Retinal Cell Transplantation Tolerance and Rejection

描述(申请人提供)：老年性黄斑变性(AMD)在美国是导致失明的主要原因。用健康的视网膜细胞替代死亡或受损的细胞是治疗这种和其他视网膜疾病的一种非常有前途的方法。我们的长期目标是开发在AMD病程早期移植视网膜色素上皮(RPE)细胞的方法，以挽救感光细胞。这一建议的中心假设是，识别导致RPE移植排斥反应的免疫学机制，将为诱导长期移植接受提供治疗靶点。 将通过过继将CD4和CD8T细胞转移到 异基因RPE移植前免疫缺陷重组酶(RAG-1)基因敲除小鼠。主要和次要组织相容性抗原对RPE排斥反应的相对贡献将使用重组近交系小鼠进行评估。RPE移植排斥的机制将通过T细胞受体(TCR)转基因小鼠和表达特定移植抗原的RPE来确定。过继转移的TCR转基因T细胞的激活和增殖将在移植受者的淋巴和眼睛中进行跟踪。从眼睛中回收的TCRT细胞将被分析用于各种功能活动。最后，在缺乏持续免疫抑制剂治疗的情况下，移植物特异性耐受可以延长RPE存活率的假说将得到验证。 这些研究的结果应该确定预防排斥的策略，这些策略可以在RPE移植的临床前模型中进行测试。

DESCRIPTION (provided by applicant): Age-related macular degeneration (AMD) is a major cause of blindness in the United States. Replacement of dead or damaged cells with healthy retinal cells is a very promising approach to the treatment of this, and other, retinal diseases. Our long-term goal is to develop the methods for transplanting retinal pigment epithelial (RPE) cells early in the course of AMD to rescue photoreceptor cells. The central hypothesis of this proposal is that the identification of the immunological mechanisms, which are responsible for RPE transplant rejection, will provide therapeutic targets for inducing long-term graft acceptance. The role of CD4+ and CD8+ T cells in rejection will be tested by adoptively transferring them into immunodeficient, recombinase (Rag-1) knockout mice before transplantation of allogeneic RPE. The relative contribution of major and minor histocompatibility antigens to RPE rejection will be assessed using recombinant, inbred strains of mice. The mechanisms by which RPE grafts are rejected will be determined using T cell receptor (TCR) transgenic mice and RPE expressing defined transplantation antigens. Activation and proliferation of adoptively transferred TCR transgenic T cells will be tracked in lymph nodes and the eyes of transplant recipients. TCR T cells recovered from the eyes will be analyzed for various functional activities. Finally, the hypothesis that allograft-specific tolerance can prolong survival of RPE in the absence of continuous treatment with immunosuppressive agents will be tested. Results from these studies should identify strategies to prevent rejection that can be tested in preclinical models of RPE transplantation.