EFFECTS OF FAS LIGAND ON TISSUE GRAFT REJECTION

本项目探讨了诱导组织耐受的可行性 通过工程化表达Fas配体的同种异体和异种移植物 用于移植的组织。 我们构建了转基因小鼠， 鼠Fas配体表达涉及 抗原呈递细胞 (APC)如Langerhans细胞 含有MHC II类Ealpha启动子。 四个创始人线有 建立和每一个线正在培育，回交和评估， 免疫细胞化学检测转基因的组织特异性表达。 在完全表征和额外的回交之后，来自 将这些小鼠移植到同种异体动物上， 移植排斥/耐受诱导。 另一个项目涉及 Fas配体对肿瘤表达的调控机制 我们观察到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 磷酸转移酶，由新霉素抗性基因介导。 该方面 因为有报道称肿瘤细胞可能具有 与Fas-配体的表达有关的存活率提高。 由于最近的研究发现， 移植组织被证明可以改变排斥反应，我们 预计FDA将收到涉及使用以下药物的临床方案： 这种用于同种异体移植物或异种移植物排斥反应的构建体用于在 近期 这一项目将使原子能机构能够以一种 科学的方式，这种意见书的优点。

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.