AFFECTING GRAFT SURVIVAL WITH DONOR IMMUNE TISSUE

在临床上常规实现同种异体移植物耐受的方法还没有 实现了。大多数策略都能在移植物中产生耐受性， 临床前模型依赖于一段时间的广泛免疫抑制治疗。作为 结果，产生对任何抗原的耐受状态的可能性 (Ag)包括存在对微生物Ag的不期望的耐受状态， 从而增加机会性感染或恶性肿瘤的风险， EBV感染的B细胞的转化。在理想的情况下， 耐受性的实现不依赖于系统应用 广泛的免疫抑制剂。我们正在努力实现这一目标 通过使用移植模型中的经验性实验得出的策略， 以及对T细胞免疫生物学的现代见解。“当免疫细胞 系统“看到”抗原在没有正确的共同信号，他们关闭 而不是攻击自己。未来的治疗方法可能会利用 反应”（1）。因此，我们假设， 具有操作的供体器官移植物和/或白细胞的同种异体移植物接受者 表达组织相容性Ags，但缺乏直接 为Ag刺激的T细胞活化传递“共同信号”，将导致 供体特异性移植物耐受和旁路的状态或大大减少 需要免疫抑制治疗。被测试的简单策略，如果 已被证明是成功的，可以在临床上迅速部署。 目的1：验证同种异体移植的假设， 已被操纵，使其不能激发CD 28/CTLA-4-通路 和/或CD 2途径共刺激T细胞信号将产生一种 供者特异性移植物体内耐受。 目的2：验证同种异体移植受者的免疫 供体白细胞制备物缺乏表达 蛋白质结合固定的CTLA-4蛋白，从而不能 激发CD 28/CTLA-4-共刺激信号将产生供体状态 体内特异性移植耐受。 目的3：检验用两种疫苗免疫操纵 移植物（见AIM 1）和白细胞制剂（见AIM 2）， 激发共刺激信号将被证明是上级的 单独操作以产生供体特异性移植物耐受的状态， 体内有/无CsA治疗。

A method to achieve allograft tolerance routinely in the clinic has not been realized. Most maneuvers creating a state of graft tolerance in preclinical models rely on a period of broad immunosuppressive therapy. As a result, the potential for creating a state of tolerance to any antigen (Ag) including an undesirable state of tolerance to microbial Ags exists, thereby heightening the risk of opportunistic infection or malignant transformation of EBV infected B-cells. In an ideal situation, graft tolerance would be achieved without reliance upon systemic application of broadly immunosuppressive agents. We are attempting to approach this goal by using strategies derived from empiric experiments in transplant models and modern insights into T cell immunobiology. "When cells of the immune system "see" antigens in the absence of the right cosignals, they shut themselves down instead of attacking. Future therapies might capitalize on that reaction" (1). Accordingly, we hypothesize that immunization of allograft recipients with manipulated donor organ grafts and/or leukocytes expressing histocompatibility Ags, but lack the capacity to directly deliver "co-signals" for Ag- stimulated T-cell activation, will cause a state of donor specific graft tolerance and bypass or vastly reduce the need for immunosuppressive treatment. The simple strategy being tested, if proven successful, can be rapidly deployed in the clinic. AIM 1: To test the hypothesis that transplantation of an allograft which has been manipulated so that it cannot instigate CD28/CTLA-4-pathway and/or CD2-pathway costimulatory T cell signals will create a state of donor specific graft tolerance in vivo. AIM 2: To test the hypothesis that immunization of allograft recipients with donor leukocyte preparations devoid of cells that express the proteins binding to immobilized CTLA-4 proteins and thereby cannot instigate CD28/CTLA-4- costimulatory signals will create a state of donor specific graft tolerance in vivo. AIM 3: To test the hypothesis that immunization with BOTH manipulated grafts (see AIM 1) an leukocyte preparations (see AIM 2) that cannot instigate costimulatory signals will prove to be superior to either maneuver alone in producing a state of donor specific graft tolerance in vivo with/without CsA therapy.