断。在同种异体皮肤移植系统中，研究了Fas配体对真皮成纤维细胞的体内功能。将组织不相容BALB/C小鼠（H-2d）供体皮肤移植到同种异体C57BL/6小鼠（H-2b）上。每日局部注射维甲酸可阻断炎症并延长移植物存活超过10天。将维甲酸注射到Fas配体突变的gold / gold donot皮肤中，并不能阻止白细胞向同种异体移植物的浸润或延长移植物的存活时间。这些实验表明，在皮肤中，维甲酸选择性地增加成纤维细胞Fas配体的表达，维甲酸具有有效的Fas/Fas配体依赖性免疫抑制活性。

Fas/Fas ligand-mediated lymphocyte apoptosis has been implicated in the suppression of immune responses and may cause immune privilege. Human corneas exhibit immune privilege and can be transplanted across allogeneic barriers without immunosuppressive therapy, perhaps, because corneal keratinocytes express Fas ligand. To characterize Fas and Fas ligand expression in skin, we examined expression by murine keratinocytes, dermal fibroblasts, melanocytes, and human umbilical endothelial cells. We also studied the regulation of Fas and Fas ligand in skin cells by retinoic acid, vitamin D3, and dexamethasone as well as various cytokines. Among the molecules and cells tested, retinoic acid selectively upregulated the expression of Fas ligand molecule by fibroblasts. Retinoic acid-induced Fas ligand+ fibroblasts killed Fas+ target cells, and this killing was blocked by anti-Fas ligand antibody. The function of Fas ligand on dermal fibroblasts in vivo was tested in a cutaneous allograft system. Histoincompatible BALB/C mouse (H-2d) donor skin was grafted on to allogeneic C57BL/6 mice (H-2b). Daily tocal injection of retinoic acid blocked iflammation and extended graft survival for more than lOd. Injection of retinoic acid into Fas ligand mutated gld/gld donot skin did not prevent leukocyte infiltration into the allograft or prolong graft survival. These experiments indicate that, in skin, retinoic acid selectively increases Fas ligand expression by fibroblasts and that retinoic acid has potent Fas/Fas ligand-dependent immunosuppressive activity.