EFFECTS OF FAS LIGAND ON TISSUE GRAFT REJECTION

该项目探索了诱导组织耐受的可行性。 Fas配体在同种和异种移植物中的工程表达 供移植用的组织。我们已经构建了转基因小鼠，在其中 小鼠Fas配体针对抗原提呈细胞的表达 (APC)，如朗格汉斯细胞 含有MHC II类Epha启动子。四个方正家族拥有 已经建立，每个品系都在进行育种、回交和鉴定 转基因组织特异性表达的免疫细胞化学。 经过充分的鉴定和额外的回交，来自 这些小鼠将被移植到同种异体动物身上，并进行评估 移植物排斥/耐受诱导。一个额外的项目，涉及 肿瘤表面Fas配体表达调控机制的研究进展 细胞从我们的观察中涌现出来，fas配体在这些细胞上的表达 细胞对细菌表达的调节非常敏感 新霉素抗性基因介导的磷酸转移酶。这一方面 引起了人们的极大兴趣，因为有报道称，肿瘤细胞可能具有 提高存活率与Fas-配体的表达有关。 由于最近的研究发现，Fas配体在 用于移植的组织被证明可以改变排斥反应 预计该机构将收到临床方案，涉及使用 这种用于评估同种或异种移植排斥反应的结构 不久的将来。该项目将使工程处能够在一个 科学的态度，这类提交材料的优点。

This project explores the feasibility of inducing tolerance to tissue allografts and xenografts by engineered expression of fas ligand on tissues for transplantation. We have constructed transgenic mice in which murine fas ligand expression is directed to antigen presenting cells (APC) such as Langerhans cells by cloning into an expression vector containing the MHC class II Ealpha promoter. Four founder lines have been established and each line is being bred, backcrossed and assessed by immunocytochemistry for tissue specific expression of the transgene. Following full characterization and additional backcrossing, tissues from such mice will be transplanted onto allogeneic animals and assessed for graft rejection/ tolerance induction. An additional project involving assessment of regulatory mechanisms in expression of fas-ligand on tumor cells has sprung from our observation that fas-ligand expression on such cells is very sensitive to modulation by the expression of a bacterial phosphotransferase, mediated by a neomycin resistance gene. This aspect is of great interest because of reports that tumor cells may have enhanced survival pertaining to their expression of fas-ligand. Because of the recent findings in which expression of fas ligand on tissues for transplantation was shown to modify rejection responses, we expect that the Agency will receive clinical protocols involving use of this construct for allograft or xenograft rejection for evaluation in the near future. This project will enable the Agency to evaluate, in a scientific manner, the merits of such submissions.