Retinal Cell Transplantation Tolerance and Rejection

视网膜细胞移植耐受和排斥

• 批准号: 6912734
• 负责人: JUDITH A KAPP
• 金额: $ 32.63万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6912734
• 关键词: T cell receptor; artificial immunosuppression; blindness; cyclosporines; eye transplantation; genetically modified animals; helper T lymphocyte; histocompatibility; histocompatibility antigens; laboratory mouse; lymph nodes; macular degeneration; retina; suppressor T lymphocyte; transplant rejection

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.

描述（由申请人提供）：视网膜相关性黄斑变性（AMD）是美国失明的主要原因。用健康的视网膜细胞替换死亡或受损的细胞是治疗这种和其他视网膜疾病的非常有前途的方法。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）细胞以拯救感光细胞的方法。该建议的中心假设是，识别负责RPE移植排斥的免疫机制，将为诱导长期移植物接受提供治疗靶点。 将通过将CD 4+和CD 8 + T细胞过继转移到免疫球蛋白中来测试它们在排斥反应中的作用。 在移植同种异体RPE之前，免疫缺陷、重组酶（Rag-1）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。将使用T细胞受体（TCR）转基因小鼠和表达确定的移植抗原的RPE来确定RPE移植物被排斥的机制。过继转移的TCR转基因T细胞的活化和增殖将在移植受体的淋巴结和眼睛中追踪。将分析从眼睛回收的TCR T细胞的各种功能活性。最后，将检验在没有连续免疫抑制剂治疗的情况下同种异体移植物特异性耐受可以延长RPE存活的假设。 这些研究的结果应该确定可以在RPE移植的临床前模型中测试的预防排斥反应的策略。