CELLULAR TRANSPLANTATION IN GENETICALLY MODULATED LIVER

描述：利用基因转移技术对肝脏进行体细胞调节 是一种允许对具有潜在应用的假设进行测试的技术 在移植环境中。在这方面，调查人员建议 如果用序列转导肝脏，可以改变免疫环境 表达能够抑制免疫反应的蛋白质/肽。在……里面 理论上，转基因肝脏可以起到“免疫学”的作用 受保护部位，能够接受同种异体细胞移植而无需 拒绝。在这个模型中，抑制体内的免疫反应 天然肝脏将通过表达蛋白质/多肽来完成 能够抑制T细胞识别(非多态MHC多肽)， 活性(病毒IL-10)或共刺激途径(CTLA4lg)。为了测试这一点 假设该提案有三个具体目标：1)应用最新的和 肝脏调控基因转移技术的未来发展 因为它准备成为细胞移植的场所。对.的使用 新型腺病毒载体构建允许独有的变量关联 移植环境：最佳表达长度、免疫反应 重组抑制物对转导肝细胞的影响 在转移序列的寿命上产生蛋白质/肽， 以及将载体表达限制在肝脏的能力；2)遵循 生物学功能和决定促进生存的条件 将同种异体肝细胞移植到调制的天然肝脏中。这个 实验将在与肝脏相关的临床相关模型中进行 蛋白质缺乏，并将相关载体表达，生物学 移植细胞的功能和同种异体免疫反应；3) 在移植环境中应用基因转移技术必须 考虑一下抑制外界免疫过程的潜在后果 被转换的器官。这些研究试图定义这种关系 系统免疫与同种异体免疫的部位特异性抑制 反应，并关联短期或长期的表达 有排斥反应的免疫抑制蛋白/肽，保存 肝外T细胞对名义抗原的反应和维持 同基因肿瘤的免疫监测。最终的目标是规范 并将免疫抑制限制在移植器官上。总而言之，这是 Proposal探索基因转移技术的应用，旨在 创造一个允许接受同种异体细胞的受保护环境， 同时保持正常的系统免疫力。

DESCRIPTION: Somatic modulation of the liver using gene transfer technology is a technique which allows testing of hypotheses with potential application in the transplant setting. In this context, the investigators propose that the immune milieu can be modified if livers are transduced with sequences expressing proteins/peptides capable of suppressing the immune response. In theory, genetically modified liver could serve as an "immunologically protected site," able to accept allogeneic cell transplantation without rejection. In this model, inhibition of the immune response within the native liver would be accomplished by expression of proteins/peptides capable of inhibiting T cell recognition (non-polymorphic MHC peptides), activity (viral IL-10), or costimulatory pathways (CTLA4lg). To test this hypothesis the proposal has three specific aims: 1) To apply recent and future developments in gene transfer technology for modulation of the liver as it is prepared to be a site for cellular transplantation. The use of novel adenovirus vector constructs allow correlation of variables unique to the transplant setting: optimal length of expression, immune response against transduced liver cells, the impact of recombinant inhibitor protein/peptide production on the life span of the transferred sequences, and the ability to restrict vector expression to the liver; 2) To follow the biological function and determine conditions which promote survival of transplanted allogeneic hepatocytes in the modulated native liver. The experiments will be performed in clinically-relevant models of liver-related protein deficiency, and will correlate vector expression, biological function of the transplanted cells, and alloimmune response; 3) The application of gene transfer technology in the transplant setting must consider the potential consequences of suppressing immune processes outside the transduced organ. These studies attempt to define the relationship between systemic immunity and site-specific suppression of the alloimmune response, and to correlate short or long term expression of immunosuppressive proteins/peptides with rejection, preservation of extrahepatic T cell response to nominal antigen, and maintenance of immune-surveillance of syngeneic tumors. The ultimate goal is to regulate and restrict immunosuppression to the transplanted organ. In summary, this proposal explores applications of gene transfer techniques which aim to create a protected environment allowing acceptance of allogeneic cells, while maintaining normal systemic immunity.