Transplant and Tumor Rejection Processes Within the Eye

眼内移植和肿瘤排斥过程

• 批准号: 7648066
• 负责人: JERRY NIEDERKORN
• 金额: $ 45.69万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1984
• 资助国家: 美国
• 起止时间: 1984-12-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7648066
• 关键词: Address; Adenoviruses; Adoptive Transfer; Antibody Formation; Antigens; C57BL/6 Mouse; CD4 Positive T Lymphocytes; Cell Transplants; Cytotoxic T-Lymphocytes; Down-Regulation; Effector Cell; Enzyme-Linked Immunosorbent Assay; Eye; Growth; Immune; Immune response; Immunity; Immunoglobulin Class Switching; Interferon Type II; Interferons; Laboratories; Mediating; Modeling; Mus; Neoplasm Transplantation; Nude Mice; Pathway interactions; Phenotype; Physiological; Principal Investigator; Process; Property; Reverse Transcriptase Polymerase Chain Reaction; Role; Study Section; T-Lymphocyte; Transplantation; Tumor Immunity; Tumor Tissue; anterior chamber; immunogenic; in vivo; neoplastic cell; prevent; prototype; tumor; tumor growth

DESCRIPTION (provided by applicant): It has been recognized for over a century that the anterior chamber (AC) of the eye is endowed with remarkable properties that permit the long-term survival of histoincompatible tissue and tumor grafts. Ocular immune privilege is the product of multiple, overlapping physiological, anatomical, and immunoregulatory properties of the eye. One of thee mechanisms is the dynamic down-regulation of antigen-specific Th1 and Th2 immune responses and alterations in isotype switching of antibody production. This phenomenon has been termed anterior chamber-associated immune deviation (ACAID) and has been a major focus of the principal investigator's laboratory for the past 25 years. In this application, we propose to characterize another curious form of immune deviation that is revealed when interferon-gamma (IFN-gamma) is not available during the initial immune response to antigens introduced into the AC. This immune deviation is a sharp departure from ACAID. The prototype model for this form of ocular immune deviation is revealed when adenovirus-induced tumor cells (Ad5E1) are introduced into the AC of syngeneic C57BL/6 mice. Intraocular tumors undergo a form of immune rejection that is: a) DTH-independent; b) cytotoxic T lymphocyte (CTL)-independent; c) CD4+ T cell-dependent; and d) interferon-gamma (IFN-gamma)-dependent. By contrast, tumor cells transplanted subcutaneously (SC) undergo immune rejection and prevent the growth of intraocular Ad5E1 tumors in IFN-gamma KO mice, indicating that the protective immune response elicited outside of the eye is IFN-gamma-independent. The SC-induced immunity that prevents intraocular tumor growth is: a) DTH-independent; b) IFN-gamma-independent; c) beta2microglobulin (B2M)-independent; and d) CTL-independent. This project will characterize and analyze this unique form of ocular immune deviation and intraocular tumor immunity. We propose that there are two fundamental pathways for the rejection of immunogenic intraocular tumors, such as Ad5E1. The first pathway is IFN-gamma-dependent and is induced by intraocular tumors. The second pathway is IFN-gamma-independent and CTL-independent, and is induced by extraocular tumors and mediates rejection of intraocular tumors. This project will address three specific aims pursuant to these forms of intraocular tumor rejection: 1) characterize the IFN-gamma-dependent mechanisms of tumor rejection; 2) characterize the IFN-gamma-independent mechanisms of tumor rejection; and 3) determine the role of IFN-gamma in the induction of ACAID.

描述（由申请人提供）：一个多世纪以来，人们已经确认眼睛的前腔（AC）具有显着的特性，这些特性允许组织不相容的组织和肿瘤移植物的长期存活。眼免疫特权是眼睛的多种，重叠生理，解剖和免疫调节特性的产物。您的机制之一是抗原特异性Th1和Th2免疫反应的动态下调以及抗体产生同种型切换的改变。这种现象被称为前腔室相关的免疫偏差（ACAID），在过去的25年中一直是首席研究者实验室的主要重点。在此应用中，我们建议表征另一种奇怪的免疫偏差形式，当干扰素 - 伽马（IFN-gamma）在对AC中引入的抗原的初始免疫反应期间没有可用时，该形式被发现。这种免疫偏差与Acaid急剧不同。当将腺病毒诱导的肿瘤细胞（AD5E1）引入Syngeneic C57BL/6小鼠的AC时，揭示了这种眼部免疫偏差的原型模型。眼内肿瘤会经历一种免疫排斥的形式，即：a）独立于DTH； b）细胞毒性T淋巴细胞（CTL）非依赖性； c）CD4+ T细胞依赖性； d）依赖性的干扰素 - 伽马（IFN-gamma）。相比之下，肿瘤细胞皮下移植（SC）受到免疫排斥，并防止IFN-Gamma KO小鼠中眼内AD5E1肿瘤的生长，表明眼外引起的保护性免疫反应是IFN-Gamma独立的。 SC诱导的防止眼内肿瘤生长的免疫力是：a）独立的DTH； b）独立于IFN-gamma； c）beta2microglobolin（B2M）非依赖性；和d）与CTL无关。该项目将表征和分析这种独特的眼部免疫偏差和眼内肿瘤免疫。我们建议有两种基本途径可以排斥免疫原性肿瘤，例如AD5E1。第一个途径是IFN-GAMMA依赖性，并由眼内肿瘤诱导。第二个途径是IFN-GAMMA独立和与CTL无关的途径，并由眼外肿瘤诱导，并介导对眼内肿瘤的排斥。该项目将根据这些形式的眼内肿瘤排斥反应来解决三个特定目标：1）表征肿瘤排斥的IFN-GAMMA依赖性机制； 2）表征肿瘤排斥的IFN-GAMMA独立机制； 3）确定IFN-GAMMA在ACAID诱导中的作用。